METHADONE TREATMENT in Memory of Vincent P

Home , Acetylmethadol, Levacetylmethadol, Pivagabine

· 1

ICRO MAREMMANI

THE PRINCIPLES AND PRACTICE OF METHADONE TREATMENT In memory of Vincent P. Dole, friend and magister · 1 ICRO MAREMMANI, MD Professor of Addiction Medicine University of Pisa and Siena, Italy Chief of “Vincent P. Dole” Dual Diagnosis Unit “Santa Chiara” University Hospital, Department of Psychiatry University of Pisa Co-Director of “G. De Lisio” Institute of Behavioural Sciences Pisa, Italy, EU

THE PRINCIPLES AND PRACTICE OF METHADONE TREATMENT

Pacini Editore Medicina, Via A. Gherardesca, 56121 Ospedaletto, Pisa, Italy, EU AU-CNS, Via XX Settembre, 83 - 55045 Pietrasanta, Lucca, Italy, EU 2 · · 3 2 · · 3

Contributors

Emanuele Bignamini, MD Psychiatrist and Psychoanalist, Director of Department of Addiction Medicine, National Health System Local Unit, Torino, Italy, EU

Stefania Canoniero, MD Psychiatrist, Addiction treatment Centre (SerT), National Health System Local Unit, Albenga and Finale Ligure, Italy, EU

Barbara Capovani, MD Psychiatrist, Addiction treatment Centre (SerT), National Health System Local Unit, Pisa, Italy, EU

Loretta Finnegan, MD Professor of Pediatrics, Psychiatry and Human Behavior, Thomas Jefferson University (Retired), Philadelphia, Pennsylvania USA

Andrea Flego, MD Psychiatrist, Director of Department of Addiction Medicine, National Health System Local Unit (Retired) Pordenone, Italy, EU 4 · · 5

Gilberto Gerra, MD Chief Health and Human Development Section, Division for Operations, United Nations Office on Drugs and Crime, Vienna

Giuseppe Giuntoli, MD Psychiatrist, Medical Director of “Incontro” Therapeutic Community, Pistoia, Italy, EU

Francesco Lamanna, MD Psychiatrist, Addiction treatment Centre (SerT), National Health System Local Unit, Pisa, Italy, EU

Mercedes Lovrecic, MD Psychiatrist, Ministry of Health of the Republic of Slovenia and Institute of Public Heath of the Republic of Slovenia, Lubiana, Slovenia, EU

Sonia Lubrano, MD Psychiatrist, Addiction treatment Centre (SerT), National Health System Local Unit, La Spezia, Italy, EU

Alexander Kantchelov, MD Psychiatrist, Director of Kantchelov Clinic, Sofia, Bulgaria, EU

Angelo Giovanni Icro Maremmani, MD Consultant Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy, EU

Andrea Michelazzi, MD General Practitioner National Health System, Trieste, Italy, EU

Matteo Pacini, MD Research Psychiatrist, “G. De Lisio” Institute of Behavioural Sciences, Pisa, Italy, EU 4 · · 5

Pier Paolo Pani, MD Psychiatrist, Social-Health Service, National Health System Local Unit, Cagliari, Italy, EU

Giulio Perugi, MD Professor of Psychiatry, University of Pisa, Italy, EU Director of “G. De Lisio” Institute of Behavioural Sciences Pisa, Italy, EU

Dina Popovic, MD Psychiatrist, “G. De Lisio” Institute of Behavioural Sciences Pisa, Italy, EU

Annella-Maria Sciacchitano, MD Pharmacologist, Addiction treatment Centre (SerT), National Health System Local Unit, Rovigo, Italy, EU

Lorenzo Somaini, MD Clinical Pharmacologist Addiction Treatment Centre (SerT), National Health System Local Unit, Biella, Italy, EU

Emanuela Trogu, MD Psychiatrist, Addiction treatment Centre (SerT), National Health System Local Unit, Cagliari, Italy, EU

Franco Vecchiet, MD General Practitioner National Health System, Trieste, Italy, EU

Andrea Vendramin, MD Professor of Pharmacology, University of Padua, Italy, EU Director of Department of Addiction Medicine, National Health System Local Unit, Padua, Italy, EU

Sara Zazza, PhD Psychologist, Department of Addiction Medicine, National Health System Local Unit, Torino, Italy, EU 6 · · 7

Preface

Several articles in magazines and symposium speeches try to answer the question “What should the physician know?” I often feel doubts about what students should be expected to know to pass a general pharmacology examination. I usually tell students they should think of themselves as athletes, while their professor should be someone with such a deep knowledge of a discipline that he or she can communicate it spontaneously. General practitioners remain athletes, with their direct experience and constant updating enhancing their skills in the handling of complex clinical syndromes and their depth of knowledge in managing specific diseases and therapeutic approaches. This explains why I feel at a loss when they ask me what the basis of pharmacological and medical knowledge should be, or what it is essential to know about specific therapeutic issues. When speaking to audiences of general practitioners, I am usually requested - when it’s a matter of explaining what disorder a drug should be used against, what the proofs and the terms of its effectiveness are, what its toxic effects are - to skip all the details and foregrounds about the pharmacological basis of how and why it works, because general practitioners are supposed not to bother much about such things. The adoption of an evidence-based substance vs. substance approach has shifted the focus of medical knowledge on to the statistical weight of clinical reports, whereas mere consistency with pathophysiological dynamics is not considered reliable as a predictor of effectiveness: in fact, clinical trials have often failed to confirm a hypothesis of effectiveness founded solely on pathophysiological speculations and open-label clinical reports. Nevertheless, the theoretical basis for the effectiveness of pharmacological treatment has not become irrelevant, and may provide warnings against risks that will not emerge from controlled clinical trials: that happened with -coxib drugs and cerivastatine, which were quickly withdrawn from the market due to surveillance warnings about toxicity - warnings which had been anticipated by preclinical pathophysiological investigations, but had not been expected on the basis of the results of later clinical trials. Often, it takes pathophysiology to inspire a clinical study, which then gives positive spin-off in return by providing evidence that deepens and enriches the level of knowledge about the biological basis of therapeutics. Medical discipline results from a continuous exchange between biological research and clinical practice through the channel of statistically weighted data. 6 · · 7

Returning now to the question of “What should a physician know?”, the answer should be translated into what each physician thinks he/she should know, into their curiosity and professional liveliness, into their need to deepen their knowledge. Both biologists and clinicians should avoid going into the fine detail of technical aspects of their practice, unless questioned about it by an audience. In any article, such details can be reported in a special section printed as a box kept separate from the main text, or else, in case of an oral presentation, the speaker may provide a reference list so that anyone can consult original data. Instead of boring an audience with superfluous notions; it is a speaker’s interest and should be within his/her grasp to know many other things that will only emerge in the open discussion of scientific issues. Actually, “What should physicians know?” should be viewed as an open-ended issue.

This book is written by clinicians and appeals to clinicians. It features a great many pharmacological details about the pharmacological kinetics and dynamics of anticraving treatment. The clinical issues are discussed by psychiatrists with accuracy and by dedicating special attention to specific problems that emerge during the course of treatment, ranging between ordinary ones and quite unexpected ones. For each situation authors discuss the possible causes and review the different therapeutic strategies. The same issues seem to recur in different chapters, with special regard to anticraving treatment and different ways to reach the same solution from different viewpoints, while taking into account the variability of drug-related clinical situations and the need to use a variety of starting points. For instance, treating a pregnant narcotic addict requires specific skills, while planning a treatment programme for jailed addicts calls for a specific knowledge of the prison environment and related legal issues. Nowadays, since addiction has become an endemic condition, it is expected to affect categories of individuals with higher exposure to risk factors, which probably include several psychopathological syndromes. As a result, it is crucial to anticipate possible dual diagnosis patterns, so as to be able to recognize them and handle such complex situations through specific treatment approaches. Several chapters deal with psychosocial issues related to the world of addiction, with special reference to narcotics, both from a patient’s and from the physician’s point of view. This subject is faced without resorting to a meaningless even if politically correct approach. Drug addiction is presented as a psychiatric disorder and a curable condition: treatment can provide complete control of its symptoms by administering specific drugs in maintenance regimens of proved effectiveness. Other interventions may be useful, in some cases crucial, as in any other chronic disease, and comprise psychiatric and somatic treatments, individual counselling to help patients cope with the family and work environment. Authors specify the tasks of different staff members, whether medical or non-medical, who need to know how to deal with the patient, while avoiding uncertainty about professional roles and hierarchical relationships. The present manual looms as an easy- to-read volume, written by skilled professionals with technical competence and an aversion for dogmatism.

Prof. Alessandro Tagliamonte Professor of Pharmacology University of Sienna Italy, EU 8 · · 9

Contents

INTRODUCTION

Definitions 11 1.1 I. Maremmani

Addiction Treatment: When will Medical Principles Matter ? 17 1.2 M. Pacini and I. Maremmani

Heroin Dependence 21 1.3 I. Maremmani and D. Popovic

Heroin Dependence: Theory of Different Levels of Intervention 31 1.4 I. Maremmani

Scientifically Based Ethical Principles in Dealing with Heroin Addicts 39 1.5 M. Pacini and I. Maremmani

Pharmacology and Neurochemistry of Methadone 43 1.6 A. Vendramin and A. M. Sciacchitano

Pharmacokinetics of Methadone 63 1.7 P.P. Pani

Neuroendocrinologic Effects of Methadone Treatment 69 1.8 G. Gerra

METHADONE TREATMENT

The History of Methadone Treatment 75 2.1 M. Pacini, A.G.I. Maremmani and I. Maremmani 8 · · 9

Enrolment and Termination 81 2.2 I. Maremmani and M. Pacini

The Phases of Treatment 87 2.3 I. Maremmani and M. Pacini

The Issue of Dosage 97 2.4 I. Maremmani and M. Pacini

Long-Term Perspectives 103 2.5 E. Trogu and P. P. Pani

Medically Supervised Withdrawal from Methadone 109 2.6 I. Maremmani and M. Pacini

Relapse Prevention and Handling 113 2.7 I. Maremmani and M. Pacini

Adverse Events During Methadone Treatment 117 2.8 I. Maremmani, A.G.I. Maremmani and M. Pacini

Clinical Meaning of Urinalyses 127 2.9 I. Maremmani, F. Lamanna, B. Capovani and M. Pacini

The Take-Home as a Clinical Tool 131 2.10 P.P. Pani and I. Maremmani

Resistance to Treatment 135 2.11 I. Maremmani and M. Pacini

Methadone Treatment in Special Populations

Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases 141 3.1 L. Somaini, M. Pacini and I. Maremmani

Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients 153 3.2 I. Maremmani, M. Pacini, S. Lubrano, S. Canoniero, M. Lovrecic and G. Perugi

Clinical Foundation for the Use of Methadone in Polyabuse Patients 181 3.3 I. Maremmani, F. Lamanna and M. Pacini

Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding 189 3.4 L. Finnegan, M. Pacini and I. Maremmani

Clinical Foundation for the Use of Methadone in Jail 197 3.5 I. Maremmani, M. Lovrecic and M. Pacini

3.6 Clinical Foundation for the Use of Methadone in Therapeutic Communities 211 M. Pacini, G. Giuntoli and I. Maremmani 10 ·

3.7 Clinical Foundation for the Use of Methadone in General Practitioner’s Office. Italy as Case Study 217 A. Michelazzi, F. Vecchiet and I. Maremmani

Psychosocial Interventions

Psychoeducation and Counseling for Methadone-Treated Patients 227 4.1 I. Maremmani, G. Giuntoli and M. Pacini

Motivational Interventions for Methadone-Treated Patients 233 4.2 A. Kantchelov

Psychotherapy for Patients in Methadone Treatment 247 4.3 E. Bignamini and S. Zazza

Quality Control

Methadone and Treatment Quality. The EFQM Excellence Model 259 5.1 A. Flego

INDEX 275 1.1

Definitions

I. Maremmani

1. Habit consequences. In other words, a subject de- cides to engage in substance abuse beyond the threshold of unwanted consequences, but does If a substance is used “habitually”, that so while experiencing a pleasurable or desir- means it is consumed frequently, either con- able state. Abuse may forerun addiction, but tinuously or intermittently. The habit of resort- is not addiction itself; the relationship with the ing to a substance depends on the subject’s substance and the reward mechanism is still proneness to its use for a variety of reasons, physiological, whereas the capacity to limit the most frequent of which is self-stimulation pleasure in order to avoid unwanted conse- and reward. Habitual use, or having the habit quences is impaired. When control is lost over of using a substance, never looms as a disor- the capacity to interrupt a habit of consump- der, although it may be of medical interest tion that no longer brings pleasure, indepen- due to the substance’s toxic effects. Although dently of its increasingly negative consequenc- the habit of using a drug may be influenced es, we will use the term “addiction” [5]. by pharmacological means, an intervention of that kind would not have a medical meaning or goal [8, 9] . 3. Addiction

2. Abuse Addiction is a form of abuse characterized by the loss of control before substance use. For addicted subjects, the only chance of holding The term “abuse” indicates recurrent sub- back from substance use is the absolute un- stance use despite known negative effects and availability of the substance. In this case, the

11 12 · CHAPTER 1.1 DEFINITIONS · 13 subject abstains with varying degrees of dis- clusively dedicated to a substance which, in comfort. In any other case, the addicted sub- his intentions, will give him pleasure, without ject will produce a stereotyped behaviour with ever being able to attain this aim, and, despite a high level of impulsiveness, which increases the loss of general resources and a deteriora- when the subject’s search for the substance is tion in the quality of life, is, by definition, ad- challenged by obstacles. In fact, the only ob- dicted to that substance. A subject who com- stacle which would extinguish the subject’s plains about having no control over a habit desire to use the substance is its unavailability. (which implies a chronic discrepancy between Such uncontrolled appetition is called craving, the drive to use a substance and the intention and is the core symptom of addiction [1-4]. to use it in a controlled way) is, by definition, The concept of “control” usually refers to addicted to that substance. However, even an incapacity to prevent negative consequenc- when a subject does not complain about an es in social and productive terms. On medical irreversible loss of control, a complaint about grounds, control is maintained as long as sub- dissatisfaction or unhappiness from an expect- jects are rewarded by substance use and are ed source of pleasure, without a physiological capable of organizing their resources so as to evolution towards the extinction of appetitive keep themselves supplied with the substance, behaviour, is enough to justify a diagnosis of although negative social consequences may addiction. develop and involvement in substance use Addiction suits a variety of situations, may leave no room for other life activities. The some featuring a chemical substance as the ob- amount or frequency of substance consump- ject of craving, others featuring a situation or tion does not permit discrimination between a gateway towards possible pleasure (such as a habit and a disease, nor do the toxic effects, pathological gambling). the exclusiveness and intensity of engagement in substance use, or the level of social adjustment. The addicted subject loses the ability to 4. Dependence vs. Addiction handle his/her habit, and that is when the disease is born. A number of substance abusers apply for treatment when driven by legal is- Dependence is that pharmacological state sues, social impairment or lack of money, and in which someone is susceptible to emerging succeed in stopping the habit when strongly discomfort if deprived of a substance, but re- challenged by its negative consequences. Oth- covers a state of well-being when the same, or ers stop when the substance no longer gives a cross-reactive, substance is reintroduced. De- them the desired effects, so that it is no longer pendence may be spontaneous, or be the result worth the effort. Unlike simple abusers, ad- of an acquired condition: insulin dependence dicted subjects may seek help even in the ab- is a spontaneous state in a diabetic person who sence of psychosocial impairment or a history has lost his/her endogenous resources. A dia- of adverse events. Heroin addicts, for example, betic will develop major metabolic disturbanc- can be classified in a variety of psychosocial es as a result of insulin deficiency, but his/her categories, which comprise the ‘stable’ mode, metabolism will be restored by the provision that is, with no course towards social disrup- of exogenous insulin supplies. Also, a person tion, but with a stable, though not satisfac- with a chronic self-immune disorder may be tory, level of working activity and significant dependent on cortisonic drugs, which do not relationships. Besides this, the “two worlder” replace any lost function, but counteract a mode has been described; that term is used to harmful pathophysiological process. evoke the condition of a subject who leads a Secondary addictive features include a de- normal life except for a recurrent involvement pendence on beta-blockers in a person with in clandestine, drug-related activities, crime chronic high blood pressure, or the depen- included. dence on barbiturates of an epileptic. In this An individual who is thoroughly and ex- case, the abrupt interruption of exposure to the 12 · CHAPTER 1.1 DEFINITIONS · 13

substance will be followed by a rebound syn- As noted above, on subjective grounds ad- drome featuring symptoms opposite to those diction is coupled with an intense feeling of de- induced by the substance. Rebound symptoms sire, which cannot be handled (i.e., craving). In are also the opposite of the symptoms that the a condition of abstinence, craving will emerge substance is meant to counterbalance. The sooner or later, regardless of withdrawal-re- pharmacological basis for this phenomenon is lated discomfort, and it will bring on relaps- known as tolerance, which consists in a pro- ing behaviour. The old word for addiction gressive lowering of the sensitivity threshold was ‘toxicomania’, which was later replaced in response to exposure to stable dosages. by the term ‘drug-addiction’ or ‘drug-depen- Tolerance is an elastic phenomenon; one re- dence’. The first word is more precise and less sult of this is that the interruption of exposure ambiguous, whereas drug-dependence should drives a tolerant subject into a sudden state of be avoided. In fact, ‘toxicomania’ suggested a imbalance due to a relative deficiency of the ‘toxic’ effect coupled with an irresistible drive substance; the outcome is that the system ‘re- to use the substance, and recalled the concept bounds’ by progressively lowering the sensi- of ‘mania’ as the psychopathological model tivity threshold until the original level is re- able to describe the syndrome. Dependence stored. Before the swing back is complete, the on a toxic substance sounds meaningless: in transient imbalance is expressed by rebound a condition of dependence, that person is un- symptoms. comfortable in the absence, not in the presence, Rebound symptoms (commonly referred of the substance. Even assuming that a toxic to as withdrawal symptoms) are usually tran- effect can be viewed as the price to be paid for sient. After withdrawal has stopped, the even- gaining some kind of benefit from substance tual state will depend on the reason why the use, the cost/benefit ratio must be in favour substance was started. If there was a therapeu- of the benefit (as happens in the treatment of tic reason, and the disease is a chronic one, the epilepsy, for example). The toxic aspect of de- original disease symptoms will strike back. If pendence cannot be attributed to withdrawal, the disease has been extinguished in the mean- which does not develop if that person is con- time, the subject will just be well. If the disease stantly exposed to the substance, and it can be is a chronic-relapsing one, subjects may stay overcome by gradual tapering [6]. symptom-free for a period of variable length On the other hand, saying that someone is before they relapse. ‘addicted to a toxic substance’ provides a cor- For addicts who are receiving treatment, rect idea of the tragic tie between that person methadone dependence is a consequence of and the substance. Some addictive diseases therapy. Its interruption means going back to also correspond to a state of dependence, but, the natural course of the addictive disease, if so, only for limited periods. Withdrawal is which implies a perspective of relapse. just incidental in an addictive syndrome, and Addiction is a radically different condi- does not add anything substantial in terms of tion. Addiction is a cerebral state consisting of diagnosis or prognosis, though it may change a behavioural drive towards the consumption presentation symptoms. Stabilization dosages, of an object, in response to a subjective feeling too, are similar in non-tolerant subjects. called craving, which is intense, self-synthonic On clinical grounds, the course of addiction and spontaneous; associated with an incapac- follows a divergent course from that taken by ity to control the urgency or exclusiveness of dependence: this drive through one’s intentions. a) the re-emergence of craving is not grad- Addiction may be compatible with a social ual; craving becomes intense even in the life, intellectual and productive functioning, absence of tolerance; and an ability to keep the law, although it usu- b) when dependence on a narcotic sets in, it ally leads in the opposite direction. Anyway, is complained about, since it makes sub- it is, by definition, incompatible with a happy stance use more awkward, and interferes life and a satisfactory level of reward. with the original reasons for using narcot- 14 · CHAPTER 1.1 DEFINITIONS · 15

ics (those reasons were forms of reward); tion, mistaking it for a strong habit, and inter- c) during attempts to ‘detoxify’, the addict- pret a request for treatment as a tricky attempt ed person can buffer withdrawal symp- to escape the consequences of one’s illicit and toms by using a cross-reacting substance, disruptive behaviours. On clinical grounds, it or, possibly, by reacting in a ‘cold turkey’ is possible to discriminate between the hope of way, that is, without getting any chemical remission, which corresponds to intention and help. Nevertheless, addicts continue to be not to will, that is, an elaborate kind of thought incapable of preventing the development inspired by personal experience, which can be of relapses after detoxification. translated into a series of graduated actions d) In order to be able to handle withdraw- tending towards adherence to treatment, and al, the addict must achieve this without is based on the activity of the cortical brain. dealing with the substance, over which Addictive behaviour, on the other hand, is he has no control. That is why addicts can produced by an instinctual drive which moves go through a ‘cold turkey’ experience, but forward side by side with an affective state, are incapable of comfortably detoxifying remains self-syntonic and becomes more and by tapering narcotics. more pertinent (an urgent priority). The instinct is directly reinforced by exposure to substances, and eventually becomes self-perpetuating by a long-lasting substance-produced 5. Addictive ambivalence imprinting. Because it is related to a subcorti- cal brain activity, an instinctual drive takes the form of a rapid, one-step process. In addicted persons, thoughts, affects and Addictive behaviour is the result of a stron- behaviours are all displayed ambivalently. ger, ‘addictive’ component, induced by sub- This observable ambivalence mirrors a psy- stances and finding expression as an instinct, chopathological one, which is itself an expres- possibly reinforced by the substance itself, and sion of a neurobiological ‘conflict’. a weaker, more rational component, which de- Addicted patients, in fact, behave in a velops gradually, in accordance with the nega- contradictory way: they apply for treatment tive consequences of substance use. with the aim of stopping their inclination to The two dynamics, the addictive instinct continue their substance use. Such behaviour and the anti-addictive intention, are chal- corresponds to their intention, or ‘will’, as it is lenged differently by the substance: in fact, the misleadingly called. A ‘will’ to stop addiction substance first has an impact on the instinctual is usually claimed when help is being asked component, and soon afterwards on the inten- for, but the drive to reproduce addictive be- tion, through the main features of substance- haviours overpowers that ‘will’. The diagnosis related experiences. In fact, the honeymoon is “addiction” - a term that allows the identifi- phase in which the person develops addiction cation of a category of ‘difficult patients’, who always precedes the later stage in which an in- apply for a therapeutic intervention against a tention to quit will develop and overlap with reckless behaviour that pulls in the opposite the earlier intention. The same sequence is re- direction; these features provide the dynam- produced before and during relapses. Even if ics of what is called ‘making allowance for the intention to stay abstinent remains promi- disease’. To make the point more simply, ad- nent after detoxification, a single episode of dicted patients are unable to counteract the consumption is enough to trigger relapse; symptoms of their disease. Since addiction is apparently sound intentions are quickly over- centred upon craving, its course will drag the whelmed by quick instinctual dynamics that patient away from a therapeutic setting in im- had apparently been extinguished [4]. It is a posing a self-perpetuating search for the sub- misconception to expect that continuous absti- stance. nence, possibly reinforced by environmental Many develop an incorrect idea of addic- rewards, should restore an addict’s capacity to 14 · CHAPTER 1.1 DEFINITIONS · 15

avoid substance use. Actually, as time passes, Ambivalence does characterize addiction the intention to stay abstinent does not be- at different degrees of severity. Higher sever- come sounder, but usually weakens and loses ity corresponds to a greater discrepancy be- the urgency originally displayed at the time of tween intention and drive; the latter turns out detoxification treatment, when it was related to be even stronger. In a severely ill addict, to heavy global impairment. As conditions with years of substance use and a history of improve, time does not heal but brings on re- repeated treatment failures, the intention to lapse. The addictive instinct, though without stop addiction may be sound and structured. any reinforcement due to enduring abstinence, However, the drive is always ‘sounder’ in the rapidly comes back to drive a person towards addict’s brain. Therefore, since the drive is in the substance against their own intentions. the process of becoming more rapid, and can In moving from relapse to relapse, a pro- count on reinforcement, the intention to ab- cess of sensitivitization seems to take place: stain is always weaker: in proportion, severely relapsing takes place more and more rapidly, ill addicts become more willing to stop, but and the period of latency between the first less capable of doing so. slip and full involvement in substance use A severely ill addict is usually pessimistic becomes shorter. In the struggle between the about acquiring the capability of stopping ad- intention to abstain and the drive to use, the diction, and staying detached from the sub- odds are always loaded against the gambler, stance. Because of this factor, along with great- and the match lasts ever shorter times. er psychosocial impairment and independent On psychopathological grounds, the am- complications (e.g. infective diseases), the in- bivalence of addicts is founded on the core of tention to abstain eventually weakens, so leav- addiction, that is the instinctual drive and its ing further room for addiction. A hard-core ad- affective correlate (craving); these are self-syn- dict will eventually think that the only realistic tonic. Some authors fail to recognize craving chance is to acquire partial control over sub- as self-syntonic and refer to it as compulsive stance use, which is the result of an addictive (sometimes this term is used to indicate very way of thinking and growing pessimism about intense craving with short-loop usage). The a healing perspective. discrepancy between the intention to abstain Often, addicts need to be motivated, just and the drive to use may be mistaken for a because of such pessimism, while the addic- compulsion, as long as the intention is mis- tive way of thinking is just a target of treat- taken for a drive. ment. Motivation should not be mistaken for The two components struggling in the an element of treatment. No patient can be addict’s mind are not of the same kind, and motivated so strongly as to make his/her in- do not come into opposition on the same lev- tention prevail over the addictive drive. On the el; the drive itself, in fact, is not ambivalent, other hand, acting on motivation is a way of and is clearly directed towards the substance. increasing the patient’s trust and compliance Craving, drive and behaviour are all clearly with treatment, so restoring a healing perspec- oriented towards the substance, which makes tive to their mind. the whole complex a self-syntonic phenom- When addicted patients approach treat- enon. The intention pulling in the opposite ment settings, they are characterized by a direction cannot be referred to as self-dystonic spontaneous request for help, a different mo- (compulsive), since it acts on a different brain tivational status, and a constant ambivalence level, rational vs. instinctual. Resorting to the towards treatment adherence, which they may substance despite the intention to stop addic- be aware of to a certain degree. tion is not a matter of compulsion; it is a conflict between a behaviour that is pursued and unwanted at the same time. The conflict takes place both during and after the behavioural output [5]. 16 · CHAPTER 1.1

6. The insight of addicted persons References 1. DOLE V. P. (1972): Narcotic addiction, physical dependence and relapse. N Engl J Med. 286 988-992. 2. DOLE V. P. (1980): Addictive behaviour. Sci Am. 243 When patients ask for help, they are usu- 138-154. 3. DOLE V. P., NYSWANDER M. E. (1983): Behavioral ally aware of the severity of their current con- pharmacology and treatment of human drug abuse: dition, and realize that they have lost control methadone maintenance of narcotic addicts. In: SMITH J. E., LANE J. D. (Eds.): The Neurobiology of over substance use. On the other hand, they opiate reward processes. Elsevier Biomedical Press, have no real insight into the nature of the dis- Amsterdam. pp. 211-233. 4. KREEK M. J., ZHON Y., SCHUSSMAN S. (2004): ease with respect to its chronicity, endogenous Craving in Opiate, Cocaine and Alcohol Addiction. pathophysiology and irreversibility [7]. Ad- Heroin Addict Relat Clin Probl. 6:(2-3) 5-52. 5. MAREMMANI I., PACINI M. (2003): Understanding dicts will think the problem is their recent past, the pathogenesis of drug addiction in order to instead of their future, and deny having any implement a correct pharmacological intervention. Heroin Addict Relat Clin Probl. 5:(3) 5-12. long-term problem with substance use con- 6. NEWMAN R. G. (2000): Discontinuation symptoms trol. In this way, addicts underrate or deny the are not addiction/dependence [Letter]. Heroin Addict Relat Clin Probl. 2:(1) 47-48. risk of relapse, and aim to achieve a controlled 7. QUILICI C., PACINI M., MAREMMANI I. (2007): The use or a spontaneous abstinence, rather than need for patient education. Opinions and attitudes on heroin addiction: Changes in Italy over ten year a relapse-prevention treatment. As soon as (1995-2005). Heroin Addict Relat Clin Probl. 9:(4) 35-54. they achieve a state of partial well-being, they 8. TAGLIAMONTE A. (1999): Heroin Addiction as normal illness. Heroin Addict Relat Clin Probl. 1:(1) 9- will identify it with definitive healing. When 12. relapses occur, they will think of each relapse 9. TAGLIAMONTE A., MAREMMANI I. (2001): The problem of drug dependence. Heroin Addict Relat Clin as a separate episode, with its own precursors, Probl. 3:(2) 7-20. reasons and treatment perspectives. 1.2

Addiction Treatment: When will Medical Principles Matter ?

M. Pacini and I. Maremmani

The medical approach to human suffering severe, on the assumption that interventions consists in practical interventions which may against severer cases would have little impact vary in accordance with the types of symp- on the future situation. Obviously, in epidem- tom, but are rooted in a set of identifiable prin- ics a population-based ratio may prevail on ciples. the individual-based ratio.

1) The principle of emergency overcome. 2) The principle of severity threshold. Symptoms should be ranked according to Under conditions that imply imminent risks, their severity, and the severity of their expect- one main treatment objective should be to re- ed consequences, so that those which can be duce the severity of symptoms. Interventions identified as bearing the most dangerous con- should at least aim to ensure a minimal level sequences (e.g. death, organ failure or meta- of functioning, so enhancing the probability bolic impairment) should be challenged as a that treatment can continue. The principle of priority. As far as addictions are concerned, severity threshold retains its validity regard- patients may be intoxicated when asking for less of how seriously the patient is impaired; an intervention, be under the effect of multiple in fact, those whose illnesses are most severe at drugs, be traumatized, metabolically impaired, the moment when they enter treatment are not dehydrated or starving, or may display ma- necessarily those who are destined to have the jor psychiatric symptoms [1]. The emergency worst or least satisfactory outcomes. On the principle can be applied to whole population other hand, it is true that severity is correlated instead of single cases, especially during epi- with the risk of relapses [16]. demics: when death rates are quite high and the chances of survival depend on the degree 3) The principle of stabilization. Once any of severity, less severe cases may be treated as treatment has proved to be effective in control- a priority, so as to stop them becoming more ling the core symptoms of a disease, it should

17 18 · CHAPTER 1.2 ADDICTION TREATMENT: WHEN WILL MEDICAL PRINCIPLES MATTER? · 19 be maintained and enhanced until a continu- the disease, its chronicity, and the degree of ous, satisfactory balance is attained. Balance damage already sustained. Medical treatment can be considered satisfactory when environ- should always aim to achieve some improve- mental factors have proved incapable of hin- ment, and, if possible, to go on from there in dering the response to treatment or of jeopar- the direction of eventual healing. A prognosis dizing the patient’s well-being [8]. of healing is a statistical possibility, but it sets up a misleading perspective. Approaches that 4) The prognostic principle. As long as we are founded on an effort towards healing as an are able to anticipate the evolution of a situa- immediate objective tend to be rather irratio- tion on statistical grounds, the choice of one nal, and to leave medical knowledge out of ac- therapeutic regimen and its design through count. When medical treatments are, indeed, time represent the transition from the treat- applied to achieve healing directly, they tend to ment of the acute phase of a disease and to lose their theoretical role, so that the supposed its possible chronicity. Once acute symptoms treatment ends up by leaving greater room have been buffered, most diseases need a for the disease to develop and become more maintenance regimen to keep the underlying severe. When healing is the question at issue, processes under control. By definition, chronic little effort is spent on improvement, balance disorders are, in fact, characterized by a spon- or control, because these are all viewed as fail- taneous, autonomous self-perpetuating trend, ures to achieve healing. From this perspective, which leads to persistence, recurrence and successful treatment is no better than no treat- phases of rising severity. Despite this, patients ment. By contrast, any period of clinical remis- with a chronic illness often put the blame on sion, no matter how brief, is highlighted as the therapies, as if a given treatment were respon- proof that healing is possible, instead of being sible for making that illness chronic. Given viewed as an interval that is only to be expect- the illogical tendency to think that long-term ed between relapses. In the end, individuals regimens maintain proneness to relapses, who have gone through healing-bound pro- rather than defending the results achieved so grammes are those most likely to fall into the far against a spontaneously relapsing disposi- categories labelled “dead, formerly healed”, or tion, patients end up by feeling they will con- those who became untreatable. Likewise, the tinue to be ill as long as they keep on attend- time spent within such programmes will result ing treatments. It follows that the meaning of in lower chances of achieving realistic goals, prognosis should be clarified from the start, so or of shrinking the therapeutic gap between as to provide adequate linkage between the targets and attainable levels of improvement treatment premises (the nature of the disease), [9]. From a physician’s point of view, healing is its course and the fact that the results that can a rare exception, just as the total impossibility be achieved will depend on the persistence of of achieving any improvement is an exception, that treatment [9]. too. Medical treatment falls between these two extremes. In reality, neither the impossibility 5) Principle of improvement. It is a com- of healing nor the impossibility of achieving mon view, especially among social workers, improvements should be considered defeats. that the golden therapeutic goal is to turn for- The only true defeat comes from a failure to mer addicts into ideal, highly productive, reli- employ the therapeutic instruments that are able citizens, who will act out a social and in- available, through ignorance or through an ir- dividual model that is completely opposed to rational resistance to scientific principles, and their previous drug-related habits [2-4, 17]. from lack of determination in pursuing achiev- All the findings that have won acceptance able results. over the years, and the consensus of opinion surrounding any known disease, point in a 6) Principle of specificity. On techni- different direction. The extent of achievable cal grounds, one needs to know which pro- results is, firstly, limited by the severity of grammes can be useful in achieving the goals 18 · CHAPTER 1.2 ADDICTION TREATMENT: WHEN WILL MEDICAL PRINCIPLES MATTER? · 19

to be pursued. The successfulness of any treat- References ment cannot be based on the soundness of the 1. AA.VV. (1993): Estimates from the Drug Abuse therapist’s intentions, the strength of the pa- Warning Network: 1992 Estimates of Drug-Related Emergency Room Episodes. Substance Abuse and tients’ motivation or the alliance between pa- Mental Health Services Administration, Advance tients and therapists. A disease is curable when Report N. 4, Rockville, MD. 2. CAPLEHORN J. R. M., HARTEL D. M., IRWIG.L. there is at least one effective instrument to be (1997): Measuring and comparing the attitudes and resorted to, and its functioning can be handled beliefs of staff working in New York methadone maintenance clinics. Subst Use Misuse. 32 399-413. scientifically in accordance with specific rules 3. CAPLEHORN J. R. M., IRWIG L., SAUNDERS J. [5, 7, 9-11]. Considering all the principles of B. (1996): Attitudes and beliefs of staff working in methadone maintenance clinics. Subst Use Misuse. medical practice, effectiveness is the least 31:(4) 437-452. understandable: the reasons for the success 4. CAPLEHORN R. M., LUMLEY T. S., IRWIG L., SAUNDERS J. B. (1998): Changing attitudes and of some highly effective instruments remain beliefs of staff working in methadone maintenance unexplained. In other cases, the discovery of programs. Aust N Z J Public Health. 22:(4) 505-508. 5. DOLE V. P. (1971): Methadone maintenance treatment effective instruments was unexpected, while for 25000 heroin addicts. JAMA. 215 1131-1134. there are many examples of candidate instru- 6. DOLE V. P., NYSWANDER M. E. (1966): Rehabilitation of heroin addicts after blockade with methadone. N Y ments which turned out to possess little, if any, State J Med. 66(15) 2011-2017. effectiveness. 7. DOLE V. P., NYSWANDER M. E. (1967): Heroin Addiction: A Metabolic Disease. Arch Intern Med. 120 In the light of the above principles, the 19-24. treatment of narcotic addiction can be thought 8. HUMENIUK R., ALI R., WHITE J., HALL W., FARREL M. (2000): Proceedings of the expert of as follows: addiction should be challenged workshop on induction and stabilisation of patients as a highly curable disease, with no realistic onto methadone. NIDA, Adelaide. 9. MAREMMANI I. (1999): Treating Heroin Addicts perspective of healing in the short or medium i.e. ‘Breaking through a Wall of Prejudices”,. Heroin term [10, 12-15]. The best approach consists in Addict Relat Clin Probl. 1:(1) 1-8. 10. MAREMMANI I., BARRA M., BIGNAMINI E., achieving a condition of therapeutic balance CONSOLI A., DELL’AERA S., DERUVO G., FANTINI by an agonist maintenance regimen that aims F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI G. P., JARRE P., MICHELAZZI A., MOLLICA R., to control and prevent relapsing behaviour [5, NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA 10]. This approach should constitute the first- C., SPAZZAPAN B., STARACE F., TAGLIAMONTE A., TIDONE L., VENDRAMIN A. (2002): Clinical line intervention against narcotic addiction, foundations for the use of methadone. Italian in order to minimize the rate of patients who Consensus Panel on Methadone Treatment. Heroin Addict Relat Clin Probl. 4:(2) 19-31. enter treatment under the burden of somatic 11. NEWMAN R. G. (1995): The Pharmacological or psychosocial concerns, and the average se- Rationale for Methadone Treatment of Narcotic Addiction. In: TAGLIAMONTE A., MAREMMANI verity of developed impairment. Drug-free I. (Eds.): Drug Addiction and Related Clinical Problems. regimens that aim to achieve absolute healing Springer-Verlag, Wien New York. pp. 109-118. 12. PAYTE T. J., KHURI E. T. (1993): Treatment duration should be regarded as anti-therapeutic, be- and patient retention. In: PARRINO M. W. (Ed.) State sides being ineffective. The sequence of treat- Methadone Treatment Guidelines. U.S. Department of Health & Human Services, Rockville,MD. pp. 119- ment goals to be pursued comprises: survival, 124. behavioural stabilization, medically-allowed 13. SIMPSON D. D. (1979): The relation of time spent in drug abuse treatment to posttreatment outcome. Am J rehabilitation. Eventually, after a long period Psychiatry. 136:(11) 1449-1453. of stability, medically supervised withdrawal 14. SIMPSON D. D. (1981): Treatment for drug abuse. Follow-up outcomes and length of time spent. Arch is conceivable, though on a strict clinical basis Gen Psychiatry. 38:(8) 875-880. and only if an extremely gradual schedule is 15. TAGLIAMONTE A., MAREMMANI I. (2001): The problem of drug dependence. Heroin Addict Relat Clin adopted [6]. Probl. 3:(2) 7-20. 16. THORNTON C. C., GOTTHEIL E., WEINSTEIN S. P., KERACHSKY R. S. (1998): Patient-treatment matching in substance abuse. Drug addiction severity. J Subst Abuse Treat 15 505-511. 17. VOSSENBERG P. (2000): Attitudes and Beliefs towards Methadone of staff working in substance abuse treatment. Heroin Addict Relat Clin Probl. 2:(1) 15-21. 20 · CHAPTER 1.2 1.3

Heroin Dependence I. Maremmani and D. Popovic

Heroin Abuse is the failure to reduce or pathogenesis, clinical presentation, course, interrupt heroin/morphine intake adminis- and therapeutic outcome, withdrawal while tered daily for at least a month, with a conse- on opioids can be defined as a “chronic dis- quent state of continued intoxication leading ease with a relapsing trend” in which, along- to overdose episodes that affect social or oc- side opioid abuse and the state of addiction, cupational activities. The term “Heroin Addic- an important role is played by the tendency to tion” includes the conditions of tolerance and become chronic, as shown by the frequency of withdrawal. Tolerance is defined as the need relapsing behaviour [19, 24]. for markedly higher amounts of the substance to achieve the same effect, or a decrease in the effects when constant amounts of substance 1. Etiopathogenesis are taken. Withdrawal is expressed through a characteristic withdrawal syndrome after the reduction or cessation of use. This definition Up till now no descriptive model of a phe- has been transposed from the Diagnostic and nomenon as complex as drug addiction has Statistical Manual of Mental Disorders [1]. been sufficiently comprehensive and explana- Both abuse and withdrawal may lead to a state tory since, generally, each of them has been of acute intoxication. The diagnostic attention limited to the interpretation of some phases in given to withdrawal from opioids, however, the course of the disorder, instead of its com- is increasingly switching towards the concept plete evolution, and these models derive from of relapsing behaviour, which is a relapse into a particular point of view [17]. Alongside par- substance abuse after a more or less prolonged tial models focusing on various social, envi- period of abstinence from the substance [18]. ronmental and cultural groups and subgroups, Based on the latest considerations on etio- it has been decided to add a search for psycho-

21 22 · CHAPTER 1.3 Heroin Dependence · 23 pathological and psychodynamic factors as fragility of his/her defenses, cannot tolerate candidates for an interpretative hypothesis anxiety and depression. Thus the substance (Figure 1). Even though many studies have seems to function as a means of protection failed to reveal specific personality factors in from narcissistic wounds resulting from the drug addicts, there is an undeniable overlap failure of an over-idealized Self. A consequence between substance abuse disorders and psy- of the weakness of the Super-Ego is the ease

Figure 1. Etiopathogenesis of drug dependence chiatric disorders, characterized by a variety with which the mental representation finds ex- of psychopathological and personality constel- pression in unexpected and incomprehensible lations. Impulsivity, inability to control anxi- ways, through aggressive discharges, whether ety, intolerance to frustration, dependent rela- these are self-oriented, following a self-pun- tions, egocentrism, are some of the ishing, self-destructive path, or hetero-direct- characteristic, even if non-specific, personality ed. In this sense, drug addicts’ behaviour ap- aspects of drug addicts that show analogies pears to be an attempt to adapt, by regulating with narcissistic personality disorder. The in- and modulating emotional expressivity [17]. ability to confirm the existence of a ‘specific Some authors have suggested that drug addic- personality’ has led to an appraisal of drug ad- tion is closely related to manic-depressive psy- diction as a transnosographic disorder not as- chosis: if, on one hand, the substance acts as a sociated with specific traits or a particular perform of defense against depression, by making sonality structure or mental disorder. From a it possible both to obtain a state of ‘artificial psychoanalytical point of view, drug addicts mania’ and experience feelings of omnipo- present a regression to the oral phase of libidi- tence, on the other hand, the withdrawal crisis nal development, while external reality and is comparable to a depressive phase. Recent instincts gradually lose their meaning. The data highlight the existence of a high level of ‘need to take drugs’ is correlated with relief comorbidity of Substance Abuse Disorder and from an unbearable psychological tension, Bipolar Disorder in which the elevation phase, since the drug addict, because of the extreme however, is primary and not due to substance- 22 · CHAPTER 1.3 Heroin Dependence · 23

induced euphoria [20, 21]. In recent years there macokinetic tolerance) and through a fall in has been an epidemic diffusion of new abuse the density of opioid membrane receptors, substances which, in terms of their modality of known as ‘downregulation’, a reduction in cel- consumption and abuse-related behaviours, lular response to the binding of the substance suggests that there is a new ‘addict genera- with the receptor, based on a lower availability tion’, with distinctive cultural, social and per- of cAMP, inhibitory feedback on synthesis, sonality features. Rigid one-factor models have and on endogenous opioid activity (pharma- proposed a limited explanation of the phe- codynamic tolerance). All this translates into a nomenon and of changes in addictive habits, marked decrease in the effects of the substance but failed to consider the interactions between with prolonged use of the same doses, and the individual, the environment and the sub- only a gradual increase in the quantity of substance. In order to achieve a better understand- stance taken will allow the desired effects to be ing of this reality, multifactorial models were achieved. Since the homeostasis of the organ- adopted – models able to integrate the socio- ism can only be preserved in the presence of cultural situation, the pharmacological prop- the substance, any abrupt interruption will erties of the substance of abuse, personality lead to alterations that manifest clinically as traits and biological determinants. The indi- stereotypical symptoms. The Locus Coeruleus vidual was finally assessed, with reference not [2, 3, 10, 14, 27-30, 34, 35] is a nucleus that plays only to his/her psychopathological structure a primary role in the psychopathological (mood disorders, anxiety disorders, psychotic mechanisms of the Withdrawal Syndrome; its episodes, personality disorders), including bi- stimulation, in fact, leads to a series of symp- ological features, since there is evidence not toms that display many similarities with with- only of a metabolic deficiency of the opioid en- drawal behaviour. This nucleus contains more dogenous system deriving from the prolonged than 50% of brain catecholamine and is listed use of opioids, but also to his/her genetic pre- as responsible for phenomena such as anxiety disposition [12, 13, 32]. It is likely that the and panic attacks. The Locus Coeruleus is in- large-scale spread of the phenomenon of hero- nervated by fibres containing endogenous opi- in abuse in Italy after the 70’s is due to ‘mar- oids with negative feedback action. The chron- ket’ causes, in a process in which Italy was ic administration of opioids produces a identified as an area of influence by drug deal- reduction in quantities of opioid receptors and ers who were ready to recognize adolescents a decrease in the release of Noradrenalin as ‘possible consumers’. The ‘consumer-com- throughout the SNC resulting in an ‘upregula- petitive’ mechanism typical of Western society, tion’ of postsynaptic adrenergic receptors. The together with its ‘adolescence crisis’, link up interruption of opioid intake removes the in- with the pharmacological properties of sub- hibitory action on LC neurons. Subsequently, stances of abuse; this linkage, in the case of the resumption of nuclear activities thus cor- prolonged use, was likely to culminate in ad- responds to a rise in noradrenergic effects due diction [9]. Whether substance-seeking is best both to a sudden increase in Noradrenalin and viewed as a fashion within consumerism, or to an increase in receptors. The term “second- simply as a way of coping with emotional dif- ary withdrawal syndrome” (otherwise known ficulties, or even as being a psychological ex- as “post-withdrawal” or “reflected” syndrome) pression of altered neurotransmitters, when- stands for a series of physical, autonomic or ever the practice of drug abuse persists, factors psychic symptoms that may even appear a such as tolerance, withdrawal and, at least long time after the administration of opioids, partly, relapsing behaviour, are supported by unleashed by emotional evocation, mental im- neurobiological alterations to gratification ages or the revival of situations and stimuli brain circuits [4, 6-8, 36-40]. Following repeat- related to the drug addiction past [25, 26]. The ed opioid misuse, in fact, adaptation mecha- Relapsing Behaviour may, in many cases, be nisms develop through the opioid metabolism, the behavioural expression of a secondary based on a rise in the levels of enzymes (phar- withdrawal syndrome, and reveal a tendency 24 · CHAPTER 1.3 Heroin Dependence · 25 to relapse even in subjects who are highly mo- 2.1 Encounter or “honeymoon” stage tivated to implement withdrawal. Of course, other vulnerability factors such as interpersonal conflicts, frustrations, intolerable feel- In a normal, non-addicted person, the ad- ings of anger and anxiety, sadness and bore- ministration of opioids produces markedly dom can play an important role in determining positive feelings of well-being (Figure 2). The a relapse. The neurotransmitter systems in- subject experiences an extreme sense of calm volved in opioid withdrawal are responsible and relaxation, not without a certain amount for various functions, such as the regulation of of euphoria, even if this is quite different from pleasure/pain, storage and memory retention, the experience produced by the selective acti- attachment/avoidance conduct. At present, vation of the dopamine system, as occurs af- however, the complexity of the endogenous ter the use of cocaine and amphetamine-like opioid system makes it difficult to determine substances. Generally, substance administra- the physiological behavioural effects typical of tion is occasional and the subject expresses the these substances, regardless of their involve- conviction that he can voluntarily interrupt at ment in the pathological behavioural aspects any time. There is no outward sign of a genu- of opioid addiction. ine drug addiction behaviour; there is no tendency to increase the dose nor an irresistible desire to use it. There are no clear signs of a 2. Natural history of heroin addiction withdrawal syndrome. The situation is often underestimated both by the patient and the social environment, because neither is capable Drug addict experience can be divided into of recognizing the subtle signs of a dysphoria three stages. which becomes increasingly predominant.

Figure 2. Natural history of drug addiction 24 · CHAPTER 1.3 Heroin Dependence · 25

2.2 Intermediate or dose-increasing stage bilitation programmes (Psychotherapeutic or Community interventions). This often leads to a ‘revolving door’ situation, unfolding as a By maintaining a constant dose, euphoric dramatic sequence of being treated, quitting effects tend to disappear gradually, while the treatment, falling out, being arrested, be- symptoms of opposite polarity appear, linked ing hospitalized, going back to treatment, and to a withdrawal syndrome that develops in so on. This perpetuates the sensation of incur- parallel to the onset of tolerance. From being ability in drug addicts and explains their mis- ‘normal’, the subject has gradually become taken belief that such situations are incurable addicted to a drug, and will have to increase in others. In this period, too, the risk of death the dose of the substance to allow the feeling from an ‘overdose’ is higher because, in a drug of euphoria to be experienced once again. In addict in detoxification, the gradual decline of any case, as a result of the same mechanism, tolerance to opioids appears alongside the on- the withdrawal symptomatology will become set of craving for the substance, which leads to more severe. The need for the substance be- the occasional use of heroin. The administra- comes increasingly more ‘imperative’ and, by tion of a dose equal to the dose administered continuing to abuse opioids, as well as intensi- during the period of tolerance will, in these fying the need to increase the dose, the subject circumstances, cause an ’overdose’ (Figure 3). will reach a point where the euphoric pole can no longer be reached and the patient will fluctuate between a greater and greater difficulty 3. Typology of heroin addiction in maintaining normality and a progressively more severe psychophysical malaise due to the withdrawal syndrome. This is the condition of The use of opioids interferes in various a decompensated drug addict. In more severe ways with the ability to reach a certain level of cases this condition evolves into a ‘depravity’ social adaptation [16]. The lowest level on this stage in which the subject is totally oriented, scale, corresponding to the maximum degree by any means, lawful or unlawful, moral or of maladjustment, is that of ‘street addicts’. immoral, towards substance-seeking. They often present the phenomenon of multiple substance abuse and an incessant demand for medical prescriptions, sometimes on the 2.3. Repeated detoxification or the “revolving borders of legality, of any substance that can door stage” alleviate the malaise of going through a withdrawal crisis or that might ease the craving for heroin. Also, the percentage of criminal activity After a more or less prolonged period of ad- that aims to raise money for ‘a daily dose’ (or diction, the impossibility of finding sufficient ‘daily doses’) is at its peak. The establishment quantities of substance, or a self-awareness of of a therapeutic approach, which they reject, his/her psycho-physical condition, spurs the is extremely difficult, too. On the other hand, heroin addict to make the earliest attempts we can identify ‘stable patients’ or ‘conform- to handle detoxification personally, and, later ists’ who lead an existence that is apparently on, apply for help to social health services. At acceptable to social conventions. They often this point, the ordeal of relapsing behaviour manage to keep their job, which in some cases begins. After a request for assistance that the may be quite important, and do not present le- subject conveys to others, and that is often gal problems. They do not tend to group with sincerely motivated, ‘after having reached the other addicts. The ‘destructive’or ‘violent’ ad- bottom’, in most cases, the next development dicts are immersed in their drug sub-culture is the rigid positions taken by operators in the and live in places and situations that are often sector to ‘quickly liberate’ the person from the at the limits of the law or may even be in open drug and set up psychological or social reha- conflict with rules or conventions. They do not 26 · CHAPTER 1.3 Heroin Dependence · 27

Figure 3. Overdose hypothesis have an honest job and often engage in crimi- 3.1 ‘Reactive’ drug addicts nal activities in order to survive. They also present unmotivated episodes of aggression, which they decided on only to cause suffering Often drug consumption is a response to to the victim. Those who ‘live in two worlds’ social interaction and family issues. In this do not care about their criminal activities or case, substance abuse can be called a normal living together with other addicts, but often adolescent crisis with concomitant specific have a regular job; these are the heroin addicts personality traits and environmental difficul- who are most socially dangerous, because of ties without full-blown personality disorders. the serious problems they are likely to cause The lack of structured critical capacities im- at work, both during acute intoxication and pedes the rejection of a useless, harmful, but during a withdrawal syndrome. Finally, the well-organized offer, such as that of heroin. ‘loners’ are not involved in the drug culture, Typically, heroin induces psychological barri- do not have a stable job and in most cases live ers to its purchase, but there are moments in on State subsidies rather than on the proceeds the life of a teenager in which he/she may can of criminal activities. Very often they are car- be caught off guard. These individuals’ domi- riers of serious psychopathological problems nant clinical presentation is that appropriate to (Schizophrenia Simplex); this makes the con- the ‘honeymoon’ stage, continuing over time, comitant drug addict behaviour very difficult but continuous use can lead to an unfavour- to diagnose or treat properly. able evolution of the ‘addiction’. Psychothera- From a clinical-nosographic point of view peutic and educational assistance, associated we can distinguish between 3 types of heroin when necessary with psychopharmacological addicts. therapy with opioid antagonists, is indicated for these subjects. 26 · CHAPTER 1.3 Heroin Dependence · 27

3.2 ‘Self-therapeutic’ drug addicts vision of the problem, it is very likely that the self-administration of opioids, because of their antidepressant, anti-anxious and antipsychot- It is known that euphoric effect is not al- ic action, will take place in situations of psy- ways sought after in a drug; initially, a subject chopathological decompensation, in subjects often “actively seeks for a substance that will affected by conditions of depression, psycho- ease dysphoria and finds out that opioids are sis, panic, social phobia and agoraphobia that able to do this better than other drug catego- often go unrecognized by family members and ries”. In other words, for some of those who even by the physician. Only an early diagnosis approach drugs the concept of seeking for a and the prompt treatment of primary forms drug functions as an unconscious attempt to may be able to prevent the development of a provide self-therapy for previously existing form of metabolic withdrawal. psychopathological disorders that might benefit from that kind of drug. This concept was confirmed, even if in a partial and not univo- 3.3 ‘Metabolic’ drug addicts cal way, by the hypothesis of the role of endorphins in psychopathology. That role was tested by trying out different strategies; using Independently of the modality of the first opioid antagonists for the treatment of mental encounter with heroin, after around two years disorders; evaluating the results of the admin- of intermediate stage and especially during the istration of endorphins; investigating baseline ‘revolving door’ phase, a chronic form char- endorphin levels in psychiatric patients; stim- acterized by withdrawal syndrome, craving ulating the endogenous release through pain and relapsing behaviour develops. Treatment or stress induction or the application of elec- with long-term drug replacement therapy re- trodes in the brain. Even though the results of inforced by psychological and social support these studies have not yet permitted a clear in a perspective of late detoxification (Figure

Figure 4. Typology of heroin addiction 28 · CHAPTER 1.3 Heroin Dependence · 29

4) is indicated for these subjects. coma, miosis, respiratory depression, often with 2, sometimes as many as 3 or 4 events per minute. Hypotension, pulmonary edema, 4. Clinical presentation cyanotic skin and cold sweat are often present. Muscles appear to be hypotonic.

4.1 Intoxication 4.3 Tolerance and withdrawal syndrome

Heroin intoxication is not of strict medical Tolerance develops to the analgesic, respi- relevance; only rarely do heroin addicts spon- ratory depressant and sedative effects, but not taneously seek a doctor’s help. Somatic effects to miosis and constipation. The intensity of the do not raise any particular concerns in the sub- withdrawal syndrome depends on the amount ject, even if they are often troublesome. These of substance that is taken and the speed of include insensitivity to pain stimuli, breathing its elimination by the body. The syndrome is difficulties, constipation, nausea and vomit- much more intense if it is precipitated by an ing, miosis and orthostatic hypotension. From antagonist such as naltrexone. In the case of a psychological viewpoint, the subject appears methadone, the symptoms are analogous, but to be euphoric, only rarely dysphoric, and gen- the onset of the syndrome is slower and less erally seems to be calm, despite difficulties in intense; on the other hand, the syndrome it- paying attention and remembering ordinary self is much more prolonged, and may even items. continue for weeks. After 8 or 10 hours have elapsed, following the interruption of chronic heroin use, anxiety, yawning, sweating, tear- 4.2 Overdose ing and compulsive searching for the substance appear. These symptoms become more and more severe, while insomnia, hot and cold An overdose event is hardly ever a serious, flashes, together with fasciculation and muscle conscious suicide attempt. Very often it is due stiffness, abdominal cramps, mydriasis and to lack of experience in a subject who is not yet tremors, appear too. After about 36 hours fa- tolerant to the drug and underestimates the tigue, severe nausea, vomiting and diarrhea amount of active product present in the ‘dose’. appear, alongside increased blood pressure Otherwise he might take the same amount of and body temperature, while the pulse shows substance even after a short period of interrup- hyperpnea. The symptomatic peak is reached tion of use of the drug. In this case tolerance, after 48-72 hours, but the syndrome continues especially to the respiratory depressor effect, for 7-10 days. Sleep and mood disorders may undergoes a rapid decline. Even subjects who linger for months. underwent premature detoxification in Pub- lic Services may overdose for this reason. The subject might also mix heroin with other cen- 4.4 Other opioid-induced disorders tral nervous system depressants such as benzodiazepines and alcohol. Lastly, the quality of heroin can vary between different ‘hits’, but what counts is always the problem of tolerance. For other disorders induced by opioid misuse, The impact of the substances used for cutting, namely Intoxication Delirium, Psychotic Dis- contrary to common opinion, may cause other orders, Mood Disorders, Sexual Disorders and problems, but it is completely decoupled from Sleep Disorders, reference should be made to overdose phenomena. The overdose syndrome the clinical presentations of individual mani- is represented by the symptomatological triad: festations. These events can be observed both 28 · CHAPTER 1.3 Heroin Dependence · 29

in the State of Intoxication and during the longer use opioids, but have switched to alco- Withdrawal Syndrome, and should be taken hol and other drugs, while 49% are not using into consideration only if the severity of the any substance of abuse and are therefore con- symptoms exceeds the usual level of intoxica- sidered clinically healed. Positive treatment tion and/or withdrawal. outcome predictors include a good social and occupational adaptation prior to addiction, while a criminal past is a predictor of future 5. Diagnosis and prognosis maladjustment; psychiatric complications favour the worst prognosis [5, 15, 23, 31, 33].

Currently a diagnosis of opioid withdrawal is adopted only if there is evidence of tolerance Bibliografia to the substance or withdrawal symptoms. However, many clinicians pay attention to a 1. A.P.A. (1994): Diagnostic and Statistical Manual of subject’s behavioural history. There must be Mental Disorders, DSM-IV. American Psychiatric a period of pathological use of the substance, Association, Washington. 2. AGHAJANIAN G. K. (1978): Tolerance of Locus when it was impossible to interrupt, or peri- Coeruleus neuron to morphine and suppression of ods when the state of intoxication persisted withdrawal response by clonidine. Nature. 276 186- 188. for most of the day. Overdose episodes, too, 3. AGHAJANIAN G. K. (1978): Tolerance of locus can act as strong indicators for the diagnosis. coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature. 276 186- The disorder must last less than a month and 188. there must be an impairment of social and 4. AMALRIC M., CLINE E. J., MARTINEZ J. L., BLOOM F. E., KOOB G. F. (1987): Rewarding properties of occupational adaptation. To verify a state of beta-endorphin as measured by confitioned place withdrawal in the absence of symptoms of preference. Psychopharmacology. 91 14-10. 5. BACKMUND M., MEYER K., EICHENLAUB D., withdrawal, the use of the naloxone test has SCHUTZ C. G. (2001 Oct 1): Predictors for completing been widely proposed, but an accurate be- an inpatient detoxification program among intravenous heroin users, methadone substituted and havioural history, IV signs and, above all, a codeine substituted patients. Drug Alcohol Depend. period of time spent in the ‘revolving door’ 64:(2) 173-180. 6. BOZARTH M. A. (1987): A Ventral Tegmental Reward phase make recourse to this test unnecessary. System. In: ENGEL J. O. (Ed.) Brain Reward System and Very often opioid addicts satisfy an addi- Abuse. Raven Press, New York. pp. 1-17. 7. BOZARTH M. A., WISE R. (1981): Heroin reward is tional DSM-IV Axis-I diagnosis for psychiat- dependent on a dopaminergic substrate. Life Sci. 29 ric disorders and/or an Axis-II diagnosis for 1881-1886. 8. BOZARTH M. A., WISE R. A. (1985): Involvement of personality disorders. Around 70% of heroin the ventral tegmental dopamine system in opioid and addicts present a multiple diagnosis [11, 22]. psychomotor stimulant reinforcement. In: HARRIS L. S. (Ed.) Problems of drug dependence. N.I.D.A., Despite the apparent inability to prevent re- Washington, DC. pp. 190-196. lapsing behaviour in most heroin addicts, the 9. CIRILLO M., MAREMMANI I., NARDINI R. (1984): Il diavolo non esiste. Per un approccio diverso al widespread nature of the phenomenon and problema della tossicodipendenza. Assessorato alla the high mortality involved, Opioid Depen- Cultura, Comune di Pietrasanta. 10. DANYSZ W., JONSSON G., MINOR B. G., POST dence is a disorder that can be cured in a high C., ARCHER T. (1986): Spinal and locus coeruleus percentage of addicts who survive the various noradrenergic lesions abolish the analgesic effects of 5- methoxy-N,N-dimethyltryptamine. BehavNeuralBiol. stages of drug addiction. In particular, subjects 46 71-86. who are not deeply involved in criminal be- 11. DARKE S., ROSS J. (1997): Polydrug dependence and psychiatric comorbidity among heroin injectors. Drug haviour can ‘exit’ through a process of matura- Alcohol Depend. 48 135-141. tion. Follow-up studies show that, among pa- 12. GEORGE F. R. (1990): Genetic approaches to studying drug abuse: correlates of drug self-administration. tients who entered any kind of treatment, 30% Alcohol. 7 207-211. are no longer detectable 6 years later, while 5% 13. GEORGE F. R., GOLDBERG S. R. (1989): Genetic approaches to the analysis of addiction processes. are dead. Of the others, 5% are in prison; 23% Trends Pharmacol Sci. 10 78-83. regularly use opioids, 3% no longer use opi- 14. GUITART X., HAYWARD M., NISENBAUM L. K., BEITNER-JOHNSON D., HAYCOCK J. W., NESTLER oids, but have had relapses, and 12% are still E. J. (1990): Identification of MARPP-58, a morphine- being treated in a ‘methadone clinic’; 8% no and cyclic AMP regulated phosphoprotein of 58 kDa, 30 · CHAPTER 1.3

as tyrosine hydroxylase: evidence for regulation of 27. NESTLER E. J., ERDOS J. J., TERWILLIGER R. Z., its expression by chronic morphine in the rat Locus DUMAN R. S., TALLMAN J. F. (1989): Regulation of Coeruleus. J Neurosci. 10 2649-2659. G-proteins by chronic morphine treatment in the rat 15. KOSTEN T. R., ROUNSAVILLE J., KLEBER H. Locus Coeruleus. Brain Research. 476 230-239. D. (1987): Multidimensionality and prediction of 28. NESTLER E. J., TALLMAN J. F. (1988): Chronic treatment outcome in opioid addicts: 2,5 years follow- morphine treatment increases cyclic AMP-dependent up. Compr Psychiatry. 28/1 3-13. protein kinase activity in the rat Locus Coeruleus. 16. LAHMEYER H. W., CHANNON R. A., SCHLEMMER MolPharmacol. 33 127-132. F. J. (1988): Psychoactive Substance Abuse. In: 29. PUCILOWSKI O., KOZAK W., VALZELLI L. FLAHERTY J. A., CHANNON R. A., DEVIS J. M. (1986): Effect of 6-OHDA injected into the locus (Eds.): Psychiatry Diagnosis & Tgerapy. Appleton & coeruleus on apomorphine-induced aggression. Lange, San Mateo, CA. pp. 182-199. PharmacolBiochemBehav. 25 773-775. 17. MAREMMANI I., CANONIERO S., PACINI M. 30. RASMUSSEN K., BEITNER-JOHNSON D. B., (2002): Psico(pato)logia dell’’addiction’. Un’ipotesi KRYSTAL J. H., AGHAJANIAN G. K., NESTLER interpretativa. Ann Ist Super Sanita. 38:(3) 241-257. E. J. (1990): Opiate withdrawal and the rat Locus 18. MAREMMANI I., CASTROGIOVANNI P. (1990): La Coeruleus: behavioral, electrophisiological, and tossicodipendenza da eroina fra progresso scientifico biochemical correlates. J Neuro Sci. 10 (7) 2308-2317. e pregiudizio culturale. Grasso Editori, Bologna. 31. ROUNSAVILLE B. J., TIERNEY T., CRITS- 19. MAREMMANI I., NARDINI R., DAINI L., ZOLESI CHRISTOPH K., WEISSMAN M. M., KLEBER H. B. O., CASTROGIOVANNI P. (1992): Il trattamento (1982): Predictors of outcome in treatment of opiate chemioterapico della dipendenza da oppiacei con addicts: Evidence for the multidimensional nature of agonisti. Stato dell’arte. Quaderni Italiani di Psichiatria. addicts’ problems. Compr Psychiatry. 23 462-478. XI (3) 234-264. 32. SCARR S., KIDD K. K. (1983): Developmental 20. MAREMMANI I., PACINI M., PERUGI G., AKISKAL behavior genetics. In: WILEY J. (Ed.) Handbook of child H. S. (2004): Addiction and Bipolar Spectrum: Dual psychology. Ed Mussen, New York. pp. 346-443. Diagnosis with a common substrate? Addictive 33. SCHAAR I., OJEHAGEN A. (2003): Predictors of Disorders and Their Treatment. 3:(4) 156-164. improvement in quality of life of severely mentally ill 21. MAREMMANI I., PERUGI G. (2003): Disturbo substance abusers during 18 months of co-operation bipolare e rischio di tossicodipendenza. Agg Psichiat between psychiatric and social services. Soc Psychiatry (Heroin Addict Rel Clin Probl Suppl). Vol 5 35-40. Psychiatr Epidemiol. 38:(2) 83-87. 22. MAREMMANI I., ZOLESI O., AGLIETTI M., 34. STRAHLENDORF H. K., STRAHLENDORF J. C., MARINI G., TAGLIAMONTE A., SHINDERMAN BARNES C. D. (1980): Endorphin-mediated inhibition M. S., MAXWELL S. (2000): Methadone Dose and of locus coeruleus neurons. Brain Research. 191 284- Retention in Treatment of Heroin Addicts with Axis 288. I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. 35. SVENNSSON T. H. (1987): Peripheral, autonomic 23. MAREMMANI I., ZOLESI O., CASTROGIOVANNI regulation of locus coeruleus noradrenergic neurons P. (1991): Psychosocial and psychopathological in brain: putative implications for psychiatry and features as predictors of response to long term and pharmacology. Psychopharmacology. 92 1-7. high dosages methadone treatment. In: LOIMER N., 36. WISE R. A. (1978): Catecholamine theories of reward: SCHMID R., SPRINGER A. (Eds.): Drug Addiction & a critical review. Brain Research. 152 215-547. AIDS. Springer-Verlag, Wien. pp. 230-237. 37. WISE R. A. (1983): Brain Neuronal Systems Mediating 24. MAREMMANI I., ZOLESI O., DAINI L., Reward Processes. Biomedical Press, Amsterdam. CASTROGIOVANNI P. (1999): Disturbi Correlati a 38. WISE R. A. (1989): The brain and reward. In: LIEBMAN Sostanze. Oppiacei. In: CASSANO G. B., PANCHERI J. M., COOPER S. J. (Eds.): The neuropharmacology of P., PAVAN L., PAZZAGLI A., RAVIZZA L., ROSSI R., reward. Oxford University Press, Oxford. pp. SMERALDI E., VOLTERRA V. (Eds.): Trattato Italiano 39. WISE R. A. (1990): The role of reward pathways in the di Psichiatria. Masson, Milano. pp. 1352-1377. development of drug dependence. In: BALFOUR D. 25. MARTIN W. R. (1972): Pathophysiology of narcotic J. K. (Ed.) Psychotropic drugs of abuse. Pergamon Press, addiction: possible role of protracted abstinence in Oxford. pp. 23-57. relapse. In: ZARAFONETIS C. J. D. (Ed.) Drug abuse. 40. WISE R. A., ROMPRE P. P. (1989): Brain dopamine Lea and Febiger, Philadelphia. pp. 153-159. and reward. Annu Rev Psychol. 40 191-225. 26. MARTIN W. R., JASINSKI D. R. (1969): Physiological parameters of morphine dependence in man, early abstinence, protracted abstinence. J Psychiatr Res. 7 9- 17. 1.4

Heroin Dependence: Theory of Different Levels of Intervention

I. Maremmani

1. Background

Given the complex nature of heroin depen- must be adapted to the patient and not vice dence there is no one method that is complete- versa [21, 22]. ly effective in the treatment of this pathology. If, as systematic observations reveal, many Drug addiction varies in intensity and drug drug addicts may remain such for a long time, addicts are a heterogeneous group in terms of some for the rest of their lives, attempts to personal resources and coping ability. treat this vast group of subjects must not be The clinician’s priority is to respond ap- abandoned. It would be sufficient to opt for propriately to each individual patient, by per- long term treatment giving the drug addict the sonalizing therapeutic planning (including possibility to gradually recuperate bio-psy- different types of interventions) in an effort to cho-social functioning. This could be defined improve the single drug addict’s functioning. as clinical improvement even if “restitutio ad Treatment should be adaptable to the patient’s integrum” has not been achieved. It is the first changing needs thus providing long term con- goal of adequate pharmacotherapy and psy- tinuity. chosocial treatment [17, 33]. Presently, almost all researchers, in the Achieving this limited goal may be the best field of drug addiction, are in agreement that result possible for some, while for others it the “retention rate” is a fundamental requisite may open the door to being able to function for the successful outcome of any program well, long term in an opioid-free state. In both [6]. This is obvious if one considers the official cases however, these subjects have a right to definition of drug addiction as a chronic and a normal life, to personal gratification, social relapsing illness. Thus therapeutic planning respectability and physical and mental well-

31 32 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 33 being [9, 10, 19, 39]. these programs refusing the biological basis of The second step in therapeutic planning is addiction also family counseling is very harsh monitoring patients during and after treatment and often implies cutting ties with the patient in order to prevent and treat the inevitable re- who is described as “lacking in will and moti- lapses. Relapses are defined as “expected” in vation”. “Reaching the bottom”, the most fa- the therapeutic alliance. They should become mous slogan of some Italian TC (CEIS group), predictable to both the clinician and the pa- for the heroin addict very often meant dying of tient. Both must be ready to face the relapse overdose, or contracting AIDS or refusing all with all available resources in order to main- types of treatment [34]. tain or exceed the prior level of functioning Comprehensive treatments need a new phi- [24]. When a relapse occurs it should be seen losophy of intervention. The staff must know as part of a normal process, not a failure, and the various levels of the treatment program the treatment plane should be altered in a way and the policies inside these levels must not be which is appropriate to restore the patients to contradictory. the pre-relapse level of function. Withdrawal of agonist medication or discharge from treatment never accomplishes restabilization. 2. Levels of intervention These are destructive responses to substance abuse in a patient [7, 8]. It is important that the staff acquires a glob- Our theory of comprehensive treatment al view of the various types of treatment avail- includes different levels of intervention which able. This view should include the probable are: outcome, length of time required, cost, indica- Level 1: prevention. Level 2: harm reductions and contraindications, as well as an un- tion. Level 3: diagnosis and treatment of asso- derstanding of when, for a particular patient ciated pathologies. Level 4: specific treatments. crossover to another modality would lead to Level 5: rehabilitation and social integration. optimal therapeutic results [2-5, 13]. Level 6: prevention and treatment of relapses. While comprehensive treatment programs These levels can be delivered individually or attempt to deal with many of the problems together in a coordinated manner, depending associated with addiction, we feel that Thera- on the needs and willingness of the patient. peutic Community re-educational programs (TCp), when based on segregation and accu- sation, must not be utilized. Examples of this 2.1 Level 1 (Prevention) kind of treatment were common in Italy and in other European countries in the 70-80ies when stigma for heroin addicts was elevate and the Currently an efficacious primary preven- treatment with opioid agonist was not accept- tion model does not exist. Educational models ed by politicians and strictly regulated [22]. based on particular cultural backgrounds are Re-educational programs on which most of rarely acceptable to all. the Italian TCp are based are methods highly Although drug dependence may have its selective and beneficial to a very limited num- roots in societal organization, or in consumer- ber of addicts, when pharmacological support ism, educational models alone are not effective is denied. In my personal experience, I could preventive measures and may cause diametri- verify cognitive disorganization of patients cally opposite results in social groups with dif- who followed TCp tending to reinforce guilt ferent cultural backgrounds. Research has not and give the idea that drug addiction is an ac- discovered specific educational impairments quired vice caused by deviant behavior. In this nor temperamental types associated with drug way the patients found themselves defenseless addiction. A large number of subjects begin and unprepared for relapses interpreting these using drugs recreationally or to facilitate so- to be an explicit sign of being irrecoverable. In cialization without knowledge of the real risks 32 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 33

and consequences of drug abuse. is presently impossible since drug addicts As a primary prevention model, we sug- live in clandestineness. The patient usu- gest a public health education program on the ally seeks help when the situation is no various psychoactive substances of abuse, ef- longer bearable and course progression is fects, consequences of use and abuse, devoid well advanced. of ideological and moralistic interpretations Proposable interventions at level 1 include: which often succeed in leaving a mythical and • expansion of agonist opioid therapy pro- mysterious imagine which fascinates [36, 37]. grams such as methadone or other opioid If health education constitutes a valid pri- therapies (LAAM, Buprenorphine). The mary prevention policy, secondary prevention Swiss experiments with heroin didn’t (harm reduction, therapy, prevention and treat- support conclusive evidence [12]. They ment of relapses) must not be overlooked. had not good control group and the her- Research indicates that the spread of heroin oin patients received much more psycho- use correlates to precise market interests which social treatment than the methadone pa- are kept alive in certain well-defined condi- tients. Also, the heroin clinics were much tions such as clandestineness which implies more expensive to run than methadone high cost, consumer-pusher phenomena and programs and is unclear where heroin when effective therapy is lacking. Within this clinics fit into the overall framework of framework depenalizing drug use and treat- treatment programs . ing drug addicts are essential cornerstones in • free distribution of disposable syringes the elimination of this problem [27]. • instructions regarding self-administration of medications. • information regarding first aid in case of 2.2 Level 2 (Harm reduction) overdose or withdrawal syndrome • information regarding the risks and consequences of continued use of illicit drugs The aims of level 2 may be summarized as and modalities of treatment and rehabili- follows: tation. • reduce the social consequences related • health education of HIV subjects to addiction, such as: criminal activity, The operative phase of level 1 would be car- spread of AIDS, extinction of the con- ried out by volunteers and specialized work- sumer-pusher phenomena, elimination of ers in "street units". Family physicians as well the clandestine market with subsequent as ambulance paramedical personnel should reduction of number of heroin users, and also be involved. In this way a tight network minor risks for the general population. of contacts between health services and drug • protect heroin addicts from syringe relat- addicts is assured and access to health services ed pathologies (HIV, hepatitis, vascular is facilitated. damage, endocarditis, overdose, with- The effectiveness of a pragmatic approach drawal syndrome, etc.); this will prove is widely demonstrated in the experience of advantageous for the patient and will re- countries such as England and Holland which duce social costs. have succeeded in limiting the spread of her- • more accessible public health services for oin addiction (e.g. in 1991 in the United King- the heroin addict population [28-31]. Es- dom 8,000 heroin addicts were officially regis- tablishing the first contact between medi- tered; there were no deaths due to overdose, cal staff and addicts means (1) reaching the spread of AIDS was limited and restricted a larger number of subjects; (2) offering to subjects at risk, prevalently homosexuals. accurate information regarding physical In Italy with its moralistic and repressive atti- and mental well-being and therapeutic tude, in the same period there were more than prospects [16]. 320,000 heroin addicts, 1,200 deaths by over- • the possibility of an early diagnosis which dose, widespread diffusion of HIV and 70% of 34 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 35 heroin addicts were seropositive). tional state will the staff be able to verify the The drawback of this first level is that it is choices made. not an actual treatment modality and therefore At the same time associated pathologies it cannot help patients recuperate bio-psycho- and psychiatric disorders are diagnosed and social functioning [16]. In order to achieve this treated [1, 15, 20, 26, 35]. goal we must pass to the next level of our program which includes services and more qualified personnel. 2.4. Level 4 (Specific treatments).

2.3 Level 3 (Diagnosis and treatment of as- This level includes therapeutic and rehabil- sociated pathologies). itate interventions after the patient has undergone clinical assessment. Generally patients may be divided into two groups: At this level the specific treatment of drug • patients who do not require opioid ago- addiction begins. The patient is examined by a nists. medical specialist and other professional per- • patients who require opioid agonist long sonnel in order to arrive at a diagnosis and es- term therapy (Methadone/Buprenor- tablish a therapeutic plan appropriate for that phine Maintenance; LAAM Maintenance; subject. Scientific literature is in agreement in Buprenorphine-Naloxone Maintenance). defining heroin addiction as an illness and experience shows that it is the patient's degree 2.4.1 Patients who do not require opioid agonists. of impairment together with other factors that determine if a particular intervention is suit- The patients included in the first group able or unsuitable at that time [32, 38]. The should satisfy the following requisites: they principal task of the specialized staff at this are subjects who meet DSM-IV or ICD-10 cri- stage is to formulate a diagnosis. and identify teria for a substance use disorder; they have potential resources (personal attributes, family no psychiatric comorbidity [18]; low craving; members or social skills), that may help in re- good social adjustment; good family support habilitating the patient. This will be possible if with the possibility of a referring family mem- interviewing techniques reactivate a two way ber; these subjects are reliable and have good communication in order to identify the needs interpersonal relationships with staff [11, 14, of the patient and offer concrete proposals. 25]. Particular attention should be given to unsuc- It is important to underline that methods cessful endeavors which are often indicative based on a “drug free state” are highly selec- of errors in the interventions proposed or in tive and applicable to a very small number monitoring of the patient. of patients [23]; however some antisocial and This level requires more qualified personnel very resistant addicts do very well in these and specialized services. Specialized centers programs and do not respond to anything for the diagnosis and treatment of addiction else. It is understandable then, the caution are needed. These centers should be equipped needed before detoxifying patients, as well as, to carry out research, collaborating with Ph. the need to control attentively behavior at risk D. Research Programs in Drug Addiction, and and immediately admit the patient to an ago- educate and train specialized personnel. nist treatment program if difficulties arise. Once a diagnosis has been made, the pa- Methods for achieving a drug free state tient undergoes the appropriate therapeutic may be outlined as follows: modality. The initial choices, however, should • Abstinence is controlled by psychothera- not be restrictive or rigid but rather open and peutic support, with or without opioid interchangeable with other modalities. Only antagonists. if the patient acquires and maintains a func- • Self-help groups which encourage social 34 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 35

reintegration during treatment. Antago- dition to pharmacotherapy. They are nists may also be used in this case. drug addicts with serious psychiatric dis- • We suggest Therapeutic Community’s orders as well as those addicts who find (TC) with more flexibility and research to themselves jobless and homeless. determine who fits best into the rigorous • In closing we would like to underline: ones that currently dominate the scene. • The therapeutic communities would be NIDA is supporting studies of more linked to social agencies and other health “flexible” TC’s (those that use medica- services. They would no longer be re- tions and treat dual diagnosis patients). clusive structures and isolate the patient from his family and social ties. They must 2.4.2 Patients who require opioid agonist long term not create an artificial world in which re- therapy. covery is obtained and quickly lost when the patient is released. Contrary to what This group includes the large majority of happens in Italy, in the US, many TC’s drug addicts who seek help. They do not meet work very hard to integrate patients back requisites for “drug free” programs which into the real world prior to discharge. It would be detrimental for these subjects. is important to have a transition phase so The first task the staff must face is that of as to help the patient overcome the prob- redefining the patient’s expectations suggest- lems associated with the artificial envi- ing long term treatment which will probably ronment. be more successful and safer. • The primacy of "drug free" programs One should aim to set up services that are should be abolished. Recovery cannot able to support and be integrated with a long be associated with a "drug free" state. It term agonist therapy should be related to the psychological • Basic counseling. Many patients on meth- and social functioning. adone or on other substitutive therapies who have obtained metabolic stabilization experience a return to normality; 2.5. Level 5 (Rehabilitation and social inte- they become socially reintegreted espe- gration). cially if they have personal resources, help from family members (home, work, hobbies, etc). For these patients therapeu- This level foresees the complete rehabili- tic success may be possible with specific tation of drug addicts independently of the information and treatment counseling. kinds of treatment modalities in progress. • Treatment of psychiatric disorders with The achievement of this goal varies (length psychotherapy and/or pharmacotherapy of time and modality) according to the needs along with drug counseling for patients and the severity of illness of each individual. with psychiatric disorders The interventions which allow the patient to • Self-help groups could provide solid achieve this status vary, for example: getting a support to those subjects who lack reha- job, reintegration into family life; methadone, bilitative resources. In future we suggest LAAM, buprenorphine detoxification. that more attention be focused on these We would like to focus the need of those groups because they are at low cost, have patients who cannot be deprived of agonist been shown to be effective in other areas therapy due to biological determinants. A sub- (alcohol, psychiatric pathologies, etc) and stantial part of the drug addict population who more subjects can be treated simultane- have good social and psychological adjustment ously. require agonist therapy but not social support • Residential communities. These commu- services. We consider these patients completely nities would serve those subjects who recuperated and feel that they are able to man- need specialized social structures in ad- age their pharmacotherapy i.e. as diabetics do. 36 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 37

For these subjects agonists availability should of heroin addiction which we feel is scientific be convenient and interfere as little as possible and pragmatic. Obstacles to the realization of with the patient's life, work and leisure time this project are the political interference and The patient could be entrusted with dosages cultural biases. What we can hope for is that that cover a longer period of time; family doc- educating the public will help correct the mis- tors would be able to prescribe methadone or conceptions that regard the problem of drug other substitutive therapies. Any community dependence. health service could dispense of methadone or of other substitutive therapies under certification in order to facilitate the patient. On in- References ternational level contacts could be established 1. BLIX O., GRÖNBLADH L. (1991): The impact of methadone maintenance treatment on the spread of between the health services of different coun- HIV among IV heroin addicts in Sweden. In: LOIMER tries permitting the patient to travel freely. The N., SCHMID R. (Eds.): Drug Addiction and AIDS. Springer Verlag, Wien, New York. pp. 200-205. organization of a heath service network would 2. BROWN B. S., JANSEN D. R., BASS III U. F. (1974): prove advantageous for the patient who need Staff attitudes and conflict regarding the use of methadone in the treatment of heroin addiction. Am J not travel great distances to reach specialized Psychiatry. 131:((2)) 215-219. centers and at the same time these centers 3. CAPLEHORN J. R., LUMLEY T. S., IRWIG L. (1998): Staff attitudes and retention of patients in methadone would not be overloaded with work-dispens- maintenance programs. Drug Alcohol Depend. 52:(1) ing of methadone or of other substitutive ther- 57-61. 4. CAPLEHORN J. R. M., IRWIG L., SAUNDERS J. apies to patients who are rehabilitated, thus B. (1996): Attitudes and beliefs of staff working in reducing social costs. methadone maintenance clinics. Subst Use Misuse. 31:(4) 437-452. 5. CAPLEHORN R. M., LUMLEY T. S., IRWIG L., SAUNDERS J. B. (1998): Changing attitudes and beliefs of staff working in methadone maintenance 2.6. Level 6 (Prevention and treatment of programs. Aust N Z J Public Health. 22:(4) 505-508. relapses). 6. COOPER J. R., ALTMAN F., BROWN B. S., CZECHOWICZ D. (1983): Research on the treatment of narcotic addiction. State of the Art. Treatment Research Monograph Series. N.I.D.A, Rockville, Maryland. Given the definition of heroin dependence 7. DÉGLON J. J. (1995): Reducing Heroin Consumption as a chronic and relapsing illness, it is logical During Methadone Treatment and Limitation of Post-Treatment Relapses:Two Crucial Public Health to emphasize the role of prevention and ther- Problems. In: TAGLIAMONTE A., MAREMMANI I. apy of relapses. This requires therapeutic mo- (Eds.): Drug Addiction and Related Clinical Problems. Spinger-Verlag, Wien New York. pp. 119-128. dalities which help in conserving the skills and 8. DOLE V. P. (1972): Narcotic addiction, physical functioning level previously achieved by the dependence and relapse. N Engl J Med. 286 988-992. 9. DOLE V. P., NYSWANDER M. E. (1966): Rehabilitation patient. Thus patients would be rapidly read- of heroin addicts after blockade with methadone. N Y mitted to methadone or to other substitutive State J Med. 66(15) 2011-2017. 10. GHODSE H., CLANCY C., OYEFESO A., ROSINGER therapies (it is obligatory with recurrences) in C., FINKBEINER T., SCHIFANO F., FORZA order to prevent harm to the patient i.e. return- G., SOMMER B., NIELSON K. R., SCHODT J., WIEVIORKA S., GIONNET C., O’CONNOR J., ing to street life. Treatment would be simpli- TIDONE L., RIGLIETTA M., LOPES I., TORRENS fied in these programs as these patients have M., SAN L., MONTES M., COPEZ C. R. (2003): The impact of methadone substitution therapy (MST) on been rehabilitated in the past. In order to ac- illicit drug use and drug abused-related quality of celerate readmission to any health service the life: A European Study. Heroin Addict Relat Clin Probl. 5:(1) 5-16. patient would be provided with documenta- 11. GREENSTEIN R. A., RESNICK R. B., RESNICK E. tion containing clinical chart data. (1984): Methadone and Naltrexone in the treatment of heroine dependence. Psychiatr Clin North Am 671- 679. 12. GUELFI G. P., CIBIN M., PANI P. P., MAREMMANI I., FOR THE BOARD OF DIRECTORS OF ITALIAN 3. Conclusions SOCIETY OF ADDICTION MEDICINE (2007): Can Heroin Maintenance Treatment Be Called a Therapy? Heroin Addict Relat Clin Probl. 9:(2) 5-10. 13. KAHN R. B. (1992): Methadone maintenance In conclusions, we have attempted to out- treatment: impact of its politics on staff and patients. J Psychoactive Drugs. 24:(3) 281-283. line a rather complex strategy for the treatment 14. KLEBER H. D. (1985): Naltrexone. J Subst Abuse Treat. 36 · CHAPTER 1.4 HEROIN DEPENDENCE: THEORY OF DIFFERENT LEVELS OF INTERVENTION · 37

2 117-122. 25. MARTIN W. R., JASINSKI D. R., MANSKY P. A. 15. LONGSHORE D., HSIEH S., ANGLIN M. (1994): (1973): Naltrexone, an antagonist for the treatment of Reducing HIV risk behaviour among injection in drug heroin dependence. Arch Gen Psychiatry. 28 784-791. users: effect of methadone maintenance treatment on 26. MASON B. J., KOCSIS J. H., MELIA D., KHURI E. number of sex partners. Int J Addict. 29 741-757. T., SWEENEY J., WELLS A., BORG L., MILLMAN 16. MAREMMANI I. (2006): Forty years of Methadone R. B., KREEK M. J. (1998): Psychiatric comorbidity in Maintenance Treatment around the world: past, methadone maintained patients. J Addict Dis. 17:(3) present and future. Heroin Addict Relat Clin Probl. 8:(3) 75-89. 7-12. 27. MICHELAZZI A. (2000): Aprohibitionism, a feasible 17. MAREMMANI I., BARRA M., BIGNAMINI E., way forward. Heroin Addict Relat Clin Probl. 2:(2) 51- CONSOLI A., DELL’AERA S., DERUVO G., FANTINI 55. F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI 28. NEWMAN R. (2001): Strategies to combat drug G. P., JARRE P., MICHELAZZI A., MOLLICA R., addiction. Lancet. 358:(9290) 1369. NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA 29. NEWMAN R. G. (1973): We’ll make them an offer C., SPAZZAPAN B., STARACE F., TAGLIAMONTE they can’t refuse. Proc Natl Conf Methadone Treat. 1 94- A., TIDONE L., VENDRAMIN A. (2002): Clinical 100. foundations for the use of methadone. Italian 30. NEWMAN R. G. (2000): Addiction and methadone: Consensus Panel on Methadone Treatment. Heroin One American’s view. Heroin Addict Relat Clin Probl. Addict Relat Clin Probl. 4:(2) 19-31. 2:(2) 19-27. 18. MAREMMANI I., PACINI M., GIUNTOLI G., 31. NEWMAN R. G. (2001): Methadone regulations in LOVRECIC M., PERUGI G. (2004): Naltrexone as USA: Comments, proposal to adopt new regulations maintenance therapy for heroin addiction: Predictors and proposed rule. Heroin Addict Relat Clin Probl. 3:(1) of response. Heroin Addict Relat Clin Probl. 6:(1) 43-52. 29-34. 19. MAREMMANI I., PANI P. P., PACINI M., PERUGI 32. NYSWANDER M. E. (1956): The Drug Addict as a G. (2007): Substance use and quality of life over 12 Patient. Grant & Stratton, New York. months among buprenorphine maintenance-treated 33. PARRINO M. W. (1993): State Methadone Treatment and methadone maintenance-treated heroin-addicted Guidelines. Treatment Improvement Protocol (TIP) patients. J Subst Abuse Treat. 33:(1) 91-98. Series, 1. U.S. Department of Health and Human 20. MAREMMANI I., ZOLESI O., AGLIETTI M., Services, Rockville, MD. MARINI G., TAGLIAMONTE A., SHINDERMAN 34. QUILICI C., PACINI M., MAREMMANI I. (2007): The M. S., MAXWELL S. (2000): Methadone Dose and need for patient education. Opinions and attitudes Retention in Treatment of Heroin Addicts with Axis on heroin addiction: Changes in Italy over ten year I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. (1995-2005). Heroin Addict Relat Clin Probl. 9:(4) 35-54. 21. MAREMMANI I., ZOLESI O., CIRILLO M., NARDINI 35. SERPELLONI G., CARRIERI M. P., REZZA G., R., CASTROGIOVANNI P., TAGLIAMONTE A. (1991): MORGANTI S., GOMMA M., BINKIN N. (1994): Drug addiction treatment in Italy in the 80s. Fear of Methadone treatment as a determinant of HIV risk treatment. In: LOIMER N., SCHMID R., SPRINGER reduction among injecting drug users: A nested case- A. (Eds.): Drug Addiction & AIDS. Springer-Verlag, control study. Aids Care. 6 215-220. Wien. pp. 223-229. 36. SZASZ T. (1961): The Myth of Mental Illness. Hoeber- 22. MAREMMANI I., ZOLESI O., CIRILLO M., NARDINI Harper, New York. R., TAGLIAMONTE A., CASTROGIOVANNI P. 37. SZASZ T. (1974): The discovery of drug addiction. (1990): Socio-cultural factors affecting drug addiction Ceremonial Chemistry. Anchor Press/Doubleday, New treatment in Italy. Fear of treatment. Drug Alcohol York. pp. 3-18. Depend. 25 235-239. 38. TAGLIAMONTE A. (1999): Heroin Addiction as 23. MAREMMANI I., ZOLESI O., DAINI L., CAPONE normal illness. Heroin Addict Relat Clin Probl. 1:(1) 9- M. R., AGLIETTI M., CASTROGIOVANNI P. (1995): 12. Pharmacotherapy for craving. In: TAGLIAMONTE 39. TORRENS M., DOMINGO-SALVANY A., ALONSO A., MAREMMANI I. (Eds.): Drug Addiction and Related J., CASTILLO C., SAN L. (1999): Methadone and Clinical Problems. Springer-Verlag, Vienna, New York. quality of life. Lancet. 353:(9158) 1101. pp. 51-56. 24. MARLATT G. A., GORDON J. R. (1985): Relapse prevention. Guilford, New York. 38 · CHAPTER 1.4 1.5

Scientifically BasedEthical Principles in Dealing with Heroin Addicts

M. Pacini and I. Maremmani

In a treatment setting for an addictive dis- inculcating the idea of incurability. order, the relationship between physician and patient may be hindered by the nature of the disease itself. Insufficient knowledge of the 1. Scientifically based ethical principles dynamics of the disease may lead to interpreting some typical features or behaviours as an abnormal and unacceptable limitation on The following ethical issues need to be ac- treatment feasibility [3]. In some ways, rais- counted for when dealing with addicted pa- ing obstacles to certain kinds of interactions tients. between the patient and treatment facilities may serve as a way of shifting patients towards a perspective of cure rather than a self- 1.1 Choice of treatment modality wise manipulation of resources. On the other hand, obstacles to treatment itself, especially if justified in terms of the presence of expected In the patient’s interest, it is up to the phy- symptoms, simply mean treatment omission sician to make therapeutic choices. If the pa- [5, 12]. Besides, patients often end up feeling tient shows he or she is compliant with one guilty, or at least responsible, for the failure treatment perspective, but not others, the deci- of a therapeutic attempt, no matter whether sion to be made by the physician should not it is inappropriate or clumsy. As a rule, treat- take the patient’s preferences into account [9]. ment programmes which require the patient’s A doctor-patient relationship has a therapeu- involvement in “stopping having the symp- tic basis, and it is bound to fail as long as it toms” have no effect other than discouraging brings no therapeutic benefits. The first-line the patient from making future attempts, while choice is the same for most patients, and corre-

39 40 · CHAPTER 1.5 SCIENTIFICALLY BASED ETHICAL PRINCIPLES IN DEALING WITH HEROIN ADDICTS · 41 sponds to an agonist maintenance programme ventions and agonist-free interventions) [1]. [7]. Even if some patients, due to a lower de- The goal and the principles of any treatment gree of disease severity, may draw additional must be clear from the beginning, whereas de- benefits from environmental interventions, or tails and related explanations can be discussed respond to antagonist maintenance, the choice later on. Whenever a centre can only provide of a broader-spectrum treatment modality will applicants with one treatment option, agonist give them the advantage of a lower likelihood maintenance should be the choice, due to its of relapse. The trend of matching less severely broader spectrum. In this case, the threshold impaired patients with less effective treat- and waiting lists must be such as to allow pa- ment options has, over the years, made most tients to be followed up individually. such cases increase in severity due to treatment failure. In no case can the choice be restricted to “no treatment” or “waiting”, in the 1.3 Therapeutic deal hope that the patient will not relapse or will stop autonomously, after hitting the bottom. When choosing between therapeutic options, While dealing with a disease which basical- it should be remembered that effectiveness is ly consists of the loss of behavioural control, it not influenced by expectations of applicants is paradoxical if behavioural control is made a or the intentions of promoters, but by scien- requirement for staying within the programme. tifically documented properties [8]. So far, at No physician should ever regard the persist- least, any therapeutic programme which does ence or recurrence of addictive symptoms as a not employ opiate-modulating drugs cannot valid reason for a patient to be terminated [11]. be considered a reasonable option in the treat- Patients applying for treatment are not in a po- ment of narcotic addiction. sition to make promises about how much they will “use”, how strictly they will comply with the rules, or how sincere they will be in report- 1.2 Availability of treatment options ing their behaviours. All this may change in the case of stabilized patients, who have made room within their brain for self-aware choices, Since many treatment options exist, the and can actually choose, day by day, whether actual availability of the most effective (ago- to comply or not with the treatment regimen. nist-based) programmes should be kept at the It follows that the achievement or maintenance highest level; availability should be lower for of abstinence as a requirement for beginning less effective (antagonist-based) ones, and still or continuing any treatment programme, re- lower for harm reduction. Harm reduction is spectively, are examples of inadmissible thera- characterized by a low threshold in terms of peutic deals. As long as addictive behaviours behavioural requirements, which means that endure, therapies must be handled promptly almost anyone qualifies for admission to it, and meaningfully with respect to the final but high-threshold facilities should be those goal. Only patients who refuse the physician’s that are made most available, meaning that prescriptions, including attendance and sam- anyone may apply for them [6]. The Centre ple delivery, can reasonably be terminated, should keep high threshold treatment as the or referred to a lower threshold programme. final goal, while continuing to run harm re- The patient is only responsible for compliance duction programmes, in the attempt to make with treatment rules, not with substance use, patients fit to be admitted to higher threshold and the physician is not there to prescribe a be- programmes. Physicians should clearly reject haviour, but a therapeutic agent. any request that is not inspired by therapeutic purposes, or is inspired by unrealistic expectations about achievable results (e.g. results expected from detoxification, drug-free inter- 40 · CHAPTER 1.5 SCIENTIFICALLY BASED ETHICAL PRINCIPLES IN DEALING WITH HEROIN ADDICTS · 41

1.4 Negotiation different from basic anticraving treatments, such facilities are optional and require the patient’s active request to be regarded as viable. At first, allowing the patient to participate On clinical grounds, the stabilization obtained in therapeutic decisions may turn out to be through anticraving treatment usually causes helpful in establishing a good relationship patients to become spontaneously willing to [13]. Addicts usually try to manipulate the engage in higher threshold facilities for addic- therapeutic setting, in a stereotyped way, and tion, and capable of satisfying the correspond- show apparent gratitude to those who allow ing requirements. them to do so. In reality, stabilized patients ap- prove of physicians who refrain from involving them in therapeutic responsibilities, and 1.6 Change of treatment modality are not influenced by their requests. A treatment which is founded, even if partially, on an addicted patient’s decision, is bound to be The flow of patients’ thoughts is spontane- a failure, and this can only be to the patient’s ously oriented towards cutting out medica- detriment. Moreover, as long as patients ditions, due to cultural bias. Sometimes, any such rectly interact with their symptoms, without trend is favoured by suggesting or supporting the autonomous mediation of a sensible phy- the idea that a drug-free state is the gold stand- sician, they will stay convinced that a possible ard, and indicative of therapeutic success. The change in the course of addiction may depend result of following this line of reasoning is that on a variety of factors pertinent to the environ- potentially effective programmes may be pre- mental sphere or to a paradoxical idea of moti- maturely aborted, so upsetting the therapeutic vation (the ability to resist one’s drive towards balance in favour of a fake perspective of heal- the substance). ing. This revolving door mechanism is, sometimes, all that patients are offered at every stage of their addiction history, until death puts an 1.5 Refusal or interruption of treatment end to it all. Lastly, it is risky and unjustified to shift to a newer treatment modality just for the novelty factor, once another modality has been Addicted patients are ambiguous by na- tried and proved to be effective (e.g. abandon- ture. However, the crucial factor which allows ing methadone for buprenorphine, or an ag- methadone treatment to be successful, is not onist for an antagonist) [2, 4, 10]. of a motivational kind, but behavioural: the administration of certain doses for a certain time can make treatment effective, beyond 2. Conclusions the subject’s intentions to stay off drugs. It is unethical to regard motivations, intentions or self-criticism as crucial for enrolment [13]. In conclusion, a physician who acts in ac- The presence of addictive symptoms, no mat- cordance with intuition and common judge- ter how severe, is never a good reason to ter- ment, runs the risk of paving the road to hell minate a patient, unless they actually make with good intentions. The fact is that handling it impossible for that patient to comply with a request for treatment by a patient implies a the minimal rules of the programme. Minimal fundamental question for any physician to ask rules correspond to the features for effective- themselves: “In what way and to what extent ness, that is, dosage and duration and registra- are my actions supposed to change the course tion of parameters. On the other hand, attend- of this disease?”. The answer to this key ques- ance of ancillary or higher threshold facilities tion is often, to one’s great surprise, far differ- cannot be considered as rules for any kind of ent from any common judgement. patient in any kind of programme. In a way 42 · CHAPTER 1.5 references G. P., JARRE P., MICHELAZZI A., MOLLICA R., 1. ADDISS S. S., HOROSKO S. (1994): Medical NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA mismanagement in public methadone programs. C., SPAZZAPAN B., STARACE F., TAGLIAMONTE Connecticut Medicine. 58:(3) 173-174. A., TIDONE L., VENDRAMIN A. (2002): Clinical 2. CAPLEHORN J. R. M., IRWIG L., SAUNDERS J. foundations for the use of methadone. Italian B. (1996): Attitudes and beliefs of staff working in Consensus Panel on Methadone Treatment. Heroin methadone maintenance clinics. Subst Use Misuse. Addict Relat Clin Probl. 4:(2) 19-31. 31:(4) 437-452. 8. NEWMAN R. (2001): Strategies to combat drug 3. DOLE V. P. (1983): Addictive behaviour and the art of addiction. Lancet. 358:(9290) 1369. medicine. Subst Alcohol Actions Misuse. 4:(6) 445-453. 9. NEWMAN R. G. (1973): We’ll make them an offer 4. MAGURA S., ROSENBLUM A. (2001): Leaving they can’t refuse. Proc Natl Conf Methadone Treat. 1 94- methadone treatment: lessons learned, lessons 100. forgotten, lessons ignored. Mt Sinai J Med. 68:(1) 62- 10. NEWMAN R. G. (1995): Methadone: prescribing 74. maintenance, pursuing abstinence. Int J Addict. 30:(10) 5. MAREMMANI I. (1999): Treating Heroin Addicts 1303-1309. i.e. ‘Breaking through a Wall of Prejudices”,. Heroin 11. PARRINO M. W. (1993): State Methadone Treatment Addict Relat Clin Probl. 1:(1) 1-8. Guidelines. Treatment Improvement Protocol (TIP) 6. MAREMMANI I. (2006): Forty years of Methadone Series, 1. U.S. Department of Health and Human Maintenance Treatment around the world: past, Services, Rockville, MD. present and future. Heroin Addict Relat Clin Probl. 8:(3) 12. TAGLIAMONTE A. (1999): Heroin Addiction as 7-12. normal illness. Heroin Addict Relat Clin Probl. 1:(1) 9- 7. MAREMMANI I., BARRA M., BIGNAMINI E., 12. CONSOLI A., DELL’AERA S., DERUVO G., FANTINI 13. WOODS J. (2001): Methadone advocacy: the voice of F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI the patient. Mt Sinai J Med. 68:(1) 75-78. 1.6

Pharmacology and Neurochemistry of Methadone A. Vendramin and A. M. Sciacchitano

1. Introduction mune system, response to stress via the hypothalamic-pituitary-adrenal axis, and the hypothalamus-pituitary-genital one). On the Methadone is a synthetic opioid with dis- other hand, it does not alter the level of pain tinctive pharmacokinetic and neurochemical sensitivity. More recently, methadone proved properties which account for its being, to date, useful as one ‘opioid rotation’ solution for the the most effective agent for the treatment of management of severe pain, which is usually heroin addiction. Studies have proved that, first treated by such opiates as morphine, co- for 50-80% of unselected addicts, methadone- deine and buprenorphine [54, 93, 107]. based treatment programmes are crucial in improving general health conditions and social functioning, while increasing compliance 2. Chemical profile rates with other non-pharmacological interventions [66]. In particular, methadone maintenance treatment, as long as it is delivered at Methadone (Figure 1) was first synthesized adequate dosages, under medical supervision in 1945 in the Hoechst Pharmaceutical Labo- and on a regular basis, is effective in reducing ratories, in the context of a research project and eventually extinguishing the craving for that aimed to find alternatives to morphine, fast-acting opiates and the drug-seeking be- with at least similar analgesic properties but haviours that are rooted in it [27, 87]. More- fewer or milder side-effects. It is the first ex- over, the administration of methadone makes ample of a phenylpropylamine derivative that it possible to restore the balance between the is structurally dissimilar from morphine, but functions that are typically impaired during acquires a similar conformation in an aqueous phases of continued heroin use (e.g. the im- solution. Such derivatives (methadone and l-

43 44 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 45

For analgesic purposes, R-S Met is available in enteral and spray formulations [23, 24].

3. Pharmacokinetics of racemic methadone

Figure 1. Neurochemistry of Methadone 3.1 Absorption

α-acetylmethadol) are the results of the progressive simplification of original compounds Methadone is well absorbed through any such as epoxymorphinanes (nalorphine and route of administration. After oral administra- nalbuphine), through morphinanes (levorpha- tion (as in the treatment of heroin addiction) nol), benzomorphanes (pentazocine), phenyl- the absorption of racemic methadone takes piperidine (pethidine) and 4-anylpiperidine place quickly, and almost reaches completion (fentanyl). A methadone molecule consists of (range 35-100%, average 80%) [33, 79]. The two aromatic rings tied to a 4-C, the sequence methadone absorption rate is influenced by proceeding to C5, C6 and eventually to one N the expression of intestinal P glycoprotein (P- basic unit. C3 is tied to an electron-attracting gp), as for several other compounds (such as ketonic part. Since the C6 atom is asymmetric, amytriptiline, digossine, diltiazem, domperi- methadone has two isomeric variants, which done, fentanyl, indinavir, loperamide, mor- share the same structure, mirroring each other, phine, nelfinavir, ranitidine, verapamil). P-gp but have a different spatial array, referred to is involved in the phenomenon of multidrug as S and R. As to other analgesics, the two iso- resistance to chemotherapeutic agents; these meric variants (or enantiomers) have certain are, in fact, pumped out from cells by P-gp specific biochemical properties. Methadone membrane units [73]. The physiologic function hydrochloride (6-dimetilamine-4, 4–dephenyl- of P-gp, which is expressed in several normal etan-3-one hydrochloride or 4, 4-diphenyl-6- tissues, is that of preventing the absorption of dimetilamine-3-eptanone) is a white, basic, toxic substances through internal and external crystalline substance (pKa= 9, 2), saturating surfaces, and favouring their elimination [5]. water over 120 mg/ml, which may be made P-gp is a twofold structure weighing 170 KD, up of R-enantiomers (R-Met or l-Met), S-ones consisting of 1,280 aminoacids with 12 trans- (S-Met or d-Met) or both in a racemic combi- membrane traits and 2 ATP-binding extracel- nation. Although most of the properties which lular domains [48]. The genetic source, known make methadone useful in the treatment of by the acronym MDR1, leads to different lev- heroin addiction and pain correspond to those els of P-gp expression, with a ten-time interin- of R-Met, methadone hydrochloride is usually dividual variability. The induction of P-gp is a employed as a 50% racemic mixture of the two plausible reason for the loss of responsiveness enantiomers, in a variety of formulations that to morphine and to antiretroviral agents. In the allow methadone to be administered in four case of methadone, the P-gp transfers it out- different ways: side the intestinal epithelium, into the bowel - 0.1, 0.2 or 0.5% syrup for oral administra- cavity. As a result, when P-gp is expressed at tion; a a high level, the administered drug is part- - 5 or 10 mg tablets for oral administration; ly kept away from the blood stream [51, 70]. - effervescent tablets containing 2,5, 5, 10 Moreover, this kind of action by P-gp across and 40 mg of the substance, for oral ad- the blood-brain barrier is responsible for the ministration; passage of racemic methadone into the brain − 1 ml parenteral vials (10 mg/ml) . tissue, so affecting the binding rate of admin- 44 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 45

istered dosages and the incidence of therapeu- three-phase exponential model gives a better tic effects and side-effects [110]. The effects of fit with actual observed kinetics. Anyway, as orally administered racemic methadone are the concentration in tissues is higher than it is evident within 30’. At dosages between 3 and in plasma, the apparent distribution volume at 100 mg/day, the enteric absorption rate is 92% the steady state (Vss) is greater that the actual [114]. The bioavailability of methadone is af- normal volume (4.2-9.2 l/Kg in the treatment of fected by the first-pass metabolism effect; it heroin addiction and 1.71-5.341 in chronic pain shows a lower rate with respect to other opi- treatment). About 2% of absorbed methadone ates (67-95%). The average time-to-peak is 2.5 remains in the plasma compartment: of this, hours for the syrup form [113] and 3 hours for 70-90% is bound to plasma proteins, while the the tablet form [82]. A single 100-120 mg oral remaining fraction is free, and it is this that is racemic methadone dose causes a 0.5-0.9 mg/l responsible for methadone’s effects. In animal plasma peak, and each 1 mg/kg oral dose in- models, too, racemic methadone is bound to crease corresponds to a plasma peak increase plasma proteins at similar rates [44, 47]. As it is of 0.263 mg/l. Time-to-peak is 30’ in cases of weakly basic, methadone binds with a certain intrathecal administration, 15-20’ for the epi- affinity to α1-acid glycoprotein (AAG), which dural form and 12’ for the intranasal. When has a high affinity site for a variety of small administered intramuscularly or subcutane- basic molecules [94, 112]. AAG concentration ously, the same methadone dose is one and a varies in some physiologic and pathologic half times more powerful and more rapid, but conditions which also affect the bound/free its effects persist for a shorter time. Methadone ratio of methadone. In fact, since AAG concen- 50% lethal dose is 95 mg/Kg in oral form in trations are higher under stressful conditions rats, or 20 mg/Kg intravenously in mice. [84], the free fraction is lower in cancer patients and heroin addicts than in healthy volunteers [2, 16]. One further factor arises from the fact 3.2 Distribution that methadone only binds to the ORM2A al- lelic variant of the AAG, not the ORMF one. Although methadone also binds to albumin As with any other lipophilic substance, to some extent, the variation of albumin levels methadone has a high tissue distribution rate in has an almost negligible influence, if any, on man and in the other animal models that have the concentration of free methadone. In heroin been studied. In pregnant rat females, racemic addicts, sex and weight are responsible for methadone spreads to the brain (4.6), bow- 33% of the inter-individual variability of Vss: els (37.2), kidneys (27.6), liver (44.2), muscles it is, in fact, higher in females, increases with (14.7) and lungs (156.3) – the respective distri- weight and falls when the plasma concentra- bution coefficients are reported here in brack- tion of AAG rises [96]. ets [43]. In other words, methadone spreads to blood and brain tissues only to a small extent, while reaching higher tissue concentrations in 3.3 Plasmatic kinetics kidneys, spleen, liver and lungs. During pregnancy, it spreads through the placental barrier, so that its concentration in the amniotic liquid Consistently with previously described is similar to that in the maternal plasma. Af- mechanisms, the plasmatic clearance of racemic ter single oral doses, its plasma kinetics can methadone after a single dose load takes the be described in terms of a two-phase open form of a biphasic curve: the first phase corre- model. After absorption, about 98% of metha- sponds to distribution to the tissues followed done passes from the central compartment by elimination through the kidneys (t1/2α =14 (plasma) through to peripheral tissues (liver, hrs appr.), while the second phase corresponds spleen, kidneys, and lungs). On the other to its more gradual elimination from tissues hand, in chronic administration regimens, a (t1/2β =54 hrs appr.). The overall result is that 46 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 47 the drug tends to accumulate within tissues (EDDP), which has a half-life ranging between in cases of repeated administration, until an 39.8 and 48 hrs [23]. equilibrium is reached that shows only minor These two metabolites are further trans- fluctuations, mostly depending on whether formed into a common hydroxypyrrolidinic administration takes place once a day or un- product by aromatic hydroxylation. The sec- der a split dose regimen. Once a steady state ond pathway combines N-demethylation has been reached (corresponding to four times with its cyclization to 2-ethyl.5-methyl-3,3,di- the t ½ during which the drug has been ad- phenylpyrrolidine and 2-ethyl-1,5-dimethyl- ministered at stable doses and time intervals) 3,3diphenyilpyrrolidine (EDDP), which has a methadone’s half-life is 28 hrs on average (var- half-life ranging between 39.8 and 48 hrs [23]. ying between 4 and 91 hrs) [111]. On the other These two metabolites are further transformed hand, in chronic regimens methadone has the into a common hydroxypyrrolidinic product property of inducing its own metabolism, so by aromatic hydroxylation. Methadone’s me- that the eventual half-life, after enzymatic in- tabolism is performed by the P450 cytochrome duction has brought it to a stable level, may be system (CYP450), mostly by the isoform 3A4, rather shorter. which is prominently expressed in the bowels and the liver [28, 29, 41]. In addition, isoforms 2D6 and 1A2 play a prominent role in the pro- 3.4 Metabolism cess [32] (Table 1). Recently, on the basis of findings from in vitro studies, it was hypothesized that isofor- The bio-transformation of a drug plays ms 2C9, 2C19 and, especially, 2B6 contribute an important role in its neutralization, by the to the metabolism of methadone [13, 33, 45, 70, synthesis of inactive metabolites. This process 79, 109]. Isoform 2C19 seems to be involved to mostly takes place in the liver, following two a higher degree during pregnancy, and to be main metabolic pathways. The first consists in responsible for the enhanced metabolic rate the para-hydroxylation of the benzene ring, af- that appears during the second and third tri- ter which there is the reduction of the ketonic mesters [80]. Differences in the expression of group, two methylations and conjugation with P450 isoforms are a primary factor affecting glucuronid acid. The second pathway com- the inter-individual variability of methadone’s bines N-demethylation with its cyclization to metabolism. CYP450 can be induced, which 2-ethyl.5-methyl-3,3,diphenylpyrrolidine and means that the clearance of methadone by 2-ethyl-1,5-dimethyl-3,3diphenyilpyrrolidine the cytochrome system is not easy to predict

Table 1. Metadone and P450 cytochrome

Has a primary role in the R-S Met metabolism. CYP3A4 Can be induced during the initial phase of MMT. Has a secondary role in the R-S Met metabolism and, in some cases can inhibit CYP2D6 the enzyme. CYP1A2 CYP2C9 Are isoenzymes probably involved in the R-S-Met metabolism. Their role is CYP2C19 still controversial. CYP2B6 May play an important role in the R-S Met metabolism. References: [13, 33, 45, 70, 79, 80, 109, 116]

Leavitt, Addiction Treatment Forum (modified) 46 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 47

on general grounds. In a steady-state condi- which is fluvoxamine. The combination of flu- tion, heroin addicts develop a metabolic rate voxamine treatment with racemic methadone that is three times what it was at the time of causes a major increase in both R-Met and treatment initiation (first dose load)[96]. Since S-Met plasma levels, so suggesting that CYP methadone can, over time, induce its own me- A12, unlike 2D6, is equally responsible for the tabolism, long-term treatment may require metabolism of both enantiomers. dose increases in order to maintain the previously effective plasma level. The 3A4 induction apparently causes a 15% reduction in the 3.5 Elimination average R-Met plasma level, although the level of 3A4 expression varies by as much as 11 or 30 times from one individual to another, in Methadone hydrochloride is mainly elimi- the bowels and the liver, respectively. The 2D6 nated through the kidneys. As much as 15-60% isoform is expressed by 90-95% of Caucasian of a single dose is excreted in urine over the people. Those who lack this isoform (due to next /24 hours. On average, 20% of the admin- the absence of functional gene sequences) are istered dosage is excreted unchanged and 13% referred to as low metabolizers, whereas those as EDDP. After repeated administration that who have a normal activity (one or two cop- kind of ratio is inverted [9]. Due to its lipophilic ies of functioning genes) are labelled as exten- and basic properties, pH changes are crucial sive metabolizers. The characterization of the in determining the rate of methadone excre- patient’s metabolic status may be performed tion: in fact, over a pH of 6, excretion through either with genetic or phenotypical methods. the kidneys falls to only 4% of the total. On Among extensive metabolizers, a subgroup of the other hand, when pH is over 6, that rate ultrarapid metabolizers, expressing three or may be as high as 30% [6, 55, 56]. In compar- more gene copies, can be identified by genetic ing situations in which pH values are equal, probing: this subpopulation is 1.5% of the to- the interindividual variability in the clearance tal population in Germany, 7% in Spain and of methadone through the kidneys is reduced 29% in Ethiopia. The same metabolic system by 27% [96]. As for liver excretion, methadone is shared by a variety of compounds, and can- can be classified as a drug with a low rate of not be induced: some commonly used drugs, hepatic clearance, around 3.1 ml/min/kg in such as fluoxetine and paroxetine, can inhibit heroin addicts or 1.5 ml/min/kg in chronic its activity. Methadone itself can cause 2D6 pain patients. Hepatic clearance also depends enzymatic inhibition to a certain extent [116]: on the free rate of plasma methadone and on extensive metabolizers who have added fluox- intrinsic hepatic clearance, which means the etine or paroxetine to an ongoing methadone level of metabolic activity. As observed previ- regimen show an increase in R-Met (but not ously with reference to AAG levels, the rate of in S-Met) plasma levels with respect to the plasma protein binding also affects the value of period before the introduction of the antide- hepatic clearance [2, 16]. Methadone is present pressant [10, 30]. This finding suggests than in bile, too: as much as 20-40% of a single dose 2D6 is somewhat stereo-selective for R-Met. In is excreted with feces, after its metabolization low metabolizers, amytriptiline, which is one and glucuronidation. In some patients, metha- 2D6 substrate, reduced methadone clearance, done reaches higher concentrations in sweat and methadone itself reduces that of desimi- than in urine. In cases of kidney failure, the pramine (another 2D6 substrate), probably interval between administrations should be through a competitive mechanism. CYP 1A2 is adequately widened to allow for the degree of involved in the metabolism of several drugs, functional impairment. On the other hand, in including clozapine and olanzapine. Its activi- stable hepatic disorders with different degrees ty can easily be probed by caffeine administra- of severity, cirrhosis included, dosage sched- tion, and is induced by tobacco smoking and ules may be maintained. Racemic methadone inhibited by some drugs, the most common of is also excreted through the breasts: almost 3% 48 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 49 of the daily dose administered to a mother is of a series of receptor-dependent K+ channels taken in by her newborn through her milk. In and the blocking of voltage-dependent Ca2+ 6 cases out of 10 this quantity is not enough - channels. This cascade takes place around to prevent the onset of neonatal withdrawal. a relatively rigid self-regulating pathway in- The data now available support the trend not volving the receptor-coupled protein-kinase to prohibit or avoid breast-feeding by racemic units (GRK), by its recruitment, consequent methadone-treated mothers. receptorial phosphorylation and eventual interaction with β-arrestin. The µ receptor is the main feature responsible for several opioider- 4. Neurochemical properties gic effects, and its stimulation directly produces analgesia, respiratory depression, tolerance to narcotic effects and addiction. In MOR1 Like all other opioidergic drugs, metha- knockout mice (expressing no MOR), the lack done exerts its action by interacting with a sys- of µ receptors renders these mice refractory to tem of three receptors, which, taken together, the main effects of morphine, both those with are referred to as “opioid receptors”; they are a therapeutic value and those that can be con- linked to G0 or Gi proteins, and are normal- sidered toxic: the same genetic product is thus ly stimulated by endogenous opioids. These responsible for an ensemble of effects. As ex- opioid receptors are commonly indicated by pected, both analgesia and morphine toxicity the Greek letters µ, κ and δ or by the acronyms persist in KOR1-knockout mice and DOR1- OP3 or MOR for µ, OP1 or DOR for δ and OP2 knockout ones [74]. Although only one gene or KOR for κ [4]. Due to its negligible affinity encoding for the µ receptor has been cloned for δ (IC50 nM 752 ± 686) and for κ (IC50 nM (located on chromosome 6 and comprising 1817 ± 573, in both cases in the bovine caudate 4 exons and 3 introns), some variants were nucleus) racemic methadone can be classified described, dependent on the use of selective as a selective agonist of µ receptors (IC50 nM ligands such as β-funaltrexamine (β-FNA), 5. 73 ± 1. 5 for µ1 and 10. 0 ±3.1 for µ2 in the naloxonazone, naloxonazine and 3-methox- bovine caudate nucleus) [68]. It was possible ynaltrexone. β-FNA produces a dose-depend- to map µ opioid receptors in thirteen brain ent stimulation of the receptor, and is used to areas of healthy individuals who had had a recognize its presence and involvement in any 8 F-Cyclofoxy probe administered to them, by supposed effect [3]. Unlike β-FNA, naloxazone using Positron Emission Tomography (PET) and naloxonazine prevent some of the effects brain scan sequences. In a descending order that are mediated by morphine, but not others, of density values: thalamus, amygdala, cau- since they interact selectively with the µ1 vari- date, insula, anterior cingulate and putamen, ant. Insensitivity to naloxonazine is responsi- followed by medial frontal cortex, parietal ble for respiratory depression and the inhibi- cortex, cerebellum, lower temporal cortex, tion of bowel motility, suggesting that possible hippocampus, white substance and occipi- µ1-selective agonists may not share these two tal cortex [59]. The human µ receptor unit is important collateral effects with morphine. a surface protein of 67kDa consisting of a se- The µ1 subtype, which is exclusively supraspi- quence of 372 aminoacids organized in seven nal, is located in the periacqueductal grey sub- hydrophobic transmembrane (TM) domains, stance, the medial hypothalamus and the great with short extra- and intracellular loops. The raphe nucleus. It mediates analgesia, psycho- N-terminal segment is extracellular, whereas motor retardation and the increased secretion the C-terminal segment is intracellular. Lig- of prolactin. The µ2 subtype has a similar dis- ands interact with the extracellular portion tribution, but is found in the spinal cord, too. of the receptor, and induce the activation of When coupled with µ1 it mediates analgesia intracellular G proteins. The activation of G and is the one feature responsible for constipa- proteins causes neuronal inhibition by the re- tion, respiratory depression, and the improved duction of adenyl-cyclase activity, the opening muscular tone of the bladder and Oddi’s 48 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 49

sphincter. Studies on the properties of mor- its non-competitive antagonism with respect phine’s metabolite, morphine-6-β-glucuronide to the NMDA receptor. The inhibition curve (M6G), made things even more complex [86]: and its Ki for the displacement of its ligands in fact, M6G binds to µ receptors selectively are very similar to those of dextrometorphan, and with a high affinity. Its pharmacologi- which is a typical NMDA antagonist. In par- cal profile is close to that of morphine and its ticular, Ki of R-Met is µmol/L 3, 4 and that of analgesic effect is antagonized by naloxona- S-Met is µmol/L 7, 4. NMDA antagonists are zine. However, 3-methoxynaltrexone is effec- characterized by the property of preventing tive against M6G-mediated analgesia at doses the onset of tolerance to morphine without which are ineffective against morphine-medi- interfering with its analgesic effects. The non- ated analgesia. On the other hand M6G also competitive antagonism exerted by R-S-Met exerts analgesic effects in CXBK mice, which should therefore favour the stability of its anal- are refractory to morphine [18]. These data gesic action in protracted treatment regimens, lead to the conclusion that another variant ex- and would explain its negligible abuse poten- ists, apart from the already known µ1 e µ2 ; this tial, together with the absence of complete tol- third variant appears to mediate an analgesic erance to some of its effects during long-term effect through M6G or other 6-substituted an- MMT at stable dosages [25]. Lastly, racemic alogues, such as heroin or 6-acetylmorphine methadone interferes with the reuptake of [95]. One possible explanation is the existence serotonin (5HT), and, to a lesser extent, with of splicing variants from the same gene, exon that of norepinephrine (NE) [20]. In rat cortical 4 being replaced by other supplementary ex- synaptosomes racemic methadone has a ki of ons [85]. Also, two receptors may interact with µM 0. 27 (±0. 038) against 5HT reuptake, which each other and build a µ/µ or µ/δ complex, means a level close to that of desimipramine which could comprise various µ subtypes with (µM 0, 43±0. 037) and minimal in comparison partly dissimilar pharmacological properties. to fluoxetine’s µ( M 0. 049±0. 0046). This prop- Studies have always indicated methadone’s erty is not maintained, however, after chronic strong affinity for its receptor, but some differ- exposure, at least in the rat model [46]. ences have emerged. In Blake’s study, based on the use of µ-transfected HEK 293 rat cells, methadone has a lower affinity than morphine 5. Specificity of the methadone (Ki 3, 51nM vs. 1, 41nM, respectively) [11]. On µ-receptor interaction the other hand, in Raynor’s study on COS-7 cells transfected with rat µ receptors, methadone has a higher affinity than morphine (Ki 0, 78nM vs. 14nM, respectively) [90]. In this 5.1 Receptorial site binding latter study, methadone had a negligible (Ki ≥1000nM) affinity for δ and for κ receptors. The same authors showed that methadone At oral dosages between 80-150 mg/day, as and other opioid drugs have a higher affinity administered to tolerant individuals, racemic for human µ receptors in transfected COS-7 methadone does not saturate available recep- cells [91]. In conclusion, racemic methadone is tors: in fact, the self-administration of heroin a complete agonist of the µ receptor popula- at doses higher than those usually employed tion, which swings between an available state can produce narcotic effects. Likewise, the and an inactive state. The affinity is higher for administration of morphine, hydromorphone the active form than for the inactive. Metha- or fentanyl upon methadone for pain control done raises the absolute number of active (or is effective in counteracting break-through activated) receptors (i.e. phosphorylated) and pain peaks. A study was conducted employ- 18 exerts maximal receptor-mediated effects, in a ing F -Cyclofoxy in MMT patients taking dose-dependent manner. Another distinctive dosages of 30-90 mg/day and plasma levels feature of R-S-Met with respect to morphine is of 127-673 ng/ml (350 ng/ml on average): 50 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 51 a PET scan was performed 22 hrs after daily the mechanism of tolerance and the distinc- oral dose, and showed a 19-32% reduction in tive features of each opiate agonist: on general the expected binding rate in all the brain ar- grounds, it is agreed upon that tolerance is a eas examined (thalamus, amygdala, caudate result of a range of pharmacological and be- nucleus, anterior cingulate cortex, putamen) havioural mechanisms, different circuits being with respect to the brain of healthy controls involved, beyond the known roles of opioid [59]. In other words, approximately 24 hours receptors. On the other hand, it is likely that after the previous administration, methadone methadone tolerance is also due (quite prob- has saturated 19-32% of µ receptors, including ably, mainly due) to variations in the level of those which have been internalized. The rate µ receptor expression [117]. The internaliza- 18 of F-Cyclofoxy binding reduction, though tion of receptors was long considered to be the limited, is significantly related to plasma lev- primary mechanism inducing change in the els of racemic methadone. As a result, 60-80% sensitivity of neurons to agonists. Research on of available µ receptors are free to interact populations of native neurons or transfected with endogenous opioid peptides. Since opi- cell lines has shown that a cascade of events oid peptides are involved in the control of the leads to the rapid desensitization and endocy- immune and endocrine systems, with special tosis of e µ receptors. The trimeric G protein, regard to the hypothalamic-pituitary-adrenal which comprises α, β and γ subunits, becomes axis, it can be hypothesized that the normaliz- detached from the receptors: while the α subu- ing effect of MMT on these functions depends nit inhibits adenyl-cyclase activity, the β/γ enon the low occupancy of receptors at thera- semble interacts with K+ and Ca++ channels, peutic dosages. In other words, methadone at and is linked to a GRK-specific kinase which dosages high enough to suppress the craving phosporylates the µ receptor. The phosphor- for heroin tends to have a rather conservative ylated receptor interacts with a cytosol protein effect on the physiology of endogenous brain called β-arrestin, which becomes bound to it opioid systems. and prevents further interactions between the receptor and the G protein. The arrestin-receptor complex is internalized by a clatrine-me- 5.2 Tolerance and endocytosis diated process of endocytosis, and is stored in the intracellular endosomal compartment. Afterwards, the receptor may be dephospho- Continued opioid use is characterized by rylated by a phosphatase and be placed back the onset of pharmacodynamic tolerance, pos- within the cell membrane, which restores the sibly combined with a pharmacokinetic com- neuron’s sensitivity. Otherwise it may be cat- ponent, at least for some compounds. Due to abolized in lysosomes without being dephos- tolerance, when drugs are used continually, phorylated, which would correspond to a they lose their effect, so that higher dosages down-regulation of sensitivity. Opioids differ are needed to restore the desired effect. Toler- in their capacity to induce receptorial endo- ance also involves some therapeutic effects, cytosis, even if the pharmacological peculiari- such as analgesia, as typically happens in cases ties that account for these differences are not of pain treatment through the chronic admin- clear. Etorphine, surfentanyl, methadone and istration of morphine [54]. Tolerance to mor- DAMGO produce endocytosis to a greater phine does not depend on increased biotrans- extent than codeine, buprenorphine, heroin, formation, but is typically pharmacodynamic. morphine-6-glucuronide and, especially, mor- Cross-tolerance is one of the key phenomena phine. DAMGO (Tyr-D-Ala-Gly-MePhe-Gly- on which the agonist treatment of heroin ad- ol-enkefaline) is similar to endogenous opioid diction is based. Fortunately, tolerance can be peptides, and is referred to as a term of com- forestalled or can be made incomplete by the parison with exogenous opioids. Some studies anticraving effect of opiate agonists. A variety have referred to the capacity of opioid agonists of strategies can be resorted to in investigating to induce endocytosis as an inverse function of 50 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 51

the so-called RA/VE ratio, indicating the rela- sponse to methadone exposure is significantly tionship between relative G protein-related ac- lower, which may reflect its greater capacity tivity and endocytosis. Morphine has a higher to induce endocytosis. The agonist-mediated RA/VE, which means it produces a high level activation of receptors, and then their desensi- of G protein activation coupled with a low µ tization and internalization, seem to constitute receptor endocytosis. By contrast, endorphins the three physiological phases of a functional and opioids such as etorphine and methadone dynamic cycle of normal opioid receptors. induce endocytosis to a greater extent with re- Tolerance to opioids may develop due to an spect to their capacity to produce intracellular abnormal activation profile, rather than to the signal transmission (low RA/VE) [38]. More down-regulation phenomenon alone. Abnor- recently, it has been proved that the capacity mal activation would produce a response that of opioids to activate G-protein-dependent differs from the normal functional recycling cascades, and thus to induce rapid desensiti- of receptors. In conclusion, methadone seems zation, is a separate property with respect to to resemble endogenous opioids in the profile their capacity to cause receptor internalization. that emerges from its receptor interactions; Bearing in mind that DAMGO’s properties in this may account for some of its therapeutic both cases are 1, the values for methadone and properties and its favourable long-term inter- morphine are 0.98 and 0.59, and 0.58 and 0.07, actions with the opioid system. respectively [14]. In other words, morphine’s effectiveness in causing internalization (0.07) is far lower than DAMGO’s (0.98) and metha- 6. Specificity of stereoselective done’s (0.59), and does not reflect its capacity enantiomers to activate G-proteins and promote desensitization (0.58). While it was previously believed that endocytosis is the reason for pharmaco- Absorption and bioavailability are similar dynamic tolerance, lately evidence has been for R-Met and S-Met [67], although the former growing that internalization may play a role is twice as strongly lipophilic as the latter (57 in counterbalancing the development of toler- of oil/water coefficient vs. 28). The difference ance [38]. Moreover, morphine and heroin are in elimination half-life between the two enan- not only capable of inducing tolerance, but are tiomers may depend on a different binding to strongly addictive. Apart from this problem, plasmatic proteins (14% for R-Met vs. 20% for methadone, which also produces endocyto- S-Met) [34]. Although that is not a large dif- sis, does induce a lower degree of tolerance, ference, it may be enough to account for the and is effective in the treatment of heroin ad- fact that R-Met’s half-life is 38 hrs vs. 29 hrs. diction. It has been hypothesized that those for S-Met. Average clearance of R-Met is 158 opioid agonists which induce a higher degree ml/min, while S-Met’s is 129 ml/min. Appar- of tolerance do so because they endure longer ent Distribution Volumes are quite variable, in their interactions with the receptor: on this around 7 L/Kg for R-Met and 4 L/Kg for S. view, tolerance develops as a consequence of R-Met has a double affinity for the µ with re- prolonged interaction with receptors, whereas spect to racemic methadone, similar to that endocytosis counterbalances this property of morphine. As for the µ1, subtype, it is ten by reducing the duration of ligand-receptor times higher for S-Met in bovine caudate that interaction, eventually limiting the degree of for R-Met (IC50 of nM 3, 01± 0, 18nM 26, 4 ± acquired tolerance. Chronic morphine treat- 3, 7) while values for µ2 subtype are nM 6, ment, both in cell lines and animal models, is 94± 1, 3 for R-Met and nM 87, 5± 9, 0 for S- associated with a compensatory up-regulation Met [68]. Consistently with these premises, of cAMP synthesis, which may be one conse- R-Met is 50 times more analgesic than S-Met quence of prolonged µ stimulation coupled [41]. R-Met prevents the onset of opiate with- with a low capacity of that ligand to induce drawal even at low dosages, while S-Met does endocytosis. On the other hand, the cAMP reso when administered at dosages of 650-1000 52 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 53 mg/day. S-Met has the distinctive property of 7. Side effects its non-competitive antagonism to the NMDA receptor, which accounts for its capacity to an- tagonize NMDA-induced hyperalgesia and On the whole, MMT is well tolerated from the development of morphine tolerance, after a long-term perspective [83]. Possible side-ef- systemic or intrathecal administration. R-met fects which may develop and endure during is therefore able to replace the racemic form in opiate agonist treatment regimens depend on the treatment of heroin addiction and pain, but a variety of factors, including duration of treat- the racemic formulation does show some ad- ment, dosage, the route of administration, age, vantages from a long-term perspective. S-Met concurrent organ impairment and combined alone, or when combined with morphine, may treatments or psychoactive substance use. be effective against neuropathic hyperalgesia, Transient adverse events such as rash or nettle or in increasing the analgesic effect in chronic rash may happen in cases of subcutaneous or morphine administration regimens [25]. As intramuscular injection. Frequently reported previously mentioned, racemic methadone in- effects include somnolence, hypotension, bradycardia, nausea, vomiting, swelling of hibits the reuptake of serotonin (Ki of µmol/L 0, 014 for R-Met and µmol/L 0, 992 for S-Met) hands or (more frequently) feet, disorders involving emetics, menstrual abnormalities, and norepinephrine (Ki of µmol/L 0, 702 and µmol/L 12, 7 respectively). In other words, it anorgasmia or delayed achievement of sexual is 5 times more selective for serotonin than for orgasm, insomnia, constipation or excessive norepinephrine, as R-Met has a greater affinity sweating. Since tolerance develops at variable for both uptake systems [20]. S-Met is effective terms for different symptoms, a low baseline against coughing in the absence of any risk tolerance is usually predictive of more severe of producing respiratory depression. Several side-effects in the early phases of treatment. It studies agree on the fact that methadone's ef- is very unlikely that side-effects will be so infectiveness depends on the administration of tense as to require treatment termination. They certain dosages. The higher the dosage, the usually improve with dose adjustment or tran- lower the risk of treatment dropout, so dosage sition to an oral route of administration, al- adequacy is the main factor affecting the rate though some cases may require symptomatic of therapeutic failure. Although 100 ng/ml treatment. Sweating, constipation, sexual dys- was initially thought to be enough to ensure functions and sleep disorders tend to endure a good outcome, a stable response requires a in the long term [62]: in patients taking dos- level of 400 ng/ml. Recently, a correlation be- ages between 80 and 120 mg/day, sleep disor- tween R- and S-Met concentrations and treat- ders, constipation and loss of libido are still ment response has been defined: 250 ng/ml of present after three years in as many as 15-20% R-Met are usually predictive of a response to of cases, while excessive sweating persists as treatment. Nevertheless, effective plasma con- often as in one case out of two. Sedation is fre- centrations of R- and S-Met, in cases where oral quently reported in the early phases of treat- doses of racemic methadone are equal, and af- ment, after the first few days of steady admin- ter accounting for body weight, vary widely istration. In these circumstances, sedation between individuals –up to 16/17 times in the depends on the progressive increase of plasma case of R-Met. In other words, oral dosages concentration due to methadone’s longer half- corresponding to effective plasma concentra- life, which corresponds to a rising narcotic ef- tions do vary widely, and may also depend on fect in non-tolerant individuals. Temporary further variables, such as combined treatments dose reduction or splitting the dose into two or that give rise to pharmacokinetic interactions. three fractions during the day may be suffi- For some individuals 55 mg/day may produce cient to counteract the sedating effect of peak- effective plasma concentrations, whereas over ing methadone. Once sedation has been extin- 900 mg/day may be required in other subjects guished, one may proceed with further dose [31, 32]. increases as requested by treatment goals. In 52 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 53

other circumstances, sedation may be induced MMT is not related to abnormalities in im- by a combination of alcohol with CNS depres- mune functioning [8, 21]. Methadone is re- sants, bearing in mind that these depressants sponsible for some changes in endocrine func- should not be co-prescribed to such patients tions: during the first three months of treatment anyway. As with other opiate agonists, another a reduced response to metopirone due to the effect of methadone is that it reduces bowel se- depletion of ACTH and cortisol can be ob- cretion and motility, so causing constipation served [22, 61, 62, 65]. Abnormalities of this and/or awkward defecation due to the dehy- kind are fully reversible during treatment dration of feces. The development of tolerance within four to five months after treatment ini- to opioid-induced constipation is quite slow, tiation. As for sexual hormones, LH levels tend so that constipation is usually a persistent to fall, whereas FSH has no predictable varia- side-effect. Diet supplements or changes, lu- tions. After one year of treatment, LH and FSH brication of bowels or pharmacological stimu- values are expected to fall to within normal lation of motility may be beneficial. Nausea ranges, while testosterone levels may continue and vomiting, which are quite rare in untreat- at lower levels than normal. Delayed ejacula- ed heroin addicts, depend on the stimulation tion, which is complained about by quite a few of the Chemoreceptor Trigger Zone (CTZ) but patients, may be handled by shifting the time also on the alteration of vestibular sensitivity, of dose administration away from times of bearing in mind that the incidence of this dis- sexual intercourse, according to individual order is greater in outpatients. In some cases, habits. Methadone causes an increase in prol- antiemetic drugs may be a rapid solution to actin levels during the first 2-8 hrs after ad- acute symptoms. In elderly patients urinary ministration. Differently from what can be ob- retention may develop, due to the increased served with antipsychotics, a flattened contraction of the inner urethral sphincter, so circadian secretion rhythmhas been docu- that untreated prostatic hypertrophy and ure- mented, which does not seem reversible while thral stenosis are not compatible with metha- on treatment [65]. High prolactin levels may done treatment.Some patients experience contribute to sexual dysfunctions, and also weight gain, which is usually related to im- cause breast hypertrophy and galactorrhea. proved life quality but may also be a sign of Bromocriptine may be useful in this case. No increased alcohol consumption. Methadone is teratogenic effects have been attributed to not toxic to the liver, and no abnormalities of methadone, nor have any been attributed to liver function are expected during methadone morphine or heroin to date [15]. Nevertheless, maintenance, apart from those depending on no appropriate studies on its possible muta- concurrent liver disorders, which may worsen genic or teratogenic properties have been per- independently [64]. A history of acute hepati- formed yet. Infants of mothers who use street tis should be regarded as a reason for starting heroin have a 50% likelihood of being born un- methadone treatment as a matter of urgency, derweight. Low birth weight (below 2500 gr) since it usually indicates a higher risk of toxic and a shorter head circumference were report- effects caused by a lack of hygiene in injection ed in newborns from mothers under R-S meth- practices. Methadone increases the liver syn- adone treatment. On the other hand, metha- thesis of albumin, which is even greater in al- done treatment is related to a decreased cohol-using patients [60, 97]. Thyroxin and incidence of spontaneous abortion, premature Thyroxin-binding-globulin levels are higher discharge or hyaline membrane disease. De- during MMT, but no reduction of free T4 was spite a report that 33% of a group of newborns observed [62]. Possible higher values of total were born underweight, and that 60-70% globulins or IgG and IgM may derive from showed signs of opiate withdrawal (neonatal pre-existing liver diseases. False positive re- withdrawal syndrome), no clear correlations sults at tests for syphilis were observed [65] in with dosage and treatment status were defined over 30% of MMT patients, whereas absolute [15]. Residual irritability, restlessness and epi- lymphocytosis can be found in 20%. However, sodes of desperate crying may recur, though to 54 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 55 a milder extent, throughout the first two or 8. Potentially lethal adverse events three months of life. Between 4 and 6 months of age those symptoms usually fade completely, and the rhythm of growth accelerates with Acute methadone intoxication involves the respect to normality, so that by 12 months automatic regulation of breathing, and is char- those newborns can be expected to be normal acterized by the triad: miosis, coma and respi- as to weight and height, that is, similar to in- ratory depression. fants of mothers without any history of addic- Intoxication may happen accidentally, as tion. Head circumference still remains around when children ingest amounts of methadone the 25th percentile at 6 months, and takes over left unlocked and within their reach. Oth- 24 months to normalize. During the first two erwise, it may be due to a deliberate suicide years, the course of mental and psychomotor attempt or an impulsive act of self-injury or development is normal, apart from a tendency suicidal behaviour by tolerant individuals. not to express one’s needs verbally or respond During the induction phase of MMT, patients to verbal requests. The developmental out- run an overdosing risk which is 6 to 7 times come does not seem to relate to the duration of that of untreated heroin addicts, and 42% of dosage of methadone treatment, or to neonatal racemic methadone-related deaths take place withdrawal severity or APGAR score at 5’ in the first week of treatment [17, 118]. Le- minutes after birth. Attention and language thal accidents often happen in the first three abnormalities fade by the time children start to days [108]. That is why it is advisable not to go to school, since comparisons with control administer more than 30 mg/day on the first children show minimal differences. In general, few days, bearing in mind that the repeated children of addicted parents show rigid tem- administration of a stable dose will result in peramental features, so that the initial features a progressive increase in peak levels for the are more likely to persevere unchanged first 4-5 days, that is, before the steady state throughout the process of development. Some is achieved. Urinalysis before admission by experience regular neurological and behav- single-use sticks for morphinuria with a cutoff ioural growth, and maintain the acquired stage level of 2000 ng is advisable as a rule to check of development later on, while others show anamnestic data and identify low-tolerance in- early defects which are likely to persist dividuals: in fact, some of those who have un- throughout the process of growth. Those who dergone self-handled detoxification may still have not shown neurological or behavioural have intense dysphoria, insomnia or diarrhea, abnormalities by 36 months of age are charac- despite the loss of tolerance, a factor that may terized by a higher cultural level of the mother itself lead to overmedication. Respiratory de- and a stable family environment. On the whole, pression by methadone develops within 2-3 MMT should be considered the standard treat- hours after intake, or within a few days after ment for pregnant heroin addicts [80]. In treat- treatment initiation. In cases of intoxication, ing pregnant heroin addicts, a couple of issues naloxone administration may quickly restore call for definitive clarification: neonatal with- an adequate breathing function, and fluma- drawal syndrome and methadone addiction. zenil may be useful, too. The patient must be Neonatal withdrawal is elicited by the abrupt hospitalized and closely monitored, repeating interruption of methadone supply to the fetus naloxone administration throughout the first after the development of tolerance through 48 hours, in order to avoid re-intoxication af- regular exposure throughout pregnancy. Its ter the fading of short-term antagonism from distinctive features are its delayed onset and a single naloxone dose. Recently, authors have prolonged course. As for methadone addic- expressed concerns about the incidence of tion, authors agree that R-S methadone, when methadone-related ventricular arrhythmias administered orally as in MMT for heroin ad- [69, 115]. In January 2004 the Swiss Regulatory diction, has no addictive liability. Agency indicated a risk of QT lengthening in patients receiving methadone for the treat- 54 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 55

Table 2. Substances which can produce opiate withdrawal when combined to methadone (modified from Leavitt, Addiction Treatment Forum)

Drug name Notes/References Buprenorphine, bu- Displace methadone from µ receptors [26, 57]). torphanol, dezocine, nalbufine, pentazocine Naltrexone, nalmefene, Displace methadone from µ receptors [26, 57, 102]. naloxone Tramadol Displace methadone from µ receptors [105].

Table 3. Substance which can interfere with methadone’s metabolism and produce unpredicta- ble effects when combined to it (modified from Leavitt, Addiction Treatment Forum)

Drug name Notes/References Alprazolam, alorazepate, estazolam, fluraze- Potential interactions due to a common meta- pam, midazolam, triazolam bolic pathway through P450 [52]. May increase methadone’s depressant effects on the CNS [102]. Cannabis Presumable interaction due to a common CYP3A4metabolic pathway [52]. Didanosine Reduces DDL concentration [89], not observed with gastro-resistant capsules [36, 42] Dextrometophan Methadone may increase its plasma concentration and effects [71]. Alpha-interferon + ribavirine Adverse events may mimic opiate withdrawal, so that methadone dose increase may be decided on a wrong basis [99, 103]. Monoaminooxidase inhibitors Potential adverse reactions reported [78]. Nifedipine Methadone may increase nifedipine’s concentration [71, 102]. Alfentanil, idrocodone, fentanil, meperidine, Possible enhancing effects due to common me- morphine, oxycodon, propoxyhen tabolic pathways. Long half-life metabolites of meperidine and propoxyphen may reach toxic concentration [52]. Stavudine (d4T) Methadone reduces d4T plasma level. d4T has no effect on methadone’s plasma level [89]. Amitriptiline, desipramine, imipramine, nor- Association with methadone increases TCA triptiline toxicity [26, 88, 92]. TCA have a variable effect on methadone’s plasma level [33, 79, 102].

Zidovudine (AZT) Methadone increases AZT level by 40% ; adverse events of AZT are more likely [76]. 56 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 57

Table 4. Substances which can decrease methadone’s plasma level and/or diminish its effects (modified from Leavitt, Addiction Treatment Forum)

Drug name Notes/References Abacavir (ABC) Methadone’s level is decreased, and so is the peak of ABC [49]. Amprenavir Induction of CYP3A4 may reduce methadone’s plasma level [19, 33]. Amprenavir’s level may also be reduced for the same reason [36] Butabarbital, mefobarbital, phenobarbi- Induce P450 [63]; Phenobarbital may cause a rapid tal, pentobarbital, secobarbital, others decrease of methadone’s concentration [49]. Usually methadone dose increase is required. Carbamazepine A strong induction of CYP3A4 may cause withdrawal . Valproate does not have a similar effect and may be a safe alternative [12, 98]. Cocaine Increases methadone’s dismission [79]. Desametasone Induces CYP3A4 [33]. Efavirenz Methadone withdrawal is common due to CYP3A4 induction. After three weeks of treatment with efavirenz, if methadone dose is not appropriately increased, the peak concentration of RS-Met is reduced by 48% [33, 75]. Ethanol in chronic exposure Induces P450 [88]. Fusidic acid Induces CYP3A4 [33, 106]. Heroin Reduces the free fraction of methadone [79]. Lopinavir + ritonavir Withdrawal may develop and dose increases be required. Ritonavir alone fails to cause a similar effect [19, 77]. Nelfinavir Induces CYP3A4 and P-gp [33], but withdrawal is rare [77]. Nelfinavir’s level too may be slightly decreased [19]. Nevirapine Induction of CYP3A4, which may lead to withdrawal [33]. Fenitoina Rapid reduction of methadone due to CYP3A4 induction [33, 63]. Rifampicine and rifampicine/isoniazid Induce P450 and may cause severe withdrawal [33, 63]. Such effects are not produced by rifabutin [49, 71]. Spironolactone Induces CYP3A4 [33]. St. John’s wort (hypericum perforatum) Induces CYP3A4; methadone’s level is reduced by 47% [35, 100]. Tabacco (habitual smokiong) Most reports indicate reduced methadone’s effectiveness in habitual smokers [79, 104]. Urinary acidifiers (e.g. ascorbic acid) The excretion of methadone through the kidney occurs more quickly at acid pH values [81, 102]. 56 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 57

ment of addiction or pain. Between 1990 and and electrolyte abnormalities. Several patients 2003, out of a total of 272 methadone-related were HIV-positive or suffered from vital hepa- adverse event reports, physicians reported 42 titis. In some cases interaction with antidepres- cases of arrhythmia in 25 patients (20 males sants, antimicrobial drugs or protease inhibi- and 5 females, aged 40 on average) who had tors was plausible. The OMS database includes had a prescription of methadone for addiction 14 cases of torsade de pointes and 16 cases of treatment. Between April 2001 and August QT lengthening, mostly reported in the USA. 2003 7 torsade de pointes and 14 QT prolon- The Italian Ministry of Health recorded just gation cases were reported. Daily methadone one case of ventricular tachycardia in a male dosages ranged between 40 and 1400 mg/day. patient taking methadone as a supplementary In almost all these cases, known risk factors medication. Patients taking racemic metha- for arrhythmias were documented, such as a done who are also affected by cardiac diseases long QT, atrio-ventricular delay, bradycardia (such as cardiac failure, bradycardia, left ven-

Table 5. Substances which can increase methadone’s plasma level or enhance its effects (modified from Leavitt, Addiction Treatment Forum)

Drug name Notes/References Cimetidine Inhibits P450 [12, 102]. Ciprofloxacine Inhibits CYP3A4 and CYP1A2 [33, 53]). Delavirdine Inhibits CYP3A4 [49]. Diazepam unknown mechanism [33]. Sporadic reports [71]. Diidroergotamine Inhibits CYP3A4 [106]. Disulfiram Reported sedation after high disulfiram doses [12]. Ethanol in acute axposure Competition for P450 [88]. Fluconazole Inhibits CYP3A4 [33]; Increases methadone’s plasma level [49]; Uncertain clinical relevance [71]. Grapefruit Inhibits bowel CYP3A4 [51] and Pg-P [33]. This effect is not observed with other fruit’s juices [58]. Ketoconazole Inhibits CYP3A4 [33]. Eritromicine, claritromicine Strongly inhibits CYP3A4. No cardiac or metabolic effects are reported for azitromicine [33]. Moclobemide Inhibits CYP2D6 and CYP1A2 [33]. Herbal products such as :uncaria Strongly inhibits CYP3A4, though no specific reports tomentosa, matricaria recutita, echina- about methadone are available [100, 106]. cea angustifolia, hydrastis canadensis, quercetina Omeprazole May obstacle methadone’s absorption [102]. Fluoxetine, fluvoxamine, paroxetine, Inhibits mainly CYP2D6 but also CYP3A4 and nefazodone, sertraline CYP1A2 [33, 71, 92]. Troleandomicine Inhibits CYP3A4 [106]. Urine-alkalinizers (e.g. sodium bicar- Alkaline urine pH reduces the elimination of metha- bonate) done through the kidneys [57, 102]. Verapamil Inhibits CYP450 [71] Substance influencing cardiac conduction to a variable extent with potential arrhythmic properties in combination with methadone. 58 · CHAPTER 1.6 pharmacology and neurochemistry of methadone · 59

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binding to orosomucoid (a1-acid glycoprotein): 107. VIGANO A., FAN D., BRUERA E. (1996): determinant of free fraction in plasma. Clin Pharmacol lndividualized use of methadone and opioid rotation Ther. 29 211-217. in the comprehensive management of cancer pain 95. ROSSI G. C., BROWN G. P., LEVENTHAL L., YANG associated with poor prognostic indicators. Pain. K., PASTERNAK G. W. (1996): Novel receptor 67:(1) 115-119. mechanisms for heroin and morphine-6b-glucuronide 108. WAGNER-SERVAIS D., ERKENS M. (2003): analgesia. Neurosci Lett. 216 1-4. Methadone-Related Deaths Associated with Faulty 96. ROSTAMI-HODJEGAN A., WOLFF W., HAY A. W. Induction Procedures. J Maint Addict. 2:(3) 57-67. M., RAISTRICK D., CALVERT R. (1999): Population 109. WANG J. S., DEVANE C. L. (2003): Involvement of pharmacokinetics of methadone in opiate users: CYP3A4, CYP2C8 and CYP2D6 in the metabolism of characterization on time-dependent changes. Br J Clin (R)- and (S)- methadone in vitro. Drug Metab Dispos. Pharmacol. 48 43-52. 31 742-747. 97. ROTHSCHILD M. A., KREEK M. J., ORATZ M., 110. WANG J. S., RUAN Y., TAYLOR R. M., DONOVAN SCHREIBER S. S., MONGELLI J. G. (1976): The J. L., MARKOWITZ J. S., DEVANE C. L. (2004): Brain stimulation of albumin synthesis by methadone. penetration of methadone (R)- and (S)-enantiomers is Gastroenterology. 71:(2) 214-220. greatly increased by P-glycoprotein deficiency in the 98. SAXON A. J., WHITTAKER S., HAWKER C. S. (1989): blood-brain barrier of Abcb1a gene knockout mice. Valproic acid, unlike other anticonvulsants has no Psychopharmacology. 173 132-138. effect on methadone metabolism: two cases. J Clin 111. WARD J., BELL J., MATTICK R. P., HALL W. Psychiatry. 50:(6) 228-229. (1996): Methadone manteinance therapy for opioid 99. SCHAFER M. (2001) Psychiatric patients, methadone dependence. CNS Drugs. 6 440-449. patients, and earlier drug users can be treated for 112. WILKINS J. N., ASHOFTEH A., SETODA D., HCV when given adequate support services. Paper WHEATLEY W. S., HUIGEN H., LING W. (1997): presented at the Digestive Disease Week, Atlanta, Ultrafiltration using the Amicon MPS-1 for assessing Georgia. methadone plasma protein binding. Ther Drug Monit. 100. SCOTT G. N., ELMER G. W. (2002): Update on natural 19 83-87. product-drug interactions. Am J Health Syst Pharm. 113. WOLFF K., HAY A. W. M., RAISTRICK D., CALVERT 59:(4) 339-347. R. (1993): Steady-state pharmacokinetics of methadone 101. SHANNON M. (1997): Drug-drug interactions and the in opioid addicts. Eur J Clin Pharmacol. 44 189-194. cytochrome P450 system: an update. Ped Emergency 114. WOLFF K., SANDERSON M., HAY A. W. M., Care. 13:(5) 350-353. RALSTRICK D. (1991): Methadone concentration in 102. STRANG J. (1999): Drug Misuse and Dependence - plasma and their relationship to drug dosage. Clinical Guidelines on Clinical Management. (2002). Norwich, Chemistry. 37:((2)) 205-209. UK. 115. WOOSLEY R. L. (2000): Drugs that prolong the 103. SYLVESTRE D. L. (2002): Treating hepatitis C in QT interval and /or induce torades de pointes. methadone maintenance patients: an interim analysis. wwwtorsadesorg. October 17 accessed Drug Alcohol Depend. 67:(2) 117-123. 116. WU D., OTTON S. V., SPROULE B. A., BUSTO U., 104. TACKE U., WOLFF K., FINCH E., STRANG J. (2001): INABA T., KALOW W. (1993): Inhibition of human The effect of tobacco smoking on subjective symptoms cytochrome P 450 2D6 (CYP2D6) by methadone. Br J of inadequacy (“not holding”) of methadone dose Clin Pharmacol. 35 30-34. among opiate addicts in methadone maintenance 117. YOBURN B. C., BARBARA B., DUTTAROY A. (1993): treatment. Addict Biol. 6:(2) 137-145. Opioid receptor regulation in mice. J Pharmacol Exp 105. ULTRAM® T. H. P. I. (1998): Ortho-McNeil Ther. 265 314-317. Pharmaceutical, Inc, Raritan, NJ. 118. ZADOR D., SUNJIC S. (2000): Deaths in methadone 106. VAN BEUSEKOM I., IGUCH I. M. Y. (2001): A Review maintenance treatment in NewSouth Wales, Australia of Recent Advances in Knowledge About Methadone 1990-1995. Addiction. 95:(1) 77-84. Maintenance Treatment. Cambridge, UK. 62 · CHAPTER 1.6 1.7

Pharmacokinetics of Methadone P.P. Pani

The efficacy of methadone in the treatment existence of an important variability in the re- of opioid dependence can be ascribed to the sponse to methadone in single subjects and be- ability that it, unlike heroin, has to maintain a tween different subjects requires an evaluation stable concentration in blood and, therefore, in of the various factors involved. The aim is to the action site located in the brain. find the dose and the treatment regimen that For any patient treated with methadone, it will be most appropriate for each patient. is possible to distinguish an antiwithdrawal In this chapter we will take care of the de- dose – a dose large enough to avoid the onset terminants of variability in the response to of a withdrawal syndrome – and an anticrav- methadone and of the interventions needed to ing dose – a dose that is able to reduce crav- handle it. ings for heroin and control the behaviour of subjects who might wish to search for it and use it. 1. Methadone blood concentrations The anticraving dose is usually higher than the antiwithdrawal dose. According to the literature on the subject there is a positive cor- When taken orally, methadone is absorbed relation between the dose of methadone taken slowly through the gastrointestinal tract. The and the outcome of treatment. By now there maximum concentration is reached around the is a general consensus that, to be effective, the second to fourth hour after the ingestion, after daily dose of methadone should range be- which it falls gradually until the moment of tween 80 and 120 mg. the next ingestion (Figure 1). These general observations represent im- If the daily dosage of methadone dosage portant points of reference for physicians is correlated with its concentration in blood, working with heroin addiction. However, the a graph of the type shown in figure 2 is ob-

63 64 · CHAPTER 1.7 pharmacokinetics of methadone · 65

Fig. 1 Concentration of methadone in plasma: percentage variations over 24 hours tained. This graph refers to 100 patients in gain control over craving [1, 6, 8]. Actually, methadone maintenance treatment, 24 hours important differences are found to persist in after their previous dose. As can seen from the the way subjects respond to methadone, even graph, the general rule according to which the when reference is made to methadone con- higher the daily methadone dosage, the higher centrations in plasma rather than methadone the concentrations in the blood will be is not doses taken. Therefore, the therapeutic aims necessarily respected. It can, in fact, be noted of terminating the use of heroin and ending that there are patients who, even when they craving can be achieved with plasma concen- take methadone doses as high as 70–170 mg trations which differ in different subjects and per day, have blood concentrations similar to differ too in a single subject under different those of patients whose doses are as low as 25 conditions. mg per day. One aspect to be considered in evaluat- Blood concentrations of methadone are ing the pharmacokinetic components of this more reliable as an indicator of its concentra- variability it is the chirality of methadone. tion in the action sites than the dose taken. For Methadone is usually produced and traded this reason, methadone plasma concentrations as a raceme divided fifty-fifty between its two measured after 24 hours have repeatedly been isomers, R and S. Some of the features of the proposed as a parameter for the evaluation two enantiomers differ: these include half- of the adequacy of treatment. At first it was life, receptor binding and opioid activity. For thought that a methadone plasma concentra- our practical purposes, we can assume that tion of 150 ng/ml would be required to provide the R component is the active one. Metha- sufficient protection against the use of heroin done is mainly metabolized in the body by [1, 9]. Subsequently this value was modified: the enzymes of the P450 cytochrome system. at present, a plasma concentration of between The literature contains observations on the in- 150 and 600 ng/ml is considered necessary to volvement of cytochromes CYP1A2, CYP2D6, 64 · CHAPTER 1.7 pharmacokinetics of methadone · 65

CYP3A4, CYP2C9 and CYP2C19, even though falls to 35 times for methadone as a whole and the contribution of each of these has not yet to 17 times for R-methadone [5]. One possible been clearly defined. outcome, therefore, is that a subject may have The existence of inter- and intra-individual a plasma concentration of methadone that is variability in the enzymatic activity of these supposed to be appropriate, but actually con- cytochromes on the two enantiomers is surely sists predominantly of inactive S-methadone. the foundation for the major variations found Ideally, to have a more realistic picture of opi- in the relative concentrations of S and R meth- oid activity at the receptor sites, the best pa- adone in blood. In practice, while an individ- rameter to refer to is the plasma R-methadone ual taking his/her daily dose consumes 50% concentration. of R-methadone and 50% of S-methadone, the With the aim of using methadone plasma relative percentages of the two isomers in the concentration as a predictor of abstention from blood show wide-ranging variations. The lit- the use of opioids, the sensitivity and specifici- erature reports ratios between R and S metha- ty of various different values of plasmatic con- done that vary as widely as 0.63-2.4 [7]. Since centration have been studied. When using the the R isomer of methadone is the active one, for negativeness of the toxicological urinalyses for practical purposes it would be better to mea- morphine over the previous two months as a sure the R isomer, rather than total methadone. parameter for abstention from the use of her- Actually, patients treated with a given dose oin, it has been observed, for example, that a of methadone, present variability in plasma level of 400 ng/ml whole methadone in plasma concentrations of up to 58 times, while dosing corresponds to a specificity of 81.1% and a sen- with R-methadone alone reduces variability to sitivity of 31.8%. This means that the probabil- 41 times. Considering only patients who take ity of using heroin falls to 18.9% above 400 ng/ no other medications, interindividual variabil- ml, while the probability of ending the use of ity for the same dose of methadone ingested heroin is 68.2% at this concentration in plasma.

Fig. 2 Correlation between doses of methadone taken and concentrations in plasma 24 hours after administration in 100 subjects on methadone maintenance treatment 66 · CHAPTER 1.7 pharmacokinetics of methadone · 67

Moving now from the methadone raceme to in plasma, and a rise in coincidence with the R-methadone, it has been shown, by contrast, trough for concentrations in plasma [2]. Even that a level of 250 ng/ml for plasma concentra- the evaluation of important subjective pa- tion corresponds to a specificity of 92.6% and a rameters related to the psychic state showed sensitivity of 24.7%. This means that the prob- significant differences when compared with ability of using heroin falls to 7.4% when the healthy controls. In particular, mood tended to R-methadone level exceeds 250 ng/ml, while become depressed while moving away from the probability of ending the use of heroin is the peak for concentrations in plasma, reach- 75.3% for this plasma concentration [5]. ing its maximum deflection at the end of the 24th hour after the ingestion of methadone. It began to improve soon after the next ingestion 2. Stability of concentrations in plasma of the medication, reaching a new maximum value that coincided with the new peak for concentrations in plasma [3]. A pharmacokinetic characteristic common These fluctuations in methadone levels in to substances of abuse is their short half-life. A plasma can explain the presence of subjects sharp increase in concentrations in plasma and who do not feel they are ‘held’ by the medica- a short length of action characterize substances tion over the full cycle of 24 hours. These are like heroin, cocaine and alcohol. The efficacy the patients who show up early in the morn- of methadone in controlling heroin addiction ing at methadone clinics, and complain about is based on the stability of its concentration in waking up too early, and about anxiety, rest- blood. lessness, nausea, malaise which all disappear Actually this is a case of relative stability. soon after methadone has been taken. It has As is shown in figure 1, methadone concentra- been reported that a percentage of subjects as tions in plasma slowly fall from a maximum high as 34% do not feel they are being ‘held’ by value recorded 2-4 hours after one intake, to methadone [4]. Actually, although a daily vari- a minimum immediately before the next. For ation in the functioning of organs and systems long-term methadone administration, as in influenced by opioid activity is a feature of the maintenance treatment, an average half-life of experience of most subjects, patients who do around 24 hours has been found. This means not feel they are being ‘held’ by methadone that at the end of the 24th hour after an inges- show variations that are significantly higher tion, the concentration of methadone should than in those who do feel that they are being have fallen to half its peak value. ‘held’ by their medication [2, 3]. It is only logical to wonder if, in the general Even when there are alterations in the sub- run of treated subjects, the activity of organs jective state of patients in the 24-hour daily and systems influenced by opioid action fol- cycle, these do not actually show a close corre- lows the oscillations of methadone in plasma. lation with methadone concentrations in plas- While the early studies on this matter do not ma. Instead, the ratio between peak and trough show important modifications, subsequent concentration seems to be the most important observations carried out with objective instru- feature to be considered: the higher this ratio, ments of measurement, reported important the higher the probability is that the patient is changes (in pupils diameter, skin conductance, suffering from a withdrawal symptomatology, and so on). More recently it has been clearly even if a mild one, which appears daily when observed, when comparing subjects receiving methadone in blood approaches the lower con- methadone maintenance treatment for opioid centration. Dyer et al., in particular, have also dependence with healthy control subjects, that pointed out that one critical aspect is the speed the former show major changes in parameters of falls in methadone concentrations in plas- such as pupil size, pain sensitivity and respi- ma. Even a small change in this value seems to ratory frequency, with a fall occurring in con- be correlated with important modifications in comitance with the peak for concentrations the subjective status of the patient [3]. 66 · CHAPTER 1.7 pharmacokinetics of methadone · 67

3. Methadone and mood 4.1 Genetic factors

It is well known that the prevalence of Besides those involved in the response giv- mood disorders is higher in opioid addicts en within the central nervous system, genetic than in the general population. It is also factors that directly alter the pharmacokinetics known as it tends to decrease during metha- of methadone have to be considered, especially done maintenance treatment [10, 11]. Opioid those that affect the activity of the microsomal withdrawal syndrome includes symptoms like systems in the liver that are dedicated to medi- anxiety, restlessness, insomnia and depression, cation metabolisms. which are also part of mood disorders. From The presence of a higher or lower level of this perspective, the presence in subjects on activity of the CYPD2 cytocrome is, for exam- methadone maintenance treatment of fluctua- ple, responsible for a more rapid or a slower tions in blood concentration of the medication elimination of methadone, with a consequent sufficient to justify a withdrawal-like symp- shortening/lengthening of its half-life and a tomatology should be considered also for their rise/fall in its levels in plasma. implications on affective pathology. In reality, it has been observed that in opioid addicts in methadone treatment there is an important 4.2 Physiological states and significantly alteration in psychological/ psychiatric status with tension-anxiety, rage, confusion, depression, vigour, and that this Linkage between methadone and plas- symptomatology is subjected to daily fluctua- matic proteins depends on the availability of tions that coincide with those of methadone the alfa 1 glycoprotein. In a condition of stress, concentrations in plasma [3]. the production of this glycoprotein rises, lead- The already noted variability in the R and ing to a fall in the concentrations of unbound S enantiomer components in the methadone methadone – the active one. found in plasma certainly makes a contribution Starvation or a diet rich in meat may lead to mood alterations in patients on methadone to urine acidification. As methadone is weakly maintenance treatment; in particular, a higher basic, acidification facilitates its urinary elimi- likelihood of withdrawal symptoms and al- nation with a consequent fall in its concentra- terations in mood tone has been observed in tions in plasma. association with a relatively higher exposure to S rather than R methadone. 4.3 Pathological conditions 4. Determinants of variability Pathological conditions may modify the kinetics of methadone in a direct way, as is the case with The determinants of this variability in the renal failure. The interference is usually indirect: response to methadone can be subdivided into one readily available example is the fall in the free pharmacodynamic and pharmacokinetic ones. fraction of methadone (consequent on any increase In reality, little is known still about the phar- in the concentrations of alfa 1 glycoprotein) that is macodynamic factors, while information on observed in neoplastic pathologies. the pharmacokinetic ones is much more solid. The latter have been divided into genetic, physiological, pathological, and pharmacolog- 4.4 Pharmacologic interactions ic. Each of these factors can affect variations in response to treatment acting on many levels. Many drugs, depending on the various 68 · CHAPTER 1.7 steps of absorption, plasma protein binding, may provide useful indications. The ideal should methabolism and excretion, may interfere with be that of being able to measure methadone plasma the concentrations of methadone in blood. In concentration at the end of 24 hours (if possible for the last few years, interference at the level of the R methadone), but also at the peak (at the end of P450 microsomal system has been evaluated with the 4th hour). special attention. This interference can translate into Independently of the availability of methadone an induction of the methadone metabolism, with a plasma concentrations, it should be borne in mind consequent fall in its levels in plasma, or an inhi- that the adequacy of a methadone dose is what will bition of its metabolism, with a rise in methadone determine the endpoint of heroin use, the control of levels in plasma (refer to chapter ** for a description craving and the lack of side-effects. A careful evalu- of single interferences). ation of the state of the patient and his/her clinical evolution is needed to be able to maintain the dosage of methadone within the range of efficacy. 5. Clinical approach References Physicians should be aware of the problem of 1. DOLE V. P. (1988): Implications of methadone maintenance for theories of narcotic addiction. JAMA. variability in responses to methadone, and in the 260 3025-3029. various factors involved. This will allow the right 2. DYER K., FOSTER D., WHITE J., SOMOGYI A., MENELAOU A., BOCHNER F. (1999): Steady- choices to be made in deciding on the most suitable state pharmacokinetics and pharmacodynamics in actions – those that will allow anomalous situations methadone maintenance patients: comparison of those who do and do not experience withdrawal and to be corrected and guarantee the maximum degree concentration-effect relationships. Clin Pharmacol of plasma stability to levels of methadone. Ther. 65:(6) 685-694. 3. DYER K., WHITE J., FOSTER D., BOCHNER A patient who complains of not feeling “held” F., MENELAOU A., SOMOGYI A. (2001): The by the dose of methadone that has been prescribed relationship between mood state and plasma methadone concentration in maintenance patients. J deserves maximum attention; the same attention Clin Psychopharmacol. 21:(1) 78-84. should be paid to a patient who continues to use 4. DYER K. R., WHITE J. M. (1997): Patterns of symptom complaints in methadone maintained patients. heroin or other substances of abuse in spite of a Addiction. 92:(11) 1445-1455. dosage of methadone that is ‘theoretically’ ad- 5. EAP C. B., BOURQUIN M., MARTIN J., SPAGNOLI J., LIVOTI S., POWELL K., BAUMANN P., DEGLON equate. In these cases it is fundamental to deepen J. (2000): Plasma concentrations of the enantiomers of the clinical investigation, by verifying, in particular, methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend. 61:(1) if the patient has any complaints about withdrawal 47-54. symptoms and when they become manifest after 6. EAP C. B., BUCLIN T., BAUMANN P. (2002): Interindividual variability of the pharmacokinetics of methadone is taken. A crucial factor is that the clini- methadone: implications for the treatment of opioid cal picture is often paucisymptomatic and charac- dependence. Clin Pharmacokinet. 41:(14) 1153-1193. 7. EAP C. B., FINKBEINER T., GASTPAR M., terized by subjective symptoms: insomnia, anxiety, SCHERBAUM N., POWELL K., BAUMANN P. restlessness and depression can be associated in (1996): Replacement of (R)-methadone by a double dose of (R,S)-methadone in addicts: interindividual various different ways and/or combined with crav- variability of the (R)/(S) ratios and evidence of ing, nausea and muscular pain. On rare occasions a adaptive changes in methadone pharmacokinetics. Eur J Clin Pharmacol. 50:(5) 385-389. patient does not refer his/her symptoms to a state 8. LEAVITT S. B., SHINDERMAN M., MAXWELL S., of withdrawal, but to a physical or psychic state of EAP C. B., PARIS P. (2000): When “enough” is not enough: new perspectives on optimal methadone discomfort. Investigations should explore the pos- maintenance dose. Mt Sinai J Med. 67:(5-6) 404-411. sibility of a rapid metabolization of methadone, 9. LOIMER N. (1992): The use of plasma levels to optimize Methadone Maintenance Treatment. Drug interference deriving from a drug, an altered physi- Alcohol Depend. 30 241-246. ological state, or exposure to stress factors. One 10. NUNES E., QUITKIN F., BRADY R., POST-KOENIG T. (1994): Antidepressant treatment in methadone possibility to be considered and assessed in single maintenance patients. J Addict Dis. 13:(3) 13-24. cases, is that of controlling the interference (by sus- 11. ROUNSAVILLE B. J., KOSTEN T. R., KLEBER H. D. (1986): Long-term changes in current psychiatric pending or replacing the drug) or modifying the diagnoses of treated opiate addicts. Compr Psychiatry. dosage of methadone and/or the frequency of its 27 480-498. administration. The dosage of methadone in blood 1.8

Neuroendocrinologic Effects of Methadone Treatment G. Gerra

The task of defining the neuroendocrino- widely recognized, is that of being a steady, logic effects of methadone in humans can be slow-acting opiate agonist. In fact, its stimu- recognized as extremely difficult and compli- lation of mu opiate receptors, which is stable cated, once it is considered that individuals and long-lasting, is in sharp contrast with the who take methadone present prolonged expo- continuous fluctuations of heroin kinetics; ac- sure to heroin and other substances of abuse cording to some authors, it is this stimulation – substances that could themselves determine that probably permits the normalization of all the biological alterations that have been de- the dysfunctions caused by exposure to heroin tected. [21]. In addition, it cannot be excluded that the Moreover, over the past few years a grow- stabilization of the stimulation of opiate recep- ing body of evidence derived from studies on tors could account for the persistent modu- biological psychiatry has revealed at-risk tem- lation of the functions arising from the main peramental factors, personality disorders, and neuro-hormonal axis [13]. psychiatric disorders associated with drug addiction that may also prove to be linked with genetic and neuroendocrinologic alterations. 1. Prolactin In fact, neuroendocrinologic dysfunctions detected in subjects in methadone therapy might at least partly derive from previously con- The hypothesis that a chronic stimulation sumed drugs and from biological correlates of the opiate receptors alters the functioning of associated with personality traits; it follows the tubero-infundibular axis and the dopami- that the data should be interpreted with great nergic control of prolactin was first formulated caution. a long time ago. Methadone produces an acute, The main quality of methadone, as is major elevation of prolactin levels. This altera-

69 70 · CHAPTER 1.8 Neuroendocrinologic Effects of Methadone Treatment · 71 tion was not detected in subjects who were University, no alterations of basal prolactin pre-treated with dopamine-agonists, suggest- level were detected after the dynorphine test; ing that opiate-induced hyperprolactinemia despite this, a significant dysfunction of the is secondary to the lowering of dopaminergic prolactin response to the kappa agonist was re- tone [36]. The alteration of prolactin levels in corded, although there was no way of conclud- patients in methadone therapy has been re- ing whether the dopaminergic alteration was ported in various studies [4, 24, 39], with conse- secondary to methadone, to heroin exposure quential impact on sexual functioning, fertility or to a psycho-biological condition primary to and menstrual irregularities. Previous studies the addiction disorder. In a recent study, atten- have shown that vitamin B6 pyridoxine, a co- tion was once again directed to the possible re- enzyme implicated in dopamine synthesis, is lationship between methadone and alterations able to reduce prolactin levels in methadone- of the menstrual cycle, without definitively treated subjects [39], once again indicating the clarifying the mechanisms that would lead to probable role of dopamine in stimulating pitu- the absence of the menstrual cycle [15]. itary prolactin-secreting cells. Higher levels of basal prolactin and an altered prolactin response to insulin hypo- 2. Hypothalamus-Pituitary-Gonadal axis glycemia were detected in patients in methadone maintenance [41]. These findings point to a complex alteration of the control systems Long-lasting concern over possible gonadic regulating hypothalamic-pituitary secretion, dysfunctions in patients in methadone mainte- together with stress-response systems, which nance has induced researchers to explore the cannot be fully accounted for by the effects impact of chronic opiate receptor stimulation of methadone. Not surprisingly, the same au- on the hypothalamus-pituitary-gonadal (HPG) thors have revealed a lower prolactin response axis. In a study performed in 1981, a reduction in phobic patients, partly attributing the neu- of FSH levels was detected in patients in meth- roendocrinologic alterations to the biological adone therapy, while LH levels stayed in a correlates of psychiatric comorbidity. When normal range [24]. According to other authors, comparing subjects in methadone treatment both LH and testosterone basal levels were re- with heroin addicts exposed to streetdrugs duced in subjects in methadone treatment [4]. but not yet treated, hyperprolactinemia was A few years later, a study on 100 heroin addicts only found in the latter, while the prolactin in methadone treatment produced evidence of levels of methadone-treated patients showed a HPG axis dysfunction, with testosterone lev- no substantial alterations [27]. These findings, els significantly below the norm [6]. in contrast with previous data, suggest that Menstrual cycle dysfunctions in patients heroin alters hypophysis secretion and that in methadone treatment have been signalled methadone promotes system adaptation, with since 1968, with oligomenorrhoea and amenor- the consequent normalization of prolactin, in rhoea [2]. These two disorders, however, pres- accordance with other studies [30]. Likewise, ent a notable individual variability and could elevated basal prolactin levels and a lack of re- be influenced by the continuation of heroin sponse to TRH stimulation were observed in consumption during maintenance treatment. patients at the beginning of methadone treat- Studies on small samples of patients that had ment, with recent exposure to heroin and all the aim of evaluating gonadotrophines and the stressful conditions typical of non-treated ovarian steroids over the menstrual cycle in addicts [33]. methadone-treated subjects, yielded conflict- More recently, the dynorphine test was ing results; cycle interruption, with the abused to assess the functioning of the tubero sence of FSH and LH peaks and no evidence infundibular dopaminergic system. In healthy of any rise in progesterone in the luteal phase, subjects dynorphine increases prolactin lev- was detected in some subjects, but not in oth- els [1]. In this study, carried out at Rockefeller ers. There is still an ongoing debate over the 70 · CHAPTER 1.8 Neuroendocrinologic Effects of Methadone Treatment · 71

impact of methadone on the HPG axis and on implications for bone metabolism and degree the possible causes of oligo/amenorrhoea in of mineralization [40]. drug addicts [31]. In a recent study, attention was once again focused on the possible correlation between 3. Hypothalamic-Pituitary-Adrenal axis methadone and alterations of the menstrual cycle, without achieving any definitive clarification of the underlying mechanisms [15]. Hypothalamic-pituitary-adrenal (HPA) In contrast with these findings, normal lev- axis functioning may play a role in alterations els of FSH, LH and testosterone have been doc- induced by chronic exposure to opiates. These umented by some authors [27] in male heroin interferences may depend on the secretion of addicts in methadone maintenance therapy, the hypothalamic corticotrophine-releasing associated with alterations of semen. Analo- factor (CRF) [25], as well as adrenocorticotro- gous alterations of the number and motility of phic hormone (ACTH), a peptide synthesized spermazoids were detected in heroin addicts from pro-opiomelanocortine, and therefore not in methadone treatment. In support of the closely related to the endogenous opiate sys- hypothesis that methadone does not interfere tem [16]. with the integrity of the hypothalamus-pitu- While it has been hypothesized that heroin itary-gonad axis, it was proposed that sexual is able to modulate the secretion of ACTH and dysfunctions in methadone maintenance pa- cortisole, as well as the HPA axis-mediated re- tients may be due to coexisting psychiatric sponse to stress, no conclusive data are avail- problems rather than being caused by metha- able on the role of methadone. done [34]: the demonstration of symptoms According to Kreek et al., methadone, con- in the sexual sphere during the treatment of sidering its stabilizing properties, might pro- maintenance should stimulate the clinician to mote regulation of the HPA axis, with normal perform a careful diagnostic examination from levels of ACTH and cortisole, along with a well- a psychiatric point of view. Therefore, when preserved circadian rhythm of these hormones phenomena emerge in the sexual sphere dur- [23]. The same authors have verified a normal ing maintenance treatment, it should prompt response to metopyrone, a medical substance the clinician to proceed to a more in-depth that, through an 11-hydroxilasis blockade, and psychiatric evaluation. through the synthesis of cortisole, is, under Contrasting data in favour of HPG axis dys- normal conditions, able to induce an increase functions being due to methadone treatment in the secretion of ACTH in patients compli- have been proposed as well. More recently, ant with a steady, stabilized methadone regi- lower basal levels of testosterone, LH and men [22]. The same authors have reported a FSH, together with a lower gonadotrophine normal response to metopyrone, a diagnostic response to the hypothalamic gonadotro- drug that determines a rise in ACTH levels phine-releasing hormone (GnRH), in associa- in normal subjects through the inhibition of tion with a weak libido, impotence and gynec- 11-hydroxilasis and cortisole synthesis, in pa- tomasty in patients in methadone maintenance tients keeping to a stable methadone treatment have been detected. A reduction of methadone regimen [22]. dosage to 40 mg in these subjects determined By contrast, according to other authors, the the remission of hormonal alterations and a same test indicated a functional impairment recovery in libido, suggesting a dose-depen- of the HPA axis, indicative of a lack of inhibi- dent effect of methadone on testosterone and tory control of cortisole over ACTH [37]. Like- on the pituitary cell response to hypothalamic wise, a certain level of cortisole suppression stimuli [30]. Likewise, even more recent data was detected in patients in methadone main- suggest significantly reduced testosterone lev- tenance; this was associated with an exagger- els in heroin addicts; these persisted after one ated response to insulinic hypoglycemia when year of methadone treatment, with possible compared to healthy controls [41]. In this case, 72 · CHAPTER 1.8 Neuroendocrinologic Effects of Methadone Treatment · 73 there was no association between the excessive 4. Endogenous opiate peptides cortisole levels and the degree of depression, which means that the hypothesis that HPA hyper-reactivity may be related to psychiatric Initial reports, at the beginning of the 80s, comorbidity must be discarded. suggested that chronic stimulation of opiate In disagreement with previous studies, receptors may have an inhibitory effect on en- which had reported a normalization of the HPA dogenous opiate peptide secretion. A direct axis in methadone maintenance, the Rockfeller and also an indirect reduction of beta-endor- University group highlighted the presence of phins were detected by Gold in patients in ACTH hyper-reactivity due to a lack of nega- methadone treatment [13, 14]. tive feedback from metopyrone, in patients Later studies, however, found a substantial with a problem of cocaine abuse during main- normalization of both plasmatic and liquoral tenance therapy [32]. It was therefore proposed beta-endorphin levels. On one hand, acute ad- that neuroendocrine alterations may be linked ministration of opiates reduces beta-endorphin with personality traits rather than arising from levels; on the other, the stabilization brought exposure to heroin or methadone. about by methadone readjusts the endogenous In accordance with previous observations, opiate syste, bringing a normalization of beta- the same group reported an increase in plas- endorphin values [18, 19]. ma ACTH and cortisole levels after hCRF had The maintenance of normal-ranged liquoral been administered to patients in methadone levels of beta-endorphins in subjects in long- maintenance, without being able to determine term methadone treatment confirms that the the underlying neurobiological mechanisms. secretion of pro-opiomelanocortine remains In various experimental protocols evaluat- intact in these patients [20]. The same Authors ing biological responses to stress, to aggres- argue that the circadian rhythm of beta-endor- sive behaviour and to negative emotions, ab- phins and the response to metopyrone con- normalities of the HPA axis were detected in tinue undisturbed in patients in methadone drug-free heroin addicts [8, 12] and in subjects treatment [22, 23]. These findings conflict with in methadone treatment [10]. An increase in hypotheses that claim there is an endogenous cortisole and ACTH basal levels and an ab- opiate system dysfunction as a result of exog- normal response to stress, already revealed in enous opiate therapy. heroin addicts, independently of methadone treatment, was also detected in amphetamine- derivate misusers [10]. 5. Thyroid function Likewise, an increased response of cortisole and MHPG to yohimbine, which increases noradrenergic activity, was detected in patients in Methadone treatment does not seem to methadone maintenance. These findings con- interfere with the hypothalamus-pituitary- firm the hypothesis that in heroin addicts al- thyroid axis; normal T3, T4 and TSH values, terations of neuroendocrinologic mechanisms both basal and after TRH stimulation, have persist during methadone treatment [35]. This been detected in heroin addicts in methadone kind of difficulty in stress response, viewed treatment [38]. A later study carried out on a from a neurobiological standpoint, has been larger sample of heroin addicts in methadone observed too in at-risk depressed adolescents maintenance showed an increase in T3, T4 and and in various conditions of social maladjust- tireoglobulin levels, but with normal levels of ment [9, 11, 28], and does not seem to be af- free fractions (free T3 and free T4) and TSH, in fected by long-term opiate treatment. It might practice confirming the euthyroid state [5]. represent one of the crucial dimensions in determining vulnerability to addictive disorders and an important risk factor for relapse, for patients already in treatment. 72 · CHAPTER 1.8 Neuroendocrinologic Effects of Methadone Treatment · 73

6. Glucose metabolism thetic nerve activity [17], were not replicated in other experimental protocols, so that further investigation of these aspects is now needed. Patients in methadone therapy display a delayed, attenuated insulin response to food ingestion, with resulting hyperglycemia [41]. References It is not clear if this dysfunction is a result of 1. BART G., BORG L., SCHLUGER J. H., GREEN M., HO A., KREEK M. J. (2003): Suppressed prolactin response an alteration of the enterohepatic axis, with to dynorphin A1-13 in methadone-maintained versus possible opiate interference with pancreatic control subjects. J Pharmacol Exp Ther. 306:(2) 581-587. 2. BLINICK G. (1968): Menstrual function and pregnancy polypeptides [26], or else to a direct action on in narcotics addicts treated with methadone. Nature. pancreatic delta cells [7]. 219:(150) 180. 3. CERIELLO A., GIUGLIANO D., PASSARIELLO N., Also insulin responses to both oral and QUATRARO A., DELLO RUSSO P., TORELLA R., intravenous glucose stimulation in heroin ad- D’ONOFRIO F. (1987): Impaired glucose metabolism in heroin and methadone users. Horm Metab Res. dicts, are similar to those detected in non-in- 19:(9) 430-433. sulin dependent diabetes mellitus and are in- 4. CHOWDHURY A. R. (1987): Effect of pharmacological agents on male reproduction. Adv Contracept Deliv dependent of methadone treatment [3]. In fact, Syst. 3:(4) 347-352. heroin addicts with and without methadone 5. ENGLISH T. N., RUXTON D., EASTMAN C. J. (1988): Abnormalities in thyroid function associated with therapy displayed the same dysfunctional re- chronic therapy with methadone. Clin Chem. 34:(11) sponses, suggesting once again that the meta- 2202-2204. 6. FRIEDRICH G., NEPITA W., ANDRE T. (1990): Serum bolic alterations that are detected are not due testosterone concentrations in cannabis and opiate to methadone. Furthermore, after performing users. Beitr Gerichtl Med. 48 57-66. 7. GARCIA-BARRADO M. J., IGLESIAS-OSMA M. C., a glucose tolerance test on heroin addicts with RODRIGUEZ R., MARTIN M., MORATINOS J. (2002): and without methadone treatment, levels of Role of mu-opioid receptors in insulin release in the presence of inhibitory and excitatory secretagogues. glycosylated haemoglobin and serum fructos- Eur J Pharmacol. 448:(1) 95-104. amine did not confirm the hypothesis of an 8. GERRA G., BALDARO B., ZAIMOVIC A., MOI G., BUSSANDRI M., RAGGI M. A., BRAMBILLA F. altered glucose metabolism in heroin addicts (2003): Neuroendocrine responses to experimentally- [29]. induced emotions among abstinent opioid-dependent subjects. Drug Alcohol Depend. 71:(1) 25-35. 9. GERRA G., ZAIMOVIC A., GIUSTI F., BARONI M. C., DELSIGNORE R., RAGGI M. A., BRAMBILLA F. (2001): Pivagabine effects on neuroendocrine 7. Vasopressin responses to experimentally-induced psychological stress in humans. Behav Brain Res. 122:(1) 93-101. 10. GERRA G., ZAIMOVIC A., GIUSTI F., DELSIGNORE R., RAGGI M. A., LAVIOLA G., MACCHIA T., The possible interference of methadone on BRAMBILLA F. (2001): Experimentally-induced aggressive behaviour in subjects with 3,4- levels of vasopressin (antidiuretic hormone), methylenedioxy-methanfetamine (MDMA; “Ecstasy”) as detected in animal models and hypothe- use hystory; psychobiological correlates. J of Substance Abuse. 13 471-491. sized in humans, has not yet been confirmed 11. GERRA G., ZAIMOVIC A., MASCETTI G. G., by any noteworthy evidence. An inability to GARDINI S., ZAMBELLI U., TIMPANO M., RAGGI M. A., BRAMBILLA F. (2001): Neuroendocrine concentrate urine when dehydrated was de- responses to experimentally-induced psychological tected in subjects in methadone treatment, but stress in healthy humans. Psychoneuroendocrinology. 26:(1) 91-107. that could be due to opiate interference on the 12. GERRA G., ZAIMOVIC A., MOI G., BUSSANDRI, M. , baroceptor system or to not-yet investigated BUBICI C., MOSSINI M., RAGGI M. A., BRAMBILLA F. (2004): Aggressive responding in abstinent heroin electrolyte imbalances [41]. addicts: neuroendocrine and personality correlates. Prog Neuropsychopharmacol Biol Psychiatry. 28:(1) 129- 139. 13. GOLD M. S., POTTASH A. C., EXTEIN I., MARTIN 8. Catecholamines D., KLEBER H. D. (1982): Methadone-induced endorphin dysfunction in addicts. NIDA Res Monogr. 41 476-482. 14. GOLD M. S., POTTASH A. L., FINN L. B., KLEBER H. D., EXTEIN I. (1980): Serum prolactin and opiate Data indicative of a fall in peripheral nor- withdrawal. Psychiatry Res. 2:(2) 205-210. epinephrine levels in patients in methadone 15. HARLOW S. D., COHEN M., OHMIT S. E., SCHUMAN P., CU-UVIN S., LIN X., GREENBLATT treatment, with a lowering of muscle sympa- R., GURTMAN A., KHALSA A., MINKOFF H., 74 · CHAPTER 1.8

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H. cortisol and beta-endorphin response to metyrapone (2001): Methadone patients exhibit increased startle testing during chronic methadone maintenance and cortisol response after intravenous yohimbine. treatment in humans. Neuropeptides. 5 277-278. Psychopharmacology (Berl). 154:(3) 274-281. 23. KREEK M. J., WARDLAW S. L., HARTMAN N., 36. TOLIS G., DENT R., GUYDA H. (1978): Opiates, RAGHUNATH J., FRIEDMAN J., SCHNEIDER B., prolactin, and the dopamine receptor. J Clin Endocrinol FRANTZ A. G. (1983): Circadian rhythms and levels Metab. 47:(1) 200-203. of beta-endorphin, ACTH and cortisol during chronic 37. VESCOVI P. P., GERRA G., MANINETTI L., methadone maintenance treatment in humans. Life PEDRAZZONI N., MICHELINI M., PIOLI G., Sci. 33 409-411. GIRASOLE G., CACCAVARI R., MAESTRI D., 24. LAFISCA S., BOLELLI G., FRANCESCHETTI F., PASSERI M. (1990): Metyrapone effects on Beta- FILICORI M., FLAMIGNI C., MARIGO M. (1981): Endorphin, ACTH and Cortisol levels after chronic Hormone levels in methadone-treated drug addicts. opiate receptor stimulation in man. Neuropeptides. Drug Alcohol Depend. 8:(3) 229-234. 15:(129-132). 25. LESCH K. P., LAUX G., SCHULTE H. M., PFULLE R. 38. VESCOVI P. P., GERRA G., RASTELLI G., CEDA G. P., H., BECKMANN H. (1988): Corticotropin and cortisol VALENTI G. (1984): Effect of methadone on TSH and response to human CRH as a probe for HPA system thyroid hormone secretion. Horm Metab Res. 16:(1) 53- integrity in major depressive disorder. Psychiatry Res. 54. 24:(1) 25-34. 39. VESCOVI P. P., GERRA G., TARDITI E., CERESINI G., 26. LUGARI R., VESCOVI P. P., SALA R., GERRA G., VALENTI G. (1985): Methadone, naloxone and PRL TAGLIAVINI P., CACCAVARI R., ZANDOMENEGHI secretion. J of Andrology. 6:(2) 91. R., MONTANARI P., PAVESI C., GNUDI A., PASSERI 40. WILCZEK H., STEPAN J. (2003): Bone metabolism in M. (1989) Pancreatic polypeptide response to standard individuals dependent on heroin and after methadone mixed meal in normal subjects and opiate addicts. administration. Cas Lek Cesk. 142:(10) 606-608. Paper presented at the 5th European Symposium on 41. WILLENBRING M. L., MORLEY J. E., KRAHN D. Metabolism, Padova. D., CARLSON G. A., LEVINE A. S., SHAFER R. B. 27. RAGNI G., DE LAURETIS L., BESTETTI O., (1989): Psychoneuroendocrine effects of methadone SGHEDONI D., GAMBARO V. (1988): Gonadal maintenance. Psychoneuroendocrinology. 14:(5) 371- function in male heroin and methadone addicts. Int J 391. Androl. 11:(2) 93-100. 28. RAO U., RYAN N. D., DAHL R. E., BIRMAHER B., Acknowledgments: Thanks to Amir Za- RAO R., WILLIAMSON D. E., PEREL J. M. (1999): Factors associated with the development of substance imovic, Gabriele Moi e Maina Antonioni for use disorder in depressed adolescents. J Am Acad their help in the early drafting of this chapter. Child Adolesc Psychiatry. 38:(9) 1109-1117. 2.1

The History of Methadone Treatment M. Pacini, A.G.I. Maremmani and I. Maremmani

1. On detoxification and anticraving tolerated for two main reasons: its consump- therapies. tion was confined to opium rooms, with no dangerous impact on society, and opium-derived drugs themselves had irreplaceable The use of opiate substances, either for medical properties. A radical change ensued; medical or recreational purposes, dates back after morphine, the moral war against opium to ancient times [27]. The social alarm arising was refuelled by the epidemic of morphine from reckless behaviours caused by craving for addiction, which proved how opium-derived opiate drugs is far more recent. Although ha- substances may have harmful consequences bitual opiate use could take place, as described for individual health and social safety [1]: in the biographies of famous historical charac- morphine addiction was the first case of mass ters, or even when documented anonymously addiction. among common people, the epidemic of opi- Drug sellers and smugglers were the first ate addiction quickly followed the commercial to understand the basic meaning of addictive spread of morphine and related substances behaviour, and the feasibility of inducing ad- (in the late 1800s). In other words, the specific diction through repeated exposure to certain drug and the route of consumption were cru- substances: in fact, drug traders realized the cial factors in changing the role of opiates and economic potential of addictive drugs, and making them harmful to society as a category launched their product during low-cost trial [33]. Thus, the spread of morphine should be periods, followed by a quick run-up in prices regarded as a milestone in the history of opiate till they reached unbelievable heights; con- use. Before morphine, opium use was disap- sumers were willing to pay those prices once proved by public opinion, because it marked addiction has hijacked their brain reward sys- a lifestyle based on a luxury, but was socially tem [27].

75 76 · CHAPTER 2.1 the history of methadone treatment · 77

On medical grounds, the reinforcing prop- stead of to the original substance. erties of older and newer opiates have been de- In other words - in a way unlike modern scribed, though it has never been clear where anticraving treatments - those loomed as sub- such properties may lead. For example, opiate stitution treatments. Reinforcement was dis- use was tried as a way of helping to wean pa- tinct from withdrawal control, as was made tients off alcohol, or off other opiates. Heroin, evident by the substitution of cocaine for mor- for instance, was effective in driving patients phine. Unfortunately, treated patients became away from morphine, as long as patients addicted to the prescribed substance, or to showed they preferred heroin itself. In the both. The second reason for failure was that no medical instruction sheet for Bayer’s heroin longer-term intervention had been thought of: the reader is told that “morphine addicts treat- the interruption of the vicious circle between ed by this drug quickly lose any craving for craving and tolerance was regarded as enough morphine”. Apart from that specific attempt, to break the cycle of relapsing behaviour. Nev- which would turn out to be a failure due to ertheless, it became clearer and clearer over the lack of knowledge about addiction biol- the years that relapses are a core feature of ad- ogy, the idea of craving control by therapeutic diction, so that no detachment from the sub- drugs had already been conceived. Apart from stance can be stable or long-lasting unless the medical objectives, Christian missionaries too means by which detachment was achieved are showed interest in the opportunity to take ad- retained. vantage of heroin’s reinforcing properties, and In the USA, as early as 1914, the failure of traded it to get people to join what was a new therapeutic heroin led to the placing of a limit religion for them, and convince them to at- on the free employment of opiates for medi- tend churches, in the hope that heroin would cal purposes, while physicians were allowed have an even stronger appeal than opium had to prescribe morphine and heroin on a regular done up till that point [8, 27]. Thus, they were basis to morphine-dependent patients only. By just making a comparative experiment involv- using this strategy, opiate addicts were no lon- ing the conditioned behaviours of a human ger socially disruptive, since they were hooked sample, using religious affiliation as an end- on a freely-delivered substance. On the other point. Other fields of employment [8], such as hand, they did not appear to proceed with any the use of the same substance (morphine for rehabilitation, and their quality of life stayed morphine) at decreasing dosages for the treat- low. Moreover, something unexpected was ment of withdrawal, failed to clarify the dif- taking place that would become increasingly ference between detoxification and addiction evident in the course of time: prescribed opi- control. Put simply, the fact that some depen- ates were diverted to non-addicted people, dent subjects found it impossible to carry out who bought them for recreational purposes. detoxification on their own by tapering dos- This meant that a legal channel had been set ages (when that could be done by opiate-free up for the general population to be exposed to methods) suggested they had no control over addictive substances, outside medical settings. the substance. Unfortunately, detoxification The fact that some doctors might decide to en- has remained the first and most commonly gage in drug trading with their patients was used, allegedly therapeutic approach to adjust a secondary consequence, not the actual dictive diseases, despite predictably negative cause of the phenomenon. outcomes. Eventually, regulations were imposed on The first two attempts to administer anti- the medical use of opiates (Conference on Opi- craving treatment (heroin for morphine, co- um, Geneva, 1924). Opiate use was permitted caine for morphine) failed for two main rea- in either of the two following situations: sons: on one hand, the putative therapeutic a) when withdrawal from morphine or her- substance owed its effectiveness to a sharper oin causes serious disorders, which can- reinforcing property, so that it only induced a not be treated effectively by resorting to harder form of addiction, though to itself in- other common medical techniques. 76 · CHAPTER 2.1 the history of methadone treatment · 77

b) when patients are rendered capable of played by addicts (starting with craving) went leading a normal or sufficiently balanced into gradual remission when challenged with life after the administration of opiates at a re-balancing drug, such as methadone. The stable doses - usually low ones - , but fail normalization by methadone of addictive be- to maintain their improvement in an opi- haviours happened at levels of stimulation ate-free condition. which were far higher than those required to On that occasion the principle of mainte- counteract withdrawal symptoms, and pre- nance as a strategy for long-term control of sumably targeted a kind of brain dysfunction an addicted patient’s behavioural balance that developed before tolerance, and persist- and productive potential was formulated for ed in detoxified subjects as a silent biological the first time. However, the presciption of low ground for relapse. dosages as standard practice can be seen a ma- An increasing number of subjects were jor limitation, now that the average level of given methadone treatment in one of two dif- effective dosages of opiate agonists can be re- ferent modalities: maintenance and short-term viewed with hindsight. Moreover, the benefit tapering. Short-term tapering turned out to be to the individual was described then in terms a failure, supporting the conclusion that no of productiveness and social harmlessness, short-term methods exist that are able to give while no definition of addiction as a source of addicts long-term control over their symptoms. individual discomfort was provided. This statement has retained its validity up till now. On the other hand, maintenance produced stable results, in the medium and long 2. Methadone treatment terms. So-called detoxification procedures cannot be expected to provide a solution to addiction, whatever method is adopted. Retention In the early 1960s addiction treatment rates and the latency of relapse after detoxifi- reached a turning point: Dole and Nyswander cation reach higher levels when the reversal of pioneered clinical research on the properties of tolerance takes place more slowly, and when an opiate agonist, methadone, in subjects who opiate agonists are employed. In other words, were already undergoing treatment with mor- detoxification seems to work better as long as phine for opiate addiction [9-11, 15-18]. Up to opiate agonists are being administered. then, substitution by morphine or heroin was The spread of methadone maintenance pro- the only therapeutic perspective, since detoxi- grammes was also characterized by a discrep- fication was ineffective in ensuring the long- ancy between scientific knowledge and clinical term prevention of relapse. The basic problem practice: in some cases professional staff were was that subjects on substitution treatment not given the requisite information about the performed poorly on social grounds, even pharmacology and behavioural properties of though their disruptive behaviors were extin- methadone; in other cases cultural bias acted as guished. When switching from legal morphine a brake on the correct application of acquired to methadone, the first evident advantage was knowledge. The heterogeneity of results and the chance to restore social and individual outcome standards between programmes is abilities to patients, as well as highlighting mainly due to variations in the dosages em- their quality of life. Positive results on small ployed, which may or may not be around the samples of hardcore patients became the ba- average effective dose value of 100 mg/day, sis for testing methadone treatment on larger and sometimes fail to reach the minimum av- samples, with results that brought further erage dosage (60 mg/day) [13, 14, 29]. encouragement. In line with their original ob- In the USA detoxification - by whatever servations, Dole and Nyswander formulated technique - is no longer featured among the a metabolic hypothesis for opiate addiction possible approaches to the treatment of opiate which moved sharply away from the concept addiction. Over the years, methadone mainte- of substitution treatment. The symptoms dis- nance has remained the gold standard of effec- 78 · CHAPTER 2.1 the history of methadone treatment · 79 tiveness with respect to the other approaches agonist effect on receptors may, in some cases, that were scientifically evaluated (naltrexone, correspond to the antagonism of a disease in- environmental isolation, slow or rapid detoxi- duced by other cross-reacting substances. fication, abstinence support, heroin maintenance, other psychopharmacotherapies). The stigma associated with methadone treatment References continues to act as a major limitation on the 1. AVERNI G. (1999): Proibizionismo e antiproibizionismo. Castelvecchi, Roma. correct handling of methadone programmes 2. BALL J., ROSS A. (1991): Follow-up study of 105 and the evaluation of their results. The main patients who left treatment. In: BALL J. C., ROSS A. (Eds.): The Effectiveness of Methadone Maintenance misunderstandings are those of viewing meth- Treatment. Springer-Verlag, New York. adone as a legally delivered narcotic, perceiv- 3. BALL J. C. (1988): The effect of methadone dose on heroin use. Presented at the Fifth Annual Northeast ing methadone treatment as a way of replac- Regional Methadone Conference. New York. pp. ing one narcotic by another, and interpreting 4. BALL J. C., CORTY E., PETROSKI S. P., BOND H., TOMMASELLO A., GRAFF H. (1986): Medical therapeutic dependence as a synonym for le- services provided to 2394 patients at methadone galized addiction. programs in three states. J Subst Abuse Treat. 3 203- 209. These misconceptions are common even 5. BALL J. C., ROSS C. A. (1991): The Effectiveness of among physicians, and are the source of some Methadone Maintenance Treatment Springer-Verlag, New York. unresolved “wars on words” in the field of ad- 6. BLIX O., GRÖNBLADH L. (1991): The impact of diction treatment [30]. methadone maintenance treatment on the spread of HIV among IV heroin addicts in Sweden. In: LOIMER Parallel to the progress made, from the ear- N., SCHMID R. (Eds.): Drug Addiction and AIDS. liest detoxification attempts to the spread of Springer Verlag, Wien, New York. pp. 200-205. 7. BOCKER F. M. (1991): Methadone and AIDS: are agonist maintenance, and from the concept of methadone maintenance treatment programs substitution to that of relapse prevention and (MMTP’S) apt to prevent HIV infections among intravenous drug users? Presented at the First European behavioural normalization, scientific knowl- Symposium on Drug Addiction and AIDS. Vienna. pp. edge about the process of addiction has become 8. CAPPUCCINO L. (1999): Dall’oppio all’eroina: un maledetto imbroglio. Cox 18 Books, Milano. deeper and sounder, too. A large body of re- 9. DOLE V. P. (1972): Detoxification of sick addicts in search papers has provided information about prison. JAmMedAssoc. 220 366-369. 10. DOLE V. P. (1972): Narcotic addiction, physical average and minimum effective dosages, and dependence and relapse. N Engl J Med. 286 988-992. an oral dose-response curve (Ball curve) [2-5]. 11. DOLE V. P. (1980): Addictive behaviour. Scientific American. 243 138-154. A precise range of effective blood methadone 12. DOLE V. P. (1990): La lotta contro l’AIDS comincia levels [19-21] has been defined, corresponding dalla droga. JAMA (Ed It). 2 (2) 189-191. 13. DOLE V. P. (1994): What have we learned from three to a wider range of oral dosages, all converg- decades of methadone maintenance treatment. Drug ing on the same circulating values through ei- Alcohol Rev. 13:(3) 330-338. 14. DOLE V. P. (1995): Methadone Maintenance. Comes ther a normal, a slower or a particularly active of Age. In: TAGLIAMONTE A., MAREMMANI I. metabolism. (Eds.): Drug Addiction and Related Clinical Problems. Springer-Verlag, Wien New York. pp. 45-49. Most studies have been performed on 15. DOLE V. P., JOSEPH H. (1978): Long term outcome sample populations of heroin addicts with a of patients treated with methadone maintenance. Ann NY Acad Sci. 311 181-189. variety of somatic and mental problems, so 16. DOLE V. P., KREEK M. J. (1973): Methadone plasma that the effectiveness of methadone treatment level: Substained by a reservoir of drug in tissue. Proceedings of the National Academy of Sciences of the on a range of comorbidity situations was dem- United States of America. 70 10-30. onstrated through real clinical case histories. 17. DOLE V. P., NYSWANDER M. E. (1976): Methadone maintenance treatment: A ten-year perspective. Lastly, specific research explored the use of JAMA. 235 2117-2119. methadone during pregnancy, in subjects with 18. DOLE V. P., VOGELSON P., LEONIGSBERG L., BACHRACH M. (1976): A survey of paperwork. The hepatitis, hepatic and kidney failure, and liver Community Treatment Foundation (Unpublished), transplantation [22-25], HIV infection [6, 7, 12, 19. EAP C. B., BOURQUIN M., MARTIN J., SPAGNOLI J., LIVOTI S., POWELL K., BAUMANN P., DEGLON 26, 28, 32], and dual diagnosis [31]. J. (2000): Plasma concentrations of the enantiomers of The history of methadone treatment pro- methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend. 61:(1) vides a curious example of how the same cat- 47-54. egory of substances (opiates) can be the source 20. EAP C. B., BUCLIN T., BAUMANN P. (2002): Interindividual variability of the pharmacokinetics of of a disease but also its cure; and of how an methadone: implications for the treatment of opioid 78 · CHAPTER 2.1 the history of methadone treatment · 79

dependence. Clin Pharmacokinet. 41:(14) 1153-1193. Storia dell’oppio. Cesco Ciapanna Editore, Roma. 21. EAP C. B., DEGLON J. J., BAUMANN P. (1999): 28. LONGSHORE D., HSIEH S., ANGLIN M. (1994): Pharmacokinetics and pharmacogenetics of Reducing HIV risk behaviour among injection in drug methadone: clinical relevance. Heroin Addict Relat Clin users: effect of methadone maintenance treatment on Probl. 1:(1) 19-34. number of sex partners. Int J Addict. 29 741-757. 22. FINNEGAN L. P. (1995): Addiction and Pregnancy: 29. LOWINSON J. H., MARION I. J., JOSEPY H., DOLE V. Maternal and Child Issues. In: TAGLIAMONTE A., P. (1992): Methadone Maintenance. In: LOWINSON J. MAREMMANI I. (Eds.): Drug Addiction and Related H., RUIZ P., MILLMAN R. B. (Eds.): Substance Abuse: Clinical Problems. Spinger-Verlag, Wien New York. pp. A Comprehensive Perspective. Williams and Wilkins, 137-147. Baltimore. pp. 23. FINNEGAN L. P. (2000): Women, pregnancy and 30. MAREMMANI I., CASTROGIOVANNI P. (1990): La methadone. Heroin Addict Relat Clin Probl. 2:(1) 1-8. tossicodipendenza da eroina fra progresso scientifico 24. GUFFENS J. M. (1998): HIV, hepatitis B, C and drug e pregiudizio culturale. Grasso Editori, Bologna. addiction IV. Revue Francaise de Gastro-Enterologie. 31. MAREMMANI I., ZOLESI O., AGLIETTI M., XXXIV 334. MARINI G., TAGLIAMONTE A., SHINDERMAN 25. GUFFENS J. M. (1999): The treatment of viral hepatites M. S., MAXWELL S. (2000): Methadone Dose and in drug addicts. Heroin Addict Relat Clin Probl. 1:(2) 35- Retention in Treatment of Heroin Addicts with Axis 38. I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. 26. KWIATKOWSKI C. F., BOOTH R. E. (2001): 32. PACINI M., MAREMMANI I. (2002): Methadone Methadone maintenance as HIV risk reduction maintenance and HIV infection. Heroin Addict Relat with street-recruited injecting drug users. Journal of Clin Probl. 4:(3) 33-44. Acquired Immune Deficiency Syndromes. 26:(5) 483-489. 33. SZASZ T. (1974): The discovery of drug addiction. 27. LATIMER M., GOLDBERG J. (1983): Fiori nel sangue. Ceremonial Chemistry. Anchor Press/Doubleday, New York. pp. 3-18. 80 · CHAPTER 2.1 2.2

Enrolment and Termination I. Maremmani and M. Pacini

1. Admission Common addiction-related somatic concerns are compatible with methadone maintenance, and are expected to improve during the A diagnosis of opiate addiction is in itself course of a successful programme. Pregnan- a valid reason for allowing methadone treat- cy constitutes a priority for enrolment [4-6], ment, as this is the gold standard for a relapse- along with HIV infection and liver diseases [7- prevention approach (see table 1) and the saf- 9]. Adopting a logical, research-based line of est kind of intervention in any perspective [1, inquiry, the effectiveness of methadone treat- 2]. ment was first assessed for hardcore addicts A methadone maintenance programme can [3]; by now it can be acknowledged to be the be handled in such a way that it becomes effec- gold standard for the average addict. It can, tive against a wide range of addictive pictures, in fact, be considered the first-line option for which may vary in the severity of addictive any degree of disease severity. In other words, symptoms and the typology of associated ill- younger addicts at their first episode of dis- nesses. ease, and/or with a short disease history (e.g. Methadone maintenance treatment (MMT) less than a year) should certainly be enrolled leads to significant improvement that covers in a methadone maintenance programme. It is a range of different initial degrees of severity unjustified to think of methadone treatment as and a variety of situations: shorter or longer a ‘heavy’ or a ‘chronic’ form of treatment (as if disease history, first episode or multiple relaps- an acute, disease-healing intervention were an es, high tolerance or no tolerance to narcotics, available option, anyway). addicts only and mentally ill addicts. MMT is It would therefore be a big mistake to re- useful too in implementing ‘harm reduction’ gard methadone treatment as a last resort, an strategies [12, 14, 16, 17]. extrema ratio, for those who have nothing to

81 82 · CHAPTER 2.2 ENROLMENT AND TERMINATION · 83

Table 1. Feasibility of methadone treatment

Enrolment criteria: First episode of narcotic addiction Mutiple-relapse narcotic addiction Narcotic addiction with additional somatic or psychiatric concerns Narcotic addiction during pregnancy Programme termination: Refusal of the setting or the therapeutic instrument Self-interested handling of methadone Violent behaviour against staff, or against other patients ‘Harm reduction’-like handling of treatment Persistent criticism about methodological aspects Refusal to undergo standardized clinical evaluations lose. In reality, any patient who is diagnosed those applying for methadone treatment, as a narcotic addict should be offered the most should not be parked in harm-reduc- reliable and effective option, with the aim of tion-based waiting lists, but be admitted stopping and reversing the addictive patho- quickly. Waiting in harm-reduction con- physiology and gaining symptom control with texts may negatively influence a patient’s a relapse-prevention guarantee in the long motivation to receive treatment, due to term. To date, such a guarantee for full-re- the underlying ambivalence of addictive sponders is inseparable from the maintenance states. Conversely, subjects who have of an agonist treatment regimen. only a poor motivation to receive treat- The Enrolment in a methadone mainte- ment may be helped by correctly run nance treatment programme should follow harm-reduction interventions to become three criteria: motivated to undergo structured treat- a) Rapidity. Any request for treatment must ment and become compliant with its ba- be followed by enrolment, once a diag- sic rules. nosis of narcotic addiction has been for- c) Case-planning. The diagnosis should be mulated. Waiting lists should be viewed as detailed as possible, in order to allow as no more than an exception that may classification of the patient in terms of all occur in the case of unexpected epidem- the known predictors of effectiveness. ics. No patient should be admitted, who For some categories of patients, expected makes it clear that he/she is applying for stabilization dose values can be formu- something radically different from ago- lated, together with the probable chronol- nist maintenance, or would like a special, ogy and latency of therapeutic goals. In unorthodox schedule to be planned for addition, ancillary and complementary him/her. Apart from that, possible in- facilities can be planned in advance, so compatibilities between the attitude of a that they are automatically resorted to in patient and the rules of the programme specific phases of the programme. can best be evaluated during the course of treatment. b) Specificity. Subjects who express a gener- 2. Treatment termination ic request for help without showing interest in the basic principles of agonist treatment (craving control, relapse prevention Methadone maintenance treatment re- and rehabilitation), should be referred to quires patients to adhere to a few rules, which a harm-reduction facility. In other cases, are intended to allow them to achieve satisfac- 82 · CHAPTER 2.2 ENROLMENT AND TERMINATION · 83

tory results in fighting their disease. tion severity to be assessed on the basis of the The rules are not intrinsically therapeutic, patient’s reaction to treatment supervision. but they do allow a drug to produce its thera- Irregular attendance, skipping days of ad- peutic effects. Generally speaking, the patient ministration, and announcements of unavail- must never be allowed to dictate or suggest ability at the centre during the times when it is any therapeutic measure, not just for technical open to the public, are all behaviours indicat- reasons, as in any other therapeutic context, ing a greater degree of severity, and may prove but because of the nature of addiction. Ad- to be incompatible with the continuation of dicts, when left free to do so, are quite likely to treatment. If flexible attitudes are adopted in steer a structured treatment towards a flexible dealing with patients who show poor compli- and extemporary intervention, which is collat- ance with attendance rules, the results are: eral to addiction and is not therapeutic at all. a) delays in intervening to combat the causes On this basis, the violation or rejection of any of behavioural disorganization and poor treatment rule is a good reason for treatment compliance - delays that are usually cor- termination [10, 15].. related with the degree of addiction severity or with concurrent destabilizing conditions (such as polyabuse); 2.1. Rejection of the therapeutic instrument. b) in the case of the average addict, a failure to ensure regular exposure to the therapeutic drug. When applying for treatment, the patient must be informed that the programme is founded on the scientific use of methadone, 2.3. Dose and duration. with the aim of keeping addiction under control and maintaining remission in the long- term, that is, preventing its natural relapsing Patients should be given clear information course. No patient should be allowed to in- about the difference between “having a persist on receiving facilities not included in the sonal opinion” about how treatment elements standard treatment package, or to adopt other should be handled and “being able to make a treatment programmes at the same centre, for free choice” about one’s condition. As regards example naltrexone maintenance or buprenor- opinions, patients are allowed to hold any phine, against the physician’s judgment. kind of opinion, because the question of what a patient may think about the effectiveness of treatment has no impact on its outcome. How- 2.2 Frequency of attendance. ever, opinions tend to change in response to improvements in addictive symptoms; in most cases, these opinions turn out to be products The frequency of supervised administra- of an addictive way of thinking. On the other tion is decided with reference to treatment hand, patients are never allowed to choose stage and patient symptom status. how they will be treated, which is one of the The purpose of daily attendance is to en- physician’s prerogatives. Apart from the lack sure that the prescribed dose is administered of specific skills, it is predictable that an addict to patients, considering that patients cannot be would be likely to evaluate available therapeu- relied on to guarantee this themselves. Reduc- tic elements in terms of addictive symptoms, ing the frequency of attendance should not be which means, in practice, in the direction of perceived as a way of verifying patients’ reli- relapse rather than clinical remission. ability or giving them greater responsibilities. On the other hand, addicts are welcome to The advantage gained by the requirement of report personal data on issues of tolerability frequent attendance during the early phases of and effectiveness. Nevertheless, many patients treatment is that it allows the degree of addic- are unable to do more than complain about 84 · CHAPTER 2.2 ENROLMENT AND TERMINATION · 85 dose and duration as if these were side-effects Violent patients, who cannot be permitted of treatment or unacceptable risk conditions; to attend a normal outpatient facility, should this should never be mistaken for a limita- be advised to undergo inpatient treatment, tion on further methadone administration or with the possibility of resorting to compulsory a threshold of tolerability. Patients should be treatment if necessary. Past violent behaviours plainly told to stop criticizing treatment before against staff do not count as a reason for ex- its outcome can be witnessed and assessed in cluding any patient from future treatment per- the light of a craving-free way of thinking. Pa- spectives. tients who oppose increases in doses and long- term maintenance so as to render treatment unfeasible should be discharged and referred 2.5 Persistent heroin use, or relapse into to harm-reduction facilities. heroin use

2.4 Violent behaviour Neither of these situations justifies treatment termination. If fact, they both impose the need for an adequate treatment regimen, An outpatient setting is inappropriate for either in terms of longer-term maintenance, or patients who give rise to concerns over aggres- of higher-dose stabilization. It would be para- sive behaviours, threats or damage [15]. In any doxical, besides being unethical, to terminate case, physicians should be able to avoid elicit- patients when they begin to display typical ad- ing aggressiveness from patients, since metha- dictive symptoms, no matter how severe. Such done treatment is highly effective in dealing a course of action would mean considering with feelings of rage and hostility, and even core symptoms of a disease as exclusion cri- with aggressive behaviours. As long as the pa- teria for treatment continuation. It is true that tient allows the administration of methadone addictive symptoms are behavioural in nature, in a supervised manner, treatment should and can be expected to create interference with never be refused, especially to addicts who are treatment procedures, but this just means that undergoing withdrawal. Also, criticism deriv- compliance with treatment rules should be ing from symptomatic attitudes that emerge in regarded as a major therapeutic target, prior behaviours, including ambivalence towards to the pursuit of stable remission. Most physi- treatment, should not be challenged as disre- cians tolerate ambivalence and opposition to spect, but handled with the aim of achieving treatment to a certain extent, but this means stabilization. A judgmental approach should they will tend to marginalize more severely never be allowed to replace statements and ill patients from treatment settings because prescriptions. most of them show low levels of spontaneous The aggressiveness of addicted patients can compliance. Forms of discrimination like these mostly be prevented or controlled by means of are not acceptable on ethical grounds, and are agonist treatment, and levels of aggressiveness not compatible with the general philosophy of show a tendency to fall while methadone dos- medicine. As for the question of latency of re- es are being increased. Symmetrically, anger, sponse to treatment, no time limitation exists hostility and violence commonly characterize after which a positive response is no longer states of opioid impairment, when tolerance is achievable, even if it is true that most patients not counterbalanced by enough endogenous can be effectively stabilized within one year. It or exogenous stimulation. Otherwise, a pa- follows that patients who are still using hero- tient’s degree of aggressiveness may be raised in after a full year of treatment should be re- by concurrent stimulant, alcohol or benzodiaz- tained in treatment unless no rehabilitative re- epine abuse, especially when levels of opioid sult or symptom reduction has been achieved. stimulation fall below the patient’s tolerance In other words, a partial response is enough level [13]. to justify treatment continuation. A strategy of 84 · CHAPTER 2.2 ENROLMENT AND TERMINATION · 85

increasing doses to the highest documented fective treatment procedures. value should be taken into consideration be- Negotiation is not the right strategy for fore labelling the patient as treatment-resistant achieving compliance, and thereby stabiliza- or a non-responder [11]. tion. Non-compliant subjects should, rather, Methadone maintenance treatment is the be referred to harm-reduction centres, while core of rehabilitation, and its standardized use allowing no room for a negotiation of metha- paves the way to scientifically pursued reha- done maintenance treatment into a harm re- bilitation, sometimes with no need for further duction hybrid with no prospect of stabiliza- psychosocial efforts. It is definitely absurd to tion. ask patients to keep their symptoms under constant review as an important requirement for a good outcome, so sidelining pharmaco- 2.6. Clinical and laboratory evaluations. logical treatment as nothing more than useful support. In this sense, it would be paradoxical to terminate treatment for patients who are Patients who refuse to deliver samples for not abstinent, ascribing the unsatisfactory out- urinalyses or undergo clinical examination come to feeble will-power or inadequate self- are usually driven to do so by the strength of control, instead of providing the patient with their addictive symptoms. Any such failure to adequate methadone dosing. comply with the rules should be prevented Some patients resist treatment rules by by adequate dose-increasing schedules, and threatening that they will ‘get a fix’ if they are it might partly be overcome psychologically not allowed to handle treatment themselves, [15]; in this way the craving is likely to fade, so violating the standard rules. In other words, so leaving room for collaboration. To this ex- some patients pose the question of whether tent, a persistent refusal to be tested may be they will continue to attend the clinic in a self- tolerated, as long as patients accept increases interested way, as an alternative to dropping in their methadone dose or having any take- out, or as a way of avoiding discomfort and home privileges suspended. As a rule, when subsequent drug use despite ongoing treat- craving is kept under control, the patient will ment. This way of reasoning and of challeng- not refuse laboratory testing. ing members of staff is symptomatic of severe addiction, and should not be considered a negotiable request. It should sound absurd to 2.7. Data collection. physicians that patients threaten to engage in the same kind of behaviour they asked treatment for in the first place, as if were up to them Patients must give their informed consent to choose whether they should use narcotics on for data collection and storage, which is need- an environmental basis. Patients are not free ed for the safe and effective handling of their to use drugs, and it makes no sense to allow condition. Patients who do not allow staff to them to do so as if it were a reaction to unjust gather and keep records of their personal data rules and permissible as their free choice. Phy- should be dismissed from the programme and sicians should therefore never feel responsible referred to harm-reduction facilities. for ongoing narcotic use by patients who fail to comply with treatment rules. Any decision to terminate the programme Moreover, negotiating with patients would should be explained to the patient, in the hope create the impression that staff are responsible that they will change their mind and ponder for the continuation of treatment, rather than their refusal to comply, bearing in mind the the patient. On that basis, staff would end up possible benefits of treatment termination pleasing the patient in order to achieve the ob- from a programme does not imply that it will jective of getting him/her to attend the clinic, be impossible to make further attempts. even if only to follow some unstructured, inef- 86 · CHAPTER 2.2

References procedures. In: PARRINO M. W. (Ed.) State Methadone Treatment Guidelines. U.S. Department of Health & 1. BALL J. C., ROSS C. A. (1991): The Effectiveness of Human Services, Rockville,MD. pp. 33-46. Methadone Maintenance Treatment Springer-Verlag, 11. MAREMMANI I., BARRA M., BIGNAMINI E., New York. CONSOLI A., DELL’AERA S., DERUVO G., FANTINI 2. COOPER J. R., ALTMAN F., BROWN B. S., F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI CZECHOWICZ D. (1983): Research on the treatment G. P., JARRE P., MICHELAZZI A., MOLLICA R., of narcotic addiction. State of the Art. Treatment NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA Research Monograph Series. N.I.D.A, Rockville, C., SPAZZAPAN B., STARACE F., TAGLIAMONTE Maryland. A., TIDONE L., VENDRAMIN A. (2002): Clinical 3. DOLE V. P., NYSWANDER M. E., WARNER A. (1968): foundations for the use of methadone. Italian Successful treatment of 750 criminal addicts. JAMA. Consensus Panel on Methadone Treatment. Heroin 206 2708-2711. Addict Relat Clin Probl. 4:(2) 19-31. 4. FINNEGAN L. P. (1995): Addiction and Pregnancy: 12. MAREMMANI I., PACINI M., LUBRANO S., Maternal and Child Issues. In: TAGLIAMONTE A., GIUNTOLI G., LOVRECIC M. (2002): Harm reduction MAREMMANI I. (Eds.): Drug Addiction and Related and specific treatments for heroin addiction. Different Clinical Problems. Spinger-Verlag, Wien New York. pp. approaches or levels of intervention?. An illness- 137-147. centred perspective. Heroin Addict Relat Clin Probl. 5. FINNEGAN L. P. (2000): Women, pregnancy and 4:(3) 5-11. methadone. Heroin Addict Relat Clin Probl. 2:(1) 1-8. 13. MAREMMANI I., PACINI M., LUBRANO S., 6. FINNEGAN L. P., KANDALL S. R. (1997): Maternal LOVRECIC M., PERUGI G. (2003): Dual diagnosis and neonatal effects of alcohol and drugs. In: heroin addicts. The clinical and therapeutic aspects. LOWINSON J. H., RUIZ P., MILLMAN R. B. (Eds.): Heroin Addict Relat Clin Probl. 5:(2) 7-98. Substance Abuse: A Comprehensive Textbook 2nd ed. 14. O’HARE P. (1994): Starring Harm Reduction Williams & Wilkins, Baltimore,Md. pp. 513-564. (Editorial). Int J Drug Policy. 5 199-200. 7. GUFFENS J. M. (1994): Toxicomanies Hépatites 15. PARRINO M. W. (1993): State Methadone Treatment SIDA. Les Empêcheurs de Penser en Rond, Le Plessis Guidelines. Treatment Improvement Protocol (TIP) Robinson. Series, 1. U.S. Department of Health and Human 8. GUFFENS J. M. (1998): HIV, hepatitis B, C and drug Services, Rockville, MD. addiction IV. Revue Francaise de Gastro-Enterologie. 16. ROSEMBACH A., HUNOT V. (1995): The introduction XXXIV 334. of a methadone prescribing program to a drug-free 9. GUFFENS J. M. (1999): The treatment of viral hepatites treatment service: implications for harm reduction. in drug addicts. Heroin Addict Relat Clin Probl. 1:(2) 35- Addiction. 90 815-821. 38. 17. WELLS B. (1994): Methadone Maintenance Treatment: 10. LANGROD J. (1993): Admissions policies and harm reduction or rehabilitation? Addiction. 89 806. 2.3

The Phases of Treatment I. Maremmani and M. Pacini

A Methadone Maintenance treatment pro- increasing the starting dosage by a maximum gramme consists of four successive phases: rate of 25% every four days. Narcotic blockade induction, stabilization, maintenance, medica- starts at around 60 mg/day, even if this level tion withdrawal. is incomplete, because it can be overcome by higher narcotic (heroin) loads. The starting dosage for withdrawal control 1. Induction phase usually falls inside a range of 20-60 mg/day, that is, below the threshold level for narcotic blockade. Some subjects, however, require As the starting phase of MMT, the induc- higher dosages, of as much as 100 mg/day: de- tion phase has two main aims, which can be spite this, induction should proceed to higher differentiated in chronological order: dosages for those subjects, too, since blockade a) to extinguish possible withdrawal symp- should be based on the individual’s recent toms at treatment entrance, by a dosage which tolerance to street narcotics, not to an aver- depends on the current level of acquired toler- age value. For heavy users, therefore, narcotic ance to opiates. This aim is usually achieved blockade must be able to guarantee full block- in the first few days, sometimes in as little as ade against heavy loads of street narcotics. 24 hours. Heavy narcotic users do, in fact, resort to very b) to increase the dosage up to a value high loads in order to keep feeling the ‘rush’, which is beyond the reach of higher narcotic beyond the control of withdrawal, whereas an doses, and provide a narcotic blockade by the addict with low tolerance can obtain the same down-regulation of binding sites and massive effects with lower narcotic loads. As a rule, competition with those still available. therefore, the final level of tolerance to opi- This second objective can be achieved by ates as a result of induction will be higher than

87 88 · CHAPTER 2.3 the phases of treatment · 89 whatever it was at treatment entrance. say, extremely hazardous. If a patient reports Some safety rules should be borne in mind feeling “completely well” throughout the first during the induction phase, as brilliantly 24 hours, the dose probably exceeds his/her pointed out by Payte [24]. tolerance level. If the patient feels “wonder- Safety rules are important, since a majority ful”, or even “better than ever before” after of methadone-related deaths among people the first dose, intoxication may follow the ad- who are in treatment take place during the ministration of similar dosages on the follow- first ten days of methadone administration [2, ing days. Euphoria following first-day metha- 5, 29]. done dosage should therefore be regarded as a First of all, the patient’s level of tolerance warning for possible intoxication to come. should be defined, and his/her daily condition When patients are not tolerant (for exam- monitored until blocking dosages have been ple, in the case of patients discharged from reached without adverse events. It should be prison, after detoxification and in a drug-free remembered that methadone blood levels and regimen) the induction schedule should be peaks rise steadily during the first few days, particularly cautious, with smaller increases at until a steady-state kinetic pattern has been longer intervals (applying a minimum of five established, even when the dosage is kept days). Safety rules for induction are summa- stable. rized in table 1. For non-tolerant subjects, the starting dos- To exemplify, if a non-tolerant patient is age is 10±5 mg, whereas for current users given a dose of 30 mg on the first day, and the whose tolerance is unknown, one can start same dose is repeated on each of the next few with 20±5 mg. If the patient’s tolerance is days, the risk of methadone-related death by known, starting dosages can be 20-40 mg; if breath arrest will be at its highest on the 4th withdrawal symptoms persist or worsen, these and 5th days (when methadone peaks before can be repeated at 2-hour intervals (when the the onset of the steady state pattern). In other level of methadone in the blood is peaking). words, a single 30 mg dose is not by itself le- The average anti-withdrawal dose is about 30 thal to a non-tolerant subject, but the repeated mg. However, if, on the first day, a dose is ad- administration of a non-lethal dose for four or ministered all at once, without being titrated five days may prove to be lethal [6]. on a clinical basis (withdrawal symptoms at 2- Once a steady state has been established, hour intervals), it may be effective on the first increases in dosage are no longer hazardous, day, but may still lead to intoxication when as long as the suggested increases specified repeated on the second or third day. The final above are respected. methadone blood levels will rise steadily dur- Also, it is not advisable to administer the ing the first few days, filling the gap between dose all at one time, on the grounds of the ap- tolerance balance and lethal intoxication. As parent severity of withdrawal: higher scores methadone is a slow, long-acting opiate, the on withdrawal scales do not always corre- development of intoxication is not immedi- spond to higher levels of tolerance. Higher ate but gradual, and accumulation is expected levels of withdrawal discomfort cannot be before the steady state condition is reached. viewed as a good reason for challenging the Also, signs of withdrawal are easier to recog- patient with higher methadone dosages with- nize than signs of intoxication. Although coma out titration (e.g. 60 mg as a single dose). Also, is the eventual outcome of opiate intoxication, while titrating the anti-withdrawal dose, uri- the pre-coma phase may be characterized by nalyses can reveal the presence of any other insomnia and psychomotor excitement, which substances (e.g. alcohol and benzodiazepines) may lead to it being mistaken for withdraw- which the patient could have become tolerant al, so prompting the administration of extra to, or which the patient could currently be in- methadone. toxicated by. Increasing the dose from the first day after The induction phase is immediately fol- withdrawal has been verified is, needless to lowed by the stabilization phase. A narcotic 88 · CHAPTER 2.3 the phases of treatment · 89

Table 1. Methadone treatment. safe induction recommendations

Early Induction Early dose adjustments to reach the "Therapeutic Window" as determined by established opioid tolerance "The Comfort Zone". Increase dose daily until patients comfortable during methadone peak levels (3-8 hours after dose), then hold dose for 3-5 days to reach steady-state before further dose adjustments Remember steady-state pharmacology Effect of a dose IS NOT determined by clinical presentation at 24 hours Initial doses WILL NOT "hold" for 24 hours Effect of a given dose is based on status at 3-6 hrs. The patient doing well at 3-6 hours does not need a dose increase, even if showing signs/symptoms of withdrawal at 24 hours. If patient thinks an increase is needed, repeat dose from previous day and ask patient to return in 3-4 hours for further assessment Any sign or symptom of over-medication during early induction requires a dose reduction Beware the subtle signs/symptoms of overmedication: feeling good, extra energy, staying awake to work, etc Patients may need more time not more medication

From Payte (2004): Heroin Addict Relat Clin Probl 6(1) pag. 37

addict induced by up to 80 mg/day of metha- attempts being made to keep one’s dosage lim- done usually still craves for narcotics. His/her ited or tapered back - and that opposition to craving may have become even worse than be- demands for dose reduction is the exit route fore, and be reported in a special way by the out of craving, although the patient may feel patient, who has become aware of having been sceptical about it. led into a condition of reduced sensitivity to Therefore, the non-compliant behaviour of opiates. Addicts who were still feeling their the addicted patient should not be disapproved rush, maybe at low dosages, may have found of as a boycott on treatment, but be challenged their craving exacerbated at blocking dosages, as one target of the treatment itself. and may react by increasing their attempts to handle treatment themselves. The transition from a blocking to a stabilizing dosage should 2. Stabilization phase therefore be implemented as quickly as possible, in order to minimize dropout rates. Be- cause of the nature of addiction, the patient Once blocking dosages have been reached, will insist on dose reduction, in order to be treatment proceeds with the aim of extinguish- able to feel the effects of narcotics without having addictive behaviours and avoiding relapsing to spend much. The physician must reject es [23]. Stabilization is enough, despite the ap- this reaction, which is an expression of crav- parent short-term interruption of narcotic use, ing, so as to achieve stabilization. Bearing this since core addictive symptoms are still pres- aim in mind, psychoeducational sessions may ent, and need to be counteracted by further be a useful way of making the patient aware therapeutic means [11]. In fact, an addict who that the physician too is mindful of the pres- is under narcotic blockade but is still craving ence of craving, the rising discomfort caused for narcotics will not automatically work for by the absence of narcotic euphoria, and the rehabilitation, or stick to the aims of treatment, 90 · CHAPTER 2.3 the phases of treatment · 91 but will tend to drop out or break treatment ment, delusions or hallucinations). In other rules until stabilization has been achieved. cases, psychiatric disorders will emerge later A minority of addicts become stabilized on, or will only become evident after the re- as soon as they take blocking dosages, even if mission of acute intoxication. This often occurs these are below 60 mg/day, but as a rule one with affective disorders, which may comprise will have to increase the dosage after success- persistent dysthymic states (termed ‘long-term ful induction. As long as they receive anti- withdrawal’) and which only improve after withdrawal dosages, patients mostly feel bet- several months. Another case is that of inter- ter and gradually lose their urgent motivation mittent, cyclic affective disorders which may for treatment. When moving on to blocking become evident during apparently successful dosages, many patients will start feeling like stabilization, and suddenly hamper the reha- leaving the programme, since their craving bilitation process. A manic phase of a bipolar will overwhelm their feeble motivation for disorder may develop after months of opiate treatment. This makes it imperative that clini- abstinence and treatment compliance; to illus- cians should not overrate the strength of moti- trate this, it may be pointed out that the con- vations to treatment as expressed during with- sequences, behavioural disruption and lack of drawal and induction, or mistake them for an insight brought about by such phases are no actual insight into the nature of the disease. less severe than those brought on by addiction When reaching the range of blocking dosage, [13, 14]. the transition to anticraving dosages should be On practical grounds, polyabusers are like- achieved as quickly as possible. ly to need higher stabilization dosages [15]. In the past, the only feasible way to stabi- For cocaine abusers this may be due to the use- lize a patient was to observe his/her behaviour ful antagonist effect of methadone towards the day by day, and adjust treatment elements on behavioural toxicity of cocaine. Alcohol abus- a case by case basis. It was possible to deepen ers, on the other hand, have a spontaneous the knowledge about the issues of stabilization tendency to stabilize at lower dosages, prob- dosage and time required for stabilization. In ably because of the synergy between alcohol the present situation, as soon as such items of and methadone in reducing craving for opi- knowledge have been acquired, they should ates. This synergy is only apparent, however, be applied, in order to shorten the latency for because it is not equivalent is terms of rehabil- stabilization and increase dosages automati- itative potential: alcohol abusers may stay in cally to certain thresholds, instead of proceed- treatment and remain abstinent from opiates, ing step by step. In other words, for a number but will probably fail to return to a normal of different categories of subjects, stabilization level of functional efficiency, despite partial can be planned as early as treatment entrance. improvement. Moreover, ongoing alcohol use, In the complex patterns of psychic impair- even when not in an addictive mode, is a risk ment of addicted people, craving for narcotics disposition for alcoholism. So too, cocaine us- is a constant, but it may not be the only desta- ers may find that the unpleasant effects of their bilizing factor. Cravings for other substances addiction are masked by methadone, but the and other mental disorders may play a signifi- unfavourable effects of their cocaine-seeking cant role, too. Besides this, subjects with little behaviours, including the risk of developing a or no residual craving for narcotics may still be full-blown cocaine addiction, will not be extin- in a mental condition which does not favour, guished [13]. or actually impedes, the treatment process. For Dual diagnosis subjects need higher stabi- instance, some psychiatric disorders may keep lization dosages, and take longer to reach such individuals completely unstable despite their dosages, beyond the time technically required continued abstinence from opiates determined to gradually increase doses [13]. Our impres- by anticraving treatment. In some cases, sig- sion is that the typical delayed recurrence of nificant psychiatric symptoms are evident manic or mixed states in these patients does from the beginning (e.g. psychomotor excite- not allow their level of stability to be mea- 90 · CHAPTER 2.3 the phases of treatment · 91

sured early in the course of stabilization. As a positive way, as a therapeutic tutoring of cere- result, the dosage cannot be increased earlier, bral functioning through which rehabilitation while dose adjustments can only be made af- can proceed spontaneously [7, 8]. ter symptom-free observation intervals, unless During the maintenance phase all facilities contingency planning has been undertaken which favour, boost, or quicken rehabilitation from the outset. are welcome. The same interventions which would be useless for street addicts, or for patients at an earlier stage in the course of treat- 3. Maintenance phase ment, become potentially useful once stabilization has been achieved. It should be borne in mind that rehabilitating a patient does not The MMT philosophy is centred on the goal mean shifting the focus of treatment from of its maintenance phase, which is to preserve pharmacological to psychosocial grounds; it stabilization. The philosophy of maintenance just means a continuing concentration on what comprises two principles, the first static and has been made possible by ongoing pharma- the second dynamic. The static principle is to cological treatment. In other words, the goal continue using the combination of therapeutic of rehabilitation has a wider scope than just elements which has led addictive symptoms to symptom control and relapse prevention, but extinction, and has allowed the achievement of does not replace these. In a chronic disease, in a satisfactory level of personal and social func- fact, no discontinuation of treatment goals is tioning. Rehabilitation is the dynamic aspect. possible: an integrated treatment programme The reconstruction of whatever has been ob- will always, before and during rehabilitation, structed, damaged, hampered or cancelled by rely on a bio-pharmacological basis [10, 16]. addiction does take place on the foundations Later psychosocial interventions on stabilized of ongoing treatment. Ongoing treatment is patients must be thought of as supplementary the only form of intervention able to ensure rather than complementary. Lastly, a number that the circuit between psychosocial function- of addicts may be not in need of any rehabili- ing and addiction-related cerebral damage op- tative effort from the outside, but be able to erates positively, by keeping the pathophysiol- benefit enough from basic treatment to enter ogy of the disease under control (“detached”), into a spontaneous process of self-directed re- and avoiding symptoms that might emerge habilitation. and interfere. As a result, the individual is free to decide and evolve. Rehabilitation, therefore, does not become a definitively acquired result 3.1 Duration of treatment or an achievement, but should be considered as a reversible result kept feasible by the maintenance of treatment, at least over the first few Generally speaking, treatment can never be years. Rehabilitation does not correspond to a labelled as no longer necessary, because there situation of positional equilibrium, but marks is no available time limit at which the likeli- a balance between two active drives, one to- hood of spontaneous relapse falls to zero [3, wards relapse (the underlying disease) and the 9, 25]. When evaluating whether treatment can other towards remission (ongoing treatment). be suspended, one should consider the follow- Even a short-term interruption of treatment ing: is therefore bound to result in a reactivation of 1) therapeutic dependence is by all means the circuit between psychosocial functioning preferable to disease chronicity; and the altered brain, in a way that rehabilita- 2) remission by treatment is far more likely tion will be counteracted by whatever instruc- than spontaneous remission (which is an tions are given by the addictive brain [26-28]. exception); Maintenance corresponds to the concept of 3) for untreated subjects, premature death is therapeutic dependence, to be interpreted in a the most likely way for addiction to come 92 · CHAPTER 2.3 the phases of treatment · 93

to a spontaneous end. of severe psychiatric disorders along with Although there is no predefined term for addiction. treatment to stop, it can be said that a minority of treated subjects (5-20%) are found to be dependent on treatment after as long as 10 years 4. Medication withdrawal of disease remission. The majority usually accomplish the phase of medication withdrawal within 10 years, running only a low risk of re- See chapter about Medically-supervised lapse. withdrawal. Duration of treatment is crucial for success. The longer the treatment lasts, the farther the person proceeds in terms of rehabilitation. 5. Treatment control measures and treat- Even when no immediate relapse takes place, ment rules one disadvantage of premature treatment withdrawal is often what could be labelled as psychosocial ‘freezing’: the subject fails to Frequency of attendance is usually corre- make any further progress on psychosocial lated with the fulfilment of therapeutic goals grounds; as a result, levels of perceived stress [1, 18-21]. When patients are in a critical condi- increase, and the subject is held back. Like- tion, they may need daily checking, and dur- wise, the quality of life is limited and nothing ing the first few days of treatment the effects is more than satisfying. of medications should be checked frequently, Our advice is to avoid withdrawing sub- if necessary more than once a day during the jects from treatment (or decreasing their dos- early stages of induction. ages) in any of the following situations: Later on, daily attendance may still be 1) Addiction is in remission and the patient functional to treatment, since addicts tend to has started rehabilitating. self-handle medications regardless of thera- 2) Addiction is in remission and rehabilita- peutic goals. The main risk is not the diver- tion has already been achieved to a cer- sion of methadone, but that the patient is not tain extent, but new and stressful factors going to take the prescribed doses. Addiction, are emerging, even if these may be due like the most other psychiatric disorders, but to the enrichment of social life and an in- unlike other somatic illnesses, is characterized crease in productive potential. Subjects by no or little insight, so that the patient is in- bearing the burden of acquired opioid capable of behaving in a way that favours a damage may feel distressed by circum- good outcome. The truth is that addicted pa- stances which stimulate normal subjects, tients will welcome any anti-withdrawal treat- such as new responsibilities at work or ment or short-term measure to improve their social challenges. present discomfort, but will fail to adhere to 3) Addiction is in remission but narcotic- any structured, long-term intervention, or will related stimuli are well represented in a try to discontinue it as soon as they feel any patient’s daily life environment. improvement. On the whole, addicts assume 4) Addiction is in remission, but the subject treatment is useful for 1) buffering withdraw- maintains a low productive potential, and al; 2) restoring their sensitivity to opiates and complains about low energy and intoler- eliminating physical dependence, so reducing ance to stress (in this case, a dose increase the waste of money spent to feel euphoria from or antidepressant treatment should be narcotics; 3) getting help when conditions are considered). critical, such as moments when they have run 5) Addiction has been in remission for out of money and can no longer rely on social years; methadone maintenance only, in support. the absence of additional psychotropics, The frequency of attendance should there- has been marked by the stable remission fore depend mainly on the severity of addic- 92 · CHAPTER 2.3 the phases of treatment · 93

tive symptoms. In relation to the phases of the expected blood peak of methadone treatment, frequency should be: (which lasts 2-6 hrs): what clinicians need a) daily. This is typically required during to verify is whether the patient refuses to induction. The involvement of signifi- take the prescribed dose, which would cant ones in the administration of daily mean he/she has not been taking it (los- doses may allow patients to attend less ing tolerance), and wants to avoid over- frequently than daily, but not before dosing or having blood levels raised up blocking dosages have been achieved. to a blocking level on that day. Refusing Opening hours of treatment units should to take the entire methadone dose in front not be limited to 9 to 5, let alone limited of the staff should be viewed as a symp- to a few hours early in the morning, as tom of addiction. often happens in some countries. Once Take-home may be suspended in the fol- blocking dosages have been reached, at- lowing cases: tendance should still be required daily in a) The patient misses appointments for the following situations: delivery, just skipping a couple of days 1) The patient has a low level of compli- or an entire week, which clearly means ance (skips days, insists on dose reduc- he/she is not taking as much metha- tion, refuses to swallow the entire dose done as prescribed. in front of the staff or throws up after b) The patient rejects prescriptions, in- leaving the room). sists on taking lower dosages and/or 2) The patient used to be stabilized, but withdrawing the medication as soon has since relapsed. as possible. Reducing dosages in take- 3) The patient is a polyabuser of synergic home regimens is acceptable when pa- drugs or has current severe psychiatric tients have been stabilized for a long symptoms that need daily checking. time, but never because the patient has b) twice a week. This may be a reasonable requested it. Conversely, if a patient in- compromise to allow working activi- sists, at any stage, on reducing the dos- ties and a productive life. Actually, any age, that should be regarded as a risk service will allow a take-home privilege disposition to relapse, and may even from the start, at least for closing days justify a decision to return to a super- (Sundays), so initial attendance is less vised daily administration regimen. than daily. Our view is therefore that c) The patient diverts take-home metha- there is no real need to pass from daily to done, selling it or just giving it to weekly attendance through an intermedi- friends. In such cases, it is preferable ate twice-a-week phase. that the patient should not be chal- c) weekly. Patients are given take-home lenged with legal issues. Physicians doses for six days after taking their meth- should remind patients that if any be- adone dose in front of the staff on the day haviour is legally censored, that goes of delivery. This is only advisable when against prescriptions to the patient: compliance has been satisfactory for some more specifically, the medical reason time and stabilization has been achieved. for suspending take-home is not be- Administration of the entire methadone cause the methadone was sold, but dose in front of the staff once a week is because that stands as evidence that the simplest way of checking that patients the patient had not been following pre- are tolerant to that dose, which means scriptions. they have been taking that amount dur- In conclusion, take-home may be sus- ing the past week. It should be noted that pended when patients behave in such this kind of test is behavioural rather than a way that they can no longer be con- pharmacological, since the patient is not sidered eligible for take-home (see required to continue waiting throughout chapter). 94 · CHAPTER 2.3 the phases of treatment · 95

d) less than weekly. In this case, general be referred to specialized centres for their in- practitioners can directly provide pa- dividual needs. tients with monthly prescriptions, allow- What is really missing in the field of addic- ing patients to receive supplies of metha- tion treatment is the availability of facilities done from pharmacies. As for weekly with first-aid units linked to residential cen- take-home, patients need to have been tres, which would meet the needs of homeless stabilized for a long time. The patient addicts who cannot be stabilized effectively in should be requested to take methadone the street. under the prescribing physician’s super- In other circumstances, coercion may be vision on the day of prescription delivery, needed to satisfy the patients’ request for in order to be able to check compliance treatment, so that jail or psychiatric wards through the behavioural testing of toler- may be the only suitable settings. Patients may ance. Patients who no longer take metha- be admitted to compulsory treatment and dis- done should be followed up regularly, charged in a free environment after induction in order to prevent them from relaps- has been accomplished. ing after not being in touch for months, On the other hand, some settings have little which increases the likelihood of a severe impact on the therapeutic course: short-term relapse. Moreover, the worsening of psy- hospitalization, for example, does not make chosocial adjustment could be monitored it possible to reach a high level of tolerance, regularly, and agonist treatment restored and does not increase the likelihood of reten- if necessary, without leaving the patient tion in treatment. Waiting lists to enter resi- with the exclusive responsibility for his/ dential centres, in the absence of methadone her problems, with only a poor prospect treatment, are equivalent to a temporary and of rehabilitation. unjustified lack of treatment. One may say that methadone treatment is not the rule within residential centres (so-called therapeutic com- 6. Methadone maintenance in different munities), so patients will probably have to be settings weaned off methadone before admission or immediately after admission. The same happens in the case of jailing. A drug-free condition, Stabilized patients can be followed up in a and a consequent admission into a therapeutic variety of settings: psychiatric in- and outpa- community, often correspond to what families tient units [15], addiction treatment units, pri- “fancy” and patients prefer, when they wish to vate practices, methadone clinics, residential lose their acquired tolerance to opiates or ‘take centres [4], jail [12, 22], general practice [17]. a breather’ on psychosocial grounds. Some settings are inappropriate for certain Requiring the withdrawal of treatment as a stages, before the achievement of stabilization, criterion for admission into a therapeutic com- because some basic therapeutic elements may munity is in conflict with any claim to a thera- be unavailable. Generally speaking, the best peutic perspective for addiction. solution for the treatment of addictive diseases is a dedicated clinic, employing a staff with skills in addiction medicine and psy- References chiatry. The presence of physicians with other 1. BROWN L. J. (1993): Responsible take-home medication practices. In: PARRINO M. W. (Ed.) State skills, such as infectivologists, allows patients Methadone Treatment Guidelines. U.S. Department of the benefits of a better therapeutic setting, ap- Health & Human Services, Rockville,MD. pp. 67-72. 2. CAPLEHORN J. R., DRUMMER O. H. (1999): plying the principle of one doctor’s shopping. Mortality associated with New South Wales Further staff specialized in steering the process methadone programs in 1994: lives lost and saved. Med J Aust. 170:(3) 104-109. of rehabilitation is advisable, though this may 3. D’AUNNO T., VAUGHN T. E. (1992): Variations in be helpful to stabilized patients only. methadone treatment practices. JAMA. 267:(2) 253- 258. Patients with special health concerns may 4. DE LEON G. (2002) Therapeutic community and 94 · CHAPTER 2.3 the phases of treatment · 95

maintenance treatment. Paper presented at the “Il MARINI G., TAGLIAMONTE A., SHINDERMAN Diavolo & l’Acquasanta – Verso una specializzazione M. S., MAXWELL S. (2000): Methadone Dose and dei trattamenti residenziali nella patologia delle Retention in Treatment of Heroin Addicts with Axis dipendenze: ‘Lucignolo & Co’ e il programma per I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. persone in mantenimento farmacologico”, Rivoli (To), 16. MAREMMANI I., ZOLESI O., DAINI L., NARDINI R., 15 Giugno. CASTROGIOVANNI P. (1995): Heroin Dependence. 5. DRUMMER O. H., OPESKIN K., SYRJANEN M., Theory of different levels of intervention. In: CORDNER S. M. (1992): Methadone toxicity causing TAGLIAMONTE A., MAREMMANI I. (Eds.): Drug death in ten subjects starting on a methadone Addiction and Related Clinical Problems. Springer- maintenance program. Am J Forensic Med Pathol. 13:(4) Verlag, Vienna, New York. pp. 225-232. 346-350. 17. MICHELAZZI A., VECCHIET F., CIMOLINO T. 6. GOSSOP M., BRADELY B., PHILIPS G. T. (1987): An (1999): General Practitioners and Heroin Addiction. investigation of withdrawal symptoms shown by Chronicle of a Medical Practice. Heroin Addict Relat opiate addicts during and subsequent to a 21-day Clin Probl. 1:(2) 39-42. inpatient methadone detoxification procedure.Addict 18. PANI P. P., PIRASTU R. (2000): Take-home and Behav. 12:(1) 1-6. compliance with methadone maintenance treatment. 7. GRÖNBLADH L., GUNNE L. M. (1989): Methadone- Heroin Addict Relat Clin Probl. 2:(1) 33-38. assisted rehabilitation of Swedish heroin addicts. 19. PANI P. P., PIRASTU R., MUSIO A., SOLINAS P., Drug Alcohol Depend. 24 31-37. GESSA G. L. (1994): Compliance and social adjustment 8. GUNNE L. M. (1983): The case of the Swedish during take-home treatment with methadone. methadone maintenance treatment program. Drug Addictive Drugs and Addictive States: The State of The Alcohol Depend. 11 99-103. Art 237-241. 9. HARGREAVES W. A. (1983): Methadone dosage and 20. PANI P. P., PIRASTU R., RICCI A., GESSA G. L. duration for maintenance treatment. In: COOPER J. (1996): Prohibition of take-home dosages: negative R., ALTMAN F., BROWN B. S., CZECHOWICZ D. consequences on methadone maintenance treatment. (Eds.): Research on the treatment of narcotic addiction Drug Alcohol Depend. 41 81-84. State of the art Treatment Research Monograph Series. 21. PARRINO M. W. (1993): State Methadone Treatment NIDA, Rockville, Maryland. pp. 19-79. Guidelines. Treatment Improvement Protocol (TIP) 10. MAREMMANI I. (1994): Comprehensive treatment Series, 1. U.S. Department of Health and Human of heroine dependence in Italy. Theory of different Services, Rockville, MD. levels of intervention, i.d. ‘breaking through a wall 22. PARRINO M. W. (2000): Methadone Treatment in Jail. of prejudices”,. The Italian Journal of Psychiatry and American Jails Magazine. XIV:(2) 9-12. Behavioural Sciences. 4:(2) 95-98. 23. PAYTE J. T., KHURI E. T. (1993): Principles of 11. MAREMMANI I., BARRA M., BIGNAMINI E., Methadone dose determination. In: PARRINO M. CONSOLI A., DELL’AERA S., DERUVO G., FANTINI (Ed.) State Methadone Treatment Guidelines. U.S. F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI Department of Health & Human Services, Rockville, G. P., JARRE P., MICHELAZZI A., MOLLICA R., MD. pp. 47-58. NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA 24. PAYTE T. J. (2004): Methadone Treatment. Safe C., SPAZZAPAN B., STARACE F., TAGLIAMONTE induction techniques. Heroin Addict Relat Clin Probl. A., TIDONE L., VENDRAMIN A. (2002): Clinical 6:(1) 35-42. foundations for the use of methadone. Italian 25. PAYTE T. J., KHURI E. T. (1993): Treatment duration Consensus Panel on Methadone Treatment. Heroin and patient retention. In: PARRINO M. W. (Ed.) State Addict Relat Clin Probl. 4:(2) 19-31. Methadone Treatment Guidelines. U.S. Department of 12. MAREMMANI I., PACINI M., LOVRECIC M. (2004): Health & Human Services, Rockville,MD. pp. 119- Clinical foundations for the use of methadone in jail. 124. Heroin Addict Relat Clin Probl. 6:(2-3) 53-72. 26. TAGLIAMONTE A. (1999): Heroin Addiction as 13. MAREMMANI I., PACINI M., LUBRANO S., normal illness. Heroin Addict Relat Clin Probl. 1:(1) 9- LOVRECIC M., PERUGI G. (2003): Dual diagnosis 12. heroin addicts. The clinical and therapeutic aspects. 27. TAGLIAMONTE A., MAREMMANI I. (2001): The Heroin Addict Relat Clin Probl. 5:(2) 7-98. problem of drug dependence. Heroin Addict Relat Clin 14. MAREMMANI I., PACINI M., PERUGI G., AKISKAL Probl. 3:(2) 7-20. H. S. (2004): Addiction and Bipolar Spectrum: Dual 28. TAGLIAMONTE A., MAREMMANI I., MELONI D. Diagnosis with a common substrate? Addictive (1991): Methadone Maintenance: a medical approach Disorders and Their Treatment. 3:(4) 156-164. to heroine addiction. In: LOIMER N., SCHMID 15. MAREMMANI I., ZOLESI O., AGLIETTI M., R., SPRINGER A. (Eds.): Drug Addiction & AIDS. Springer-Verlag, Wien. pp. 178-186. 29. ZADOR D. A., SUNJIC S. D. (2002): Methadone- related deaths and mortality rate during induction into methadone maintenance, New South Wales, 1996. Drug Alcohol Rev. 21:(2) 131-136. 96 · CHAPTER 2.3 2.4

The Issue of Dosage I. Maremmani and M. Pacini

The complex of addictive symptoms, com- methadone blood levels, that is, the biologi- prising the affective, the cognitive and the cally active portion of administered dosages behavioural, may be controlled by a range of [5, 6]. Since methadone blood dosing is not different methadone dosages for different in- performed as a routine (as it is in the case of dividuals, or for the same individuals at dif- lithium and some anticonvulsants), and can ferent times or stages of their addictive history be replaced by ‘on-the-spot’ clinical evalua- [1]. tions, almost all available data are expressed A minority of subjects can be stabilized ear- in terms of oral dosage, leaving out metha- ly on, with dosages below 60 mg/day, whereas done pharmacokinetics such as intestinal ab- a majority can be stabilized on a dosage rang- sorption and P450-related liver metabolism. ing between 60 and 140 mg/day, depending Studies carried out to investigate the correla- on the severity of addictive symptoms at the tion between oral dosages and expected blood time of treatment initiation [9]. levels indicate that higher dosages depend Other subjects require higher dosages, in on a condition of rapid liver metabolism: as some cases of as much as 1200 mg/day [13, a result, subjects needing two-to-ten times as 18]. much as the average oral dosage turn out to Lastly, some subjects require minimal dos- have the same expected blood levels as those ages (e.g. 10 mg/day) to be maintained in the requiring average-to-low oral dosages. Indi- long-term. This is needed to allow them to rectly, in the absence of direct blood dosing, a stay functional and avoid relapses, even when condition of rapid metabolism can be inferred no worsening of clinical conditions and no from the absence of expected metabolic in- relapse took place during a gradual tapering teractions which would increase blood level, from higher dosage levels [11, 12]. Better said, or lead to reports of symptoms indicative of the variability of dosage should be referred to emerging withdrawal before daily administra-

97 98 · CHAPTER 2.4 the issue of dosage · 99 tions (e.g. insomnia, sweating, shivering, run- or continue to worsen [21, 22]. Such an admin- ny nose, and yawning early in the morning, in istration schedule is effective and has proved cases where administration is scheduled for to be the safest in managing acute withdrawal the morning). The average effective metha- within the first 24 hours. From the second day done dosage, that is, the maintenance dosage, on, the cumulative dose applied on the first is around 100 mg/day (± 40 mg). The need to day can be safely administered every day in employ dosages over 140 mg/day is far more the morning. likely than a stable response with lower-than- In cases of ongoing or upcoming with- 60 mg/day dosages. On clinical grounds, the drawal from known dosages of methadone, terms ‘high’ and ‘low’ dosages are meaning- a patient can receive his/her habitual dose, less unless in comparison with one another. unless one or more days have passed. If one The terms ‘higher’ and ‘lower’ may be used to day has passed, one can administer half as indicate how a dosage value can be ranked in much as the habitual dose, gradually raising comparison with the effective average. the dose until the original value is reached Beyond that, dosages can be classified as within the next three days. If the subject has ‘lower-than-adequate’ or ‘adequate’, in terms not been taking any opiate for two days, one of their impact on the course of the disease third of the original methadone dosage is the (non-stabilized or stabilized, respectively), at advisable starting dose, followed by a gradual least up to the highest documented value of increase up to the original value within 5 days. 1200 mg/die. If three or more days have passed since the last known administration, the safest option is to employ the acute withdrawal first-day 1. Anti-withdrawal dosage schedule. If there has been recent exposure to various different opiates (e.g. if heroin is being used during methadone maintenance, or The administration of dosages of up to 60 if methadone is being self-administered due to mg/day is usually successful in buffering, or heroin unavailability) the safest rule is to as- preventing, symptoms of withdrawal, in case sume that the individual is tolerant to the dose the level of tolerance to opiates can be roughly of the weakest opiate habitually administered quantified. In (typical) circumstances, where (methadone, or heroin with respect to the pre- an individual’s present tolerance to opiates vious examples) [21]. cannot be estimated, the initial dose should not exceed 20 mg. If withdrawal symptoms persist or worsen after two hours, the same 2. Induction dosage dose can be administered a second time, and so on at two-hourly intervals until withdrawal symptoms start to become less severe. To fa- The medically assisted raising of tolerance cilitate such decisions, physiological param- levels (induction) is the phase leading from a eters (consciousness and wakefulness, myosis state of balanced somatic tolerance to opiates and breath rate) should be recorded from the towards the extinction of relapsing behaviour. beginning and re-checked at expected peaking Induction may start right after the buffering times after each single administration (these of withdrawal, or directly in the initial phase are given every two hours, approximately). of treatment, if no withdrawal is expected (i.e. It should be borne in mind that, when a dose with non-tolerant treatment-enterers). is repeated by using more than just one dose Since peak blood levels of methadone tend on the same day, the final peak induced is to rise during the first few days, before toler- higher than in the case of the earlier dose(s), ance has had time to develop, subsequent dose due to a cumulative effect. No further dosage increases should not be made more often than is required, and none should ever be admin- weekly. istered, unless withdrawal symptoms persist For as long as the first three days after 98 · CHAPTER 2.4 the issue of dosage · 99

the resolution of withdrawal, it is advisable higher methadone blood levels and a greater not to increase the dosage further. At a later likelihood of methadone intoxication. stage, dose increases can be as high as 10 mg per week. Usually, patients who are tolerant to higher dosages can have their dose increased 3. Stabilization dosage safely by higher amounts (20 mg per week). On the other hand, if patients are tolerant to lower dosages, especially in the presence of When the patient has been kept abstinent any factor acting in synergy with opiates (e.g. from street opiate use for at least six months, alcohol or benzodiazepines) rates of increase and is free of major psychopathological symp- can be kept lower (5 mg per week). The crucial toms, one can refer to the highest methadone leading general concept is that the equivalent dosage taken for at least two weeks in that pe- ‘excess’ corresponding to equal differences in riod as the stabilization dosage, meaning that oral dosages is inversely related to the level of the patient is stably guaranteed against the baseline tolerance. risk of relapse by treatment at that dosage. For subjects who are non-tolerant to opi- The time needed to reach the stabilization ates when starting treatment, the induction dosage varies; it is, predictably, longer for phase should proceed very cautiously, never higher dosages. It should be noted that some exceeding the low threshold increase of 5 mg patients, such as those with a dual diagnosis per week. for DSM-IV TR axis I mood disorders, take a Induction should be interrupted when particularly long time. Moreover, some pa- there are symptoms of opiate intoxication or tients may need to have their dose adjusted on adverse events related to methadone (e.g. itch- account of somatic or cerebral changes (e.g. in- ing, cholestasis) [22]. creased body mass index, pregnancy, stressful A patient entering the blocking range (usu- life events, or, alternatively, because of quick ally above 60 mg/day) may report an unde- progress in rehabilitation and a return to social fined form of discomfort due to the interfer- life). The outcome is that a stabilization dos- ence with heroin’s expected effects: a situation age can be interpreted as a stable target to be of this type does not justify any dose-reduction pursued through the use of a flexible dosage. or limitation of scheduled dose-increases. In fact, the goal of maintenance (see next para- Needless to say, ongoing opiate use while graph) is to preserve and restore stabilization, on methadone treatment does not increase the mainly by adjusting pharmacological treat- risk of overdosing, since opiates are competi- ment [21]. tive at the same receptorial binding sites, and there cannot be any kind of additive effect between them. On the other hand, the risk of 4. Maintenance dosage overdosing through the self-management of an abused opiate is curtailed both due to competition with methadone and to increased tol- The ultimate aim of maintenance mirrors erance (cross-tolerance). Even when a subject one primary reason for treatment initiation, self-administers higher drug dosages in order that is, individual and social adjustment. As a to overcome his/her acquired tolerance to result, ongoing rehabilitation, even beyond the methadone and feel the ‘rush’, the risk of over- level recorded before the onset of the disease, dosing is comparable to that of an opiate-naive does justify continuation of the maintenance individual who takes average street doses of phase. The loss of individual and social func- the drug. tioning during methadone treatment, even It is unsafe to administer methadone at in- when this occurs in the absence of full-blown creasing dosages together with other poten- psychopathology or relapse, should be inter- tially synergic agents or metabolic competi- preted as signs of inadequate dosing, and lead tors, because this will result in unpredictably to adaptation of the stabilization dosage [15]. 100 · CHAPTER 2.4 the issue of dosage · 101

5. Dosages in relation to phases and with chronic liver diseases are not expect- pharmacology ed to metabolize methadone to a lower extent than healthy subjects, so much so that subjects with chronic hepatitis C re- As a rule, the anti-withdrawal dosage is quire higher methadone dosages due to lower than the stabilization dosage, although an acceleration of the liver metabolism the gap is extremely variable. The blockade of [20]. a street opiate’s effects usually corresponds to b) patients who also take drugs which raise a threshold of 60 mg/die of methadone, and expected methadone blood levels [10]. becomes stronger at higher dosages [2-4]. Nar- c) patients who request a reduction in their cotic blockade is therefore likely to start taking dose after years of successful mainte- effect at anti-withdrawal dosages, before a full nance, in the absence of any narcotic use, anticraving (stabilization) dosage is reached. though minimal. Such patients may have Independently of this, a small minority of nar- their dose tapered to lower values and cotic addicts stop using street opiates in the ab- still maintain a satisfactory level of indi- sence of narcotic blockade (below 60 mg/day), vidual and social adjustment [17]. which indicates that craving suppression can Patients who do not tolerate effective be achieved directly, without interfering with methadone dosages should be directed to bu- the effects of self-administered narcotics. In prenorphine maintenance. The combination of any case, the interference with narcotic effects sub-effective methadone dosages with ancil- achieved by a heightened tolerance (i.e. by in- lary facilities, such as psychosocial treatment duction on full agonists) is far more effective or psychotherapies, though potentially useful, than that granted by antagonists. The induc- is not the best choice, since the latter do have a tion of high levels of tolerance to opiates, in significant impact on rehabilitation when core other words, is crucial for narcotic addiction symptoms are under control due to pharmaco- treatment to be successful. For some addicts, logical treatment [23]. who are tolerant to multiple synergic drugs The patient’s request to keep dosages low (e.g. opiates and benzodiazepines), anti-with- despite the presence of addictive symptoms, drawal dosages tend to be quite higher, so that or a past history of good response to lower they may already be in the blocking range. In dosages, is not a criterion for avoiding the em- order to rule out any confusion arising from ployment of average effective dosages. baseline withdrawal, subjects should first be Pregnancy is by no means a good reason for ‘detoxified’ as a preliminary to induction into using lower dosages; the induction of a preg- methadone by using slow dose-increasing nant narcotic addict into methadone should schedules. In approaching the average patient, follow the general rules [7, 8]. anti-withdrawal, blocking and stabilization dosages are best reached sequentially, through gradual dose increases. 6.2. Patients requiring higher dosages

6. Principles of good clinical practice As already mentioned, patients who consume high amounts of street opiates require higher withdrawal dosages, and, as a result, higher stabilization dosages. Moreover, some 6.1. Categories of patients who normally categories of patients are likely to require high- require lower dosages: er stabilization dosages regardless of baseline levels of withdrawal. Knowing the target dose in advance makes it possible to proceed by a) patients with liver or kidney failure. It adopting a dose-increasing schedule without should be borne in mind that patients wasting time, so shortening the time needed to 100 · CHAPTER 2.4 the issue of dosage · 101

achieve stabilization. a) Patients with a dual diagnosis for mood a) patients who start treatment with a drug disorders or psychotic disorders [14, 16, that inhibits the methadone metabolism 19]; during the treatment period; b) polyabusers; b) medically supervised withdrawal (see c) patients treated with drugs which accel- chapter). erate methadone’s liver metabolism [10]. On the basis of current trends, unjustified dose limitations or reductions can be said to be considerably more likely than unjustified dose 6.3. Dose increases increases. Moreover, the risk of unnecessary dose increases, unless too steep, are limited to a few side-effects, whereas the use of inad- The following situations require increases equate dosages or the premature reduction of in methadone dose: dosage may favour a relapse, or hamper the a) patients who report gathering extra process of rehabilitation. methadone on the black market. Increas- The following cases of dose reduction or ing the patients’ dosage, contrary to what limitations can be considered as malpractice, one might think, leads to a fall in the de- since they loom as a self-justifying aim: mand for methadone outside therapeutic - reduction of the stabilization dosage be- contexts. Moreover, an increase in metha- fore a two year maintenance period has done employed for therapeutic purposes elapsed; will result in a reduction of illegal metha- - reduction of dosage in cases of persistent, done employed for non-therapeutic prac- though occasional, narcotic use; tices. Methadone holds no spontaneous - reduction of dosage to satisfy a patient’s appeal to narcotic addicts, but it may be request; resorted to occasionally by them to buffer - reduction of dosage before full rehabilita- withdrawal, or to detoxify in order to be tion is achieved; able to start again on cycles of euphoriz- - reduction of dosage in dual diagnosis ing narcotic use. When self-administering patients stabilized by methadone mono- methadone for non-therapeutic purposes, therapy, with a history of refractoriness addicts typically use low dosages, falling to standard psychiatric therapies or in the in the ‘anti-withdrawal range’; absence of other potentially effective psy- b) patients who still use heroin, although chotropics (it is worth noting that the sub- less often than before; traction of methadone treatment, with the c) patients who report craving, or behave as aim of replacing methadone with another their aim were to increase the likelihood psychotropic on the grounds of narcotic of their being offered the drug, or be able addiction control, is never advisable). to purchase it, even when no actual relapse has taken place yet; d) patients who are being treated with a References drug, or drugs, which accelerate the 1. CAPLEHORN J. R. M., BELL J. (1991): Methadone dosage and retention of patients in maintenance methadone metabolism; treatment. The Medical Journal of Australia. 154 195- e) pregnancy, beyond the sixth month. 199. 2. DOLE V. P., NYSWANDER M. E. (1966): Rehabilitation of heroin addicts after blockade with methadone. N Y State J Med. 66(15) 2011-2017. 3. DOLE V. P., NYSWANDER M. E. (1967): Heroin 6.4. Dose Reductions Addiction: A Metabolic Disease. Arch Intern Med. 120 19-24. 4. DOLE V. P., NYSWANDER M. E., KREEK M. J. (1966): Narcotic Blockade. Arch Intern Med. 118 304-309. The following situations may justify a re- 5. EAP C. B., BOURQUIN M., MARTIN J., SPAGNOLI J., LIVOTI S., POWELL K., BAUMANN P., DEGLON duction in methadone dose: J. (2000): Plasma concentrations of the enantiomers of 102 · CHAPTER 2.4

methadone and therapeutic response in methadone 15. MAREMMANI I., BARRA M., BIGNAMINI E., maintenance treatment. Drug Alcohol Depend. 61:(1) CONSOLI A., DELL’AERA S., DERUVO G., FANTINI 47-54. F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI 6. EAP C. B., DEGLON J. J., BAUMANN P. (1999): G. P., JARRE P., MICHELAZZI A., MOLLICA R., Pharmacokinetics and pharmacogenetics of NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA methadone: clinical relevance. Heroin Addict Relat Clin C., SPAZZAPAN B., STARACE F., TAGLIAMONTE Probl. 1:(1) 19-34. A., TIDONE L., VENDRAMIN A. (2002): Clinical 7. FINNEGAN L. P. (2000): Women, pregnancy and foundations for the use of methadone. Italian methadone. Heroin Addict Relat Clin Probl. 2:(1) 1-8. Consensus Panel on Methadone Treatment. Heroin 8. FINNEGAN L. P., HAGAN T., KALTENBACH K. Addict Relat Clin Probl. 4:(2) 19-31. (1991): Opioid dependence: Scientific foundations 16. MAREMMANI I., CANONIERO S., PACINI M. of clinical practice. Pregnancy and substance abuse: (2000): Methadone dose and retention in treatment of Perspective and directions. Bulletin of the New York heroin addicts with Bipolar I Disorder comorbidity. Academy of Medicine. 67 223-239. Preliminary Results. Heroin Addict Relat Clin Probl. 9. HARGREAVES W. A. (1983): Methadone dosage and 2:(1) 39-46. duration for maintenance treatment. In: COOPER J. 17. MAREMMANI I., NARDINI R., ZOLESI O., R., ALTMAN F., BROWN B. S., CZECHOWICZ D. CASTROGIOVANNI P. (1994): Methadone Dosages (Eds.): Research on the treatment of narcotic addiction and Therapeutic Compliance During a Methadone State of the art Treatment Research Monograph Series. Maintenance Program. Drug Alcohol Depend. 34 163- NIDA, Rockville, Maryland. pp. 19-79. 166. 10. IRIBARNE C., DREANO Y., BARDOU L. G., MENEZ 18. MAREMMANI I., PACINI M., LUBRANO S., J. F., BHERTHOU F. (1997): Interaction of methadone LOVRECIC M. (2003): When ‘enough’ is still not with substrates of human hepatic cytochrome P450 ‘enough’. Effectiveness of high-dose methadone in 3A4. Toxicology. 117 13-23. the treatment of heroin addiction. Heroin Addict Relat 11. KING V. L., STOLLER K. B., HAYES M., UMBRICHT Clin Probl. 5:(1) 17-32. A., CURRENS M., KIDORF M. S., AL. E. (2002): A 19. MAREMMANI I., ZOLESI O., AGLIETTI M., multicenter randomized evaluation of methadone MARINI G., TAGLIAMONTE A., SHINDERMAN medical maintenance. Drug Alcohol Depend. 65:(2) 137- M. S., MAXWELL S. (2000): Methadone Dose and 148. Retention in Treatment of Heroin Addicts with Axis 12. KREEK M. J. (1992): Epilogue: Medical maintenance I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. treatment for heroin addiction, from a retrospective 20. MAXWELL S., SHINDERMAN M. S., MINER A., and prospective viewpoint. State Methadone BENNET A. (2002): Correlation between hepatitis C Maintenance Treatment Guidelines. Office for Treatment serostatus and methadone dose requirement in 1.163 Improvement, Division for State Assistance, 255-272. methadone-maintained patients. Heroin Addict Relat 13. LEAVITT S. B., SHINDERMAN M., MAXWELL S., Clin Probl. 4:(2) 5-9. EAP C. B., PARIS P. (2000): When “enough” is not 21. PAYTE J. T., KHURI E. T. (1993): Principles of enough: new perspectives on optimal methadone Methadone dose determination. In: PARRINO M. maintenance dose. Mt Sinai J Med. 67:(5-6) 404-411. (Ed.) State Methadone Treatment Guidelines. U.S. 14. LOVRECIC M., CANONIERO S., AGLIETTI M., Department of Health & Human Services, Rockville, MAREMMANI I. (1999): Methadone stabilization MD. pp. 47-58. dosages and retention in treatment in heroin addicts 22. PAYTE T. J. (2004): Methadone Treatment. Safe with Axis I Psychiatric Comorbidity for Mood induction techniques. Heroin Addict Relat Clin Probl. Disorders. Zdravniski vestnik. 68 555-558. 6:(1) 35-42. 23. RAMER B. S., ZASLOVE M. O., LANGAN J. (1971): Is methadone enough? The use of ancillary treatment during methadone maintenance. Am J Psychiatry. 127 1040-1044. 2.5

Long-Term Perspectives E. Trogu and P. P. Pani

1. Premise standard prognosis. - It implies a high level of subjective discomfort and an incapacity to behave in Once addiction sets in, even if a late spon- line with one’s intentions, especially as taneous remission cannot be excluded, it is far as pleasure, motivation and self-stim- likely to last for several decades. A variety of ulation are concerned. factors are relevant to the initiation of opiate - It is characterized by an altered state of narcotic use. Once a person has experienced the brain’s opiate metabolism, which the effects of illegal narcotics, an evolution tends to resist healing, even after a long towards abuse is possible, and one probable period of stable abstinence from narcot- outcome is addiction. Out of 10 individuals ics, as shown by Kreek and colleagues who try heroin, 3-5 become addicted at some [17]. The main clinical element mirroring stage. Once addiction has developed, periods this kind of damage is craving, which is of active use alternate with drug-free intervals the pathological equivalent of desire. which may continue for decades. Addictive - It ‘runs in the family’ in a way homolo- symptoms are directly related to as many as gous to, or displaying indirect indicators 20-25% of the deaths of narcotic addicts. shared by, various forms of abuse/addic- Addiction is a chronic disease: tion impulsiveness and affective instabil- - It is characterized by a set of commonly ity. shared signs and symptoms, regardless of - Standardized treatment can modify the race, personal details and socioeconomic natural course of the disease, regardless variables. of other factors. ·- It has a relapsing course, which, in the ab- - Its distinctive clinical picture is ‘craving’, sence of treatment, must be considered its which is responsible for a high percent-

103 104 · CHAPTER 2.5 long-term perspectives · 105

age of post-detoxification relapses. ment varied considerably (1-6 years) in a co- Any rehabilitative effort, even if strong hort perspective, showing improvement for all and long-lasting, will be ineffective, if applied groups through time in terms of arrests, work- alone, in preventing relapses. On the other ing status and social skills (including rises in hand, a correct pharmacological regimen, with personal income as witnessed by the ability to craving as the clinical target, allows rehabilita- pay for treatment with one’s own resources). tion to proceed, at times spontaneously. The results recorded for ‘office-based’ treat- Long-term methadone treatment counter- ment regimens showed similar results. acts and curtails the abnormalities displayed Ball and Ross [2] indicate duration as the by an addict’s brain [15]. Moreover, metha- most relevant factor in influencing outcome, done treatment normalizes the hormonal dys- together with dosage, level of staff competence, regulation accompanying narcotic addiction, good staff-patient relationships, and allowing for instance, the excessive cortisol release elic- patients admission to take-home regimens. ited by stressful events [17]. 3. Long term safety 2. Duration as a predictor of outcome

Research and clinical studies suggest that, Methadone maintenance treatment has no on medical grounds, MMT can be considered pre-defined duration. This perspective was safe [3]. Kreek showed that methadone is free presented as an original feature of effective of toxic effects and its side-effects are accept- methadone treatment in the very first studies able in the long term (14 years or longer for by Dole and Nyswander [4, 5] in the 60’s, but adult patients and 5 years or longer for under- it continues to be controversial. The first long- age youngsters) [17]. term observations about methadone treatment Novick [28] confirmed a high safety level were published by Gearing in 1974 [10], as an among patients treated for 11-18 years, and the independent evaluation of Dole’s treatment absence of unexpected adverse events. Long- programmes at Manhattan General Hospital at term treatment is neutral on the heart, lungs, the end of ten years. Results indicated a global live, kidneys, bone, blood, brain and other positive impact as evaluated by such parame- vital organs. Recent studies [1, 12, 16, 21, 31, ters as reduction of disruptive and criminal be- 33] and the Cochrane review [8] agreed with haviour, increase in productivity, craving con- previous evidence: as in Dole’s early works trol and abstinence from narcotic use, as well [6, 7], recent studies [31] report the absence of as engagement in other treatment programmes treatment-related mortality in a group of 158 designed to challenge further substance use patients observed under treatment for over 15 disorders, mental illness, and somatic diseas- years. The Consensus Conference of the Na- es. Evidence of this kind, followed by further tional Institute on Health [25] concluded that confirmation, led to the spread of methadone the “safety and effectiveness of opiate agonist maintenance treatment programmes. maintenance has been undoubtedly proved”. Appel and colleagues [1] compared pa- As for cognitive functions, Wechsler rating tients in treatment for over 10 years with oth- scale scores indicated no impairment over a ers treated for less than five, on the basis of 10-year treatment period [11]. variables such as number of arrests, hospital- Before the spread of MMT, death rates in izations, resorting to first aid care, working sta- the USA ranged from 13 to 44/1000 inhab, tus, and other substance use: patients treated 21/1000 on average. Interestingly, after MMT over longer periods proved to do better, espe- had spread, these rates fell to 13/1000 inhab cially as regards number of arrests and work- on average. In Switzerland, the spread of ing status. Kott [16] examined a population of MMT was followed by a sharp decline in the patients whose length of time spent in treat- incidence of lethal overdoses [30]. The most 104 · CHAPTER 2.5 long-term perspectives · 105

compelling evidence of the impact of MMT Actually, one study [22] found that the on survival rates emerges from the compari- higher the maintenance dose (80 mg in this son between MM-treated subjects and other case), the higher the probability that the pa- addicts: in studies dealing with this issue, the tient will become drug-free. On the other death rates of MM patients are less than one hand, other studies reported the consequences third of those among non-MM addicts [13, of premature medication withdrawal: Ball and 25]. Ross [2] found a 82% relapse rate into intravenous narcotic use among detoxified subjects after 10 months, 50% of relapses taking place in 4. Maintenance dosage and the problem the first three months. Older addicts may stay of premature withdrawal abstinent, but with a higher risk of switching to heavy alcohol use. Dole and Joseph [7] also reported the failure of detoxification to reduce Effective methadone dosage is reached relapse-related mortality. during the stabilization/maintenance phase, Physicians should not suggest medication on Payte’s definition [29], and corresponds to withdrawal or force the patient to undergo the achievement of craving extinction, narcotic it. A major part of the global treatment effort blockade, and abstinence from narcotics. Once should, in fact, be directed to getting the patient stabilization has been achieved, ongoing meth- to stay in treatment comfortably for as long as adone administration has the aim of maintain- necessary. A diagnosis of addiction is enough, ing the state of clinical remission. This form of even without considering the likelihood that stability is made possible by a stable binding the patient has suffered from multiple relapses balance with available opioid receptors, which or has already reached a revolving-door stage, allows methadone’s activity on the opiate sys- to justify long-term treatment. The urgency of tem to persist indefinitely, as long as the dose the need to become drug-free, mirrored by the is held stable (over periods of up to 20 years, or quickness of detoxification procedures, stems even longer) [18]. Nevertheless, some patients directly from the idea that one can manage to may require dose adjustment as time passes. ‘quit addiction’ by quitting treatment. A state Remission should never be the only reason for of well-being is not predictive of stable absti- a decision on dose reduction. In fact, this is one nence when it is reached quickly (or abrupt- major concern about the long-term handling ly, as in ultra-rapid detoxification); in other of methadone maintenance by physicians and words, it does not correspond to a lower risk its perception by the patient: the ‘lower is bet- of relapse. Also, with regard to environmental ter’ approach stems from the conviction that factors, becoming drug-free in favourable en- maintenance is just a delay, though necessary, vironmental conditions - an event sometimes in achieving a drug-free state. If this way of described by patients as ‘turning over a new thinking is adopted, the philosophy of metha- leaf’ - does not correspond to any newborn done maintenance is completely lost, and the balance. Long addiction histories clearly show idea that treatment is ‘the real enemy’ grows how periodic abstinence and apparently spon- in the patient’s mind to the point where com- taneous remission are the rule between relaps- pliance is endangered. Other groundless no- es. A healthy lifestyle with habitual abstinence tions support such a feeling, such as those of from the use of any substance, alcohol includ- the supposedly lower toxicity associated with ed [32], is a positive predictor on rehabilitative lower-dose maintenance, and the need to step grounds, but is not reliable as a predictor of no closer to eventual medication withdrawal by further relapses. In conclusion, if detoxified or staying low on one’s dose. Some myths about rehabilitated patients start complaining about methadone are widespread among street ad- re-emerging drug-related thoughts and crav- dicts and physicians, such as the idea that it ings, or slips, they should be started on treat- is toxic to the bones, or that it is harder to do ment again [20]. without than heroin itself. 106 · CHAPTER 2.5 long-term perspectives · 107

5. Cultural factors and their interaction coupled with a good prognosis (i.e. low risk with maintenance treatment of relapse) still remains an ideal condition: to date, however, there are no technical instruments available to make this possible for the Methadone treatment is strongly stigma- vast majority of narcotic addicts [25]. On the tized by public opinion. The main point at is- other hand, we can provide those patients sue is that this treatment is often seen as ruling with a treatment regimen that can control their out any possibility of true healing by making disease in the long-term, if necessary through- the patient’s condition chronic and merely out their lives. replacing heroin with methadone, while add- One day, it may be that methadone-main- ing a risk of worsening the original condition tained subjects who started treatment at a through the accumulation of chronic toxic ef- younger age, and at adequate dosages - sub- fects. jects who are still in treatment years later - will According to McLellan [23, 24], scepticism have a realistic prospect of staying out of treat- of this kind originates from the groundless ment with only a negligible risk of relapse. conviction that addiction is a transient disor- Concerns about retaining patients in treat- der, rather than a chronic illness. On that view, ment prompt the need to minimize the draw- the quality of a treatment can be judged by its backs of methadone maintenance treatment. power to extinguish the disorder in the short Patients may drop out because of heavy side- term, with the implication that no relapse can effects, or because the treatment is too expen- be expected unless it arises from a patient’s sive, or else interferes with normal daily life wilful intention. Addiction is thought of in a and working activity. It is true that methadone different way from other chronic disorders, maintenance does not have a heavy impact in so that people often fail to understand that terms of side-effects, but, especially in the long remission means symptom extinction and the term, the requirement of weekly attendance, let normal functioning of the individual. Prob- alone daily attendance, is an important draw- lems arise because the persistence of symp- back, and is perceived as creating a stigma, in toms after treatment reduction or discontinu- the sense that it makes patients feel different ation is regarded primarily as a proof of the from other categories of patients [25]. treatment’s ineffectiveness in extinguishing Different treatment settings have been ex- the original disorder. The focus of judgement perimented so far, such as office-based and is not on what an addictive disease implies by primary care programmes, where opiate-ad- definition - chronicity, and, along with that, dicted patients are managed like any other proneness to relapse - but on treatment, with category of ill people. Taken together, those perspectives driven by an unrealistic expec- de-stigmatizing settings are referred to as tation: that short-term healing is attainable. ‘medical maintenance’. For any chronic disorder, the right premise to obtaining good results is a long-term maintenance of the therapeutic state, with no limits to 6. Medical maintenance duration and medication dosage. Methadone treatment corresponds to the general rule of maintenance treatment for chronic disorders: The expression ‘Medical Maintenance’ the expected results must be rooted in the ef- indicates a treatment stage at which rehabili- fects of ongoing treatment - craving control, tated addicts can be integrated into the nor- the prevention of continuous use and poly- mal health system. They no longer need to abuse, narcotic blockade, the normalization be treated in dedicated clinics, as in front-line of functions while allowing ample scope for maintenance programmes, but are referred to rehabilitation and psychosocial interventions, general practitioners or private physicians, as crime control and reduction of infective risk). with any other category of patient [19]. Medi- A drug-free and treatment-free condition cal Maintenance allows continuing metha- 106 · CHAPTER 2.5 long-term perspectives · 107

done maintenance in a way that is specifically some substance of abuse, while no cases of suited to rehabilitated patients who work reg- methadone overdose or diversion were docu- ularly, abstain from street drugs and have no mented. Participants reported significant im- relationships with other ‘active’ addicts [27]. provements in their quality of life. Medical Maintenance offers a way of making Salsitz [31] examined 158 patients followed long-term treatment as compatible as pos- up for 15 years by Medical Maintenance and sible with a normal life, for patients who have found an 83.5% compliance rate, retained pa- been asymptomatic for years. Another factor tients reporting fewer obstacles in improving to be consdered is that rehabilitated patients their working and private life. As many as usually dislike attending clinics where they 8% became drug free after 17.7 years on aver- meet active addicts, whereas in these settings age. Death rate was 13%, with no cases due they are rewarded by an increasing level of to methadone-related causes, while nicotine autonomy and trust. Self-esteem is positively smoking was indirectly responsible for 40% of influenced when reasons for the imposition of deaths. The most frequent cause of treatment cultural stigmas, such as treatment promiscu- failure was crack/cocaine use. ity or strict supervision in specialized clinics, Fiellin [9] compared a standard methadone are eliminated [27]. treatment setting to a primary care access set- The first attempts date back to 1985, when ting in a controlled, single-blind randomized Dole and Nyswander transferred 25 metha- manner. Patients were less stable on average, done-maintained patients to a general medical because they had been abstinent for at least setting [27]. Patients had been selected by ap- one year (instead of three). Patients were eval- plying the following criteria: at least five years uated over a six-month period, with weekly of standard treatment, regular and licit work- access. Whenever appropriate, patients were ing activity for the last three years, no record granted ancillary facilities. The only differ- of criminal activitiy; no alcohol or substance ence between groups concerned the patients’ use; satisfactory compliance with treatment; satisfaction with treatment, a higher number affective stability; no relationships with active of primary care probands rating it as excellent. addicts (in order to avoid diversion). Physicians were highly satisfied with their Patients were evaluated monthly, had to work with these patients. Episodic substance deliver a urine sample and took their whole use was frequent in the whole sample (52% day’s methadone dose under supervision, but slipped at least once on some illicit drug), and received a take-home supply for the following 20% were clinically unstable. Authors conclude 28 days. Medical concerns and other problems that primary care can be equivalent in terms were discussed on the spot. of effectiveness, and superior on rehabilitative That original pilot programme was gradu- grounds, but only a subgroup of patients are ally expanded. A follow-up study on the first suitable for such a regimen. 40 patients reported a 94% retention rate and a The ‘shared care’ model [34] consists of a low incidence of substance use [26, 27]. About group of specialized physicians and dedicated 6% of patients were sent back to standard social workers collaborating with a network methadone maintenance due to loss of some of GPs. Brooner performed a multicentric ran- inclusion criteria, such as abstinence from sub- domized trial [14] which proved that Medi- stances (cocaine, 12%, was the most frequent). cal Maintenance can be successful when run Some 5% were withdrawn from methadone. within a standard medical setting. Authors The perception of the regime by patients was also point out that the intensity of care should sharply positive, both in terms of effectiveness be based on clinically assessed needs, in accor- and setting [27]. dance with a ‘stepped care’ model: patients are Schwartz [33] performed a 12-year follow- given additional care when necessary, but step up evaluation on 12 patients treated in a GP back to the standard level of care when their setting and reported a 28% dropout rate. As need disappears. few as 0.5% of urinalyses turned positive for 108 · CHAPTER 2.5

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P., Y Acad Sci. 311 181-189. KLEBER H. D. (2000): Drug dependence, a chronic 8. FAGGIANO F., VIGNA-TAGLIANTI F., VERSINO medical illness: implications for treatment, insurance, E., LEMMA P. (2003): Methadone maintenance at and outcomes evaluation. Jama. 284:(13) 1689-1695. different dosages for opioid dependence. Cochrane 25. NIH (1998): Effective medical treatment of opiate Database Syst Rev. 3:(CD00 2208). addiction. National Consensus Development Panel 9. FIELLIN D. A., O’CONNOR P. G., CHAWARSKI M., on Effective Medical Treatment of Opiate Addiction. PAKES J. P., PANTALON M. V., SCHOTTENFELD R. Jama. 280:(22) 1936-1943. S. (2001): Methadone maintenance in primary care: a 26. NOVICK D. M., JOSEPH H., SALSITZ E. A. (1994): randomized controlled trial. Jama. 286:(14) 1724-1731. Outcomes of treatment of socially rehabilited MMP in 10. GEARING F. R., SCHWEITZER M. D. (1974): An physicians’office (Medical Maintenance): follow-up epidemiologic evaluation of long-term methadone at three and half to nine and a fourth years. Journal of maintenance treatment for heroin addiction. Am J General Internal Medicine. 9:(3) 127-130. Epidemiol. 100 101-112. 27. NOVICK D. M., PASCARELLI E. F., JOSEPH H., 11. GORDON N. B., WARNER A., HENDERSON A. SALSITZ E. A., RICHMAN B. L., DES JARLAIS D. (1967): Psychomotor and intellectual performance C., ANDERSON M., DOLE V. P., NYSWANDER M. under Methadone Maintenance. National Academy E. (1988): Methadone maintenance patients in general of Sciences, National Research Council, Committee medical practice: A preliminary report. JAMA. 259(22) on Problems of Drug Dependence, Washington, DC. 3299-3302. 12. GOSSOP M., MARSDEN J., STEWART D., TREACY S. 28. NOVICK D. M., RICHMAN B. L., FRIEDMAN (2001): Outcomes after methadone maintenance and J. M., FRIEDMAN J. E., FRIED C., WILSON J. P., methadone reduction treatments: two-year follow- TOWNLEY A., KREEK M. J. (1993): The medical up results from the National Treatment Outcome status of methadone maintained patients in treatment Research Study. Drug Alcohol Depend. 62:(3) 255-264. for 11-18 years. Drug Alcohol Depend. 33 235-245. 13. GRÖNBLADH L., ÖHLUND L. S., GUNNE L. M. 29. PAYTE J. T., KHURI E. T. (1993): Principles of (1990): Mortality in heroin addiction: impact of Methadone dose determination. In: PARRINO M. methadone treatment. Acta Psychiatr Scand. 82 223- (Ed.) State Methadone Treatment Guidelines. U.S. 227. Department of Health & Human Services, Rockville, 14. KING V. L., STOLLER K. B., HAYES M., UMBRICHT MD. pp. 47-58. A., CURRENS M., KIDORK M. S., CARTER J. 30. PERRET G., DEGLON J. J., KREEK M. J., HO A., LA A., SCHWAETZ R. E., BROONER R. K. (2002): A HARPE R. (2000): Lethal methadone intoxications in multicenter randimized evaluation opf methadone Geneva, Switzerland, from 1994 to 1998. Addiction. medical maintenance. Drug Alcohol Depend. 65 137- 95:(11) 1647-1653. 148. 31. SALSITZ E. A., JOSEPH H., FRANK B., PEREZ 15. KOSTEN T. R., GEORGE T. P. (2002): The Neurobiology J., RICHMAN B. L., SALONON N., KALIN M. of Opioid Dependence: Implications for Treatment. F., NOVICK D. M. (2000): Methadone medical Research Reviews - Science & Practice perspectives. mainenance (MMM): treating chronic opioid 16. KOTT A., HABEL E., NOTTINGHAM W. (2001): dependence in private medical practice - a summary Analysis of behavioral patterns in fice cohorts report (1983-1998). Mt Sinai J Med. 67:(5-6) 388-397. of patients retained in methadone maintenance 32. SAMHSA (1995): Matching treatment to Patient programs. Mt Sinai J Med. 68:(1) 46-54. Needs in Opioid Substitution therapy - TIP Series 20. 17. KREEK M. J. (2000): Methadone-related opioid agonist SAMHSA,, Washington, DC. pharmacotherapy for heroin addiction. History, recent 33. SCHWARTZ R. P., BROONER R. K., MONTOYA I. D., molecular and neurochemical research and future in CURRENS M., HAYES M. (1999): A 12-year follow-up mainstream medicine. Ann N Y Acad Sci. 909 186-216. of a methadone medical maintenance program. Am J 18. LOWINSON J., MARION I., JOSEPH H., DOLE V. Addict. 8:(4) 293-299. (1992): Methadone maintenance. In: LOWINSON J., 34. WEINRICH M., STUART M. (2000): Provision of RUIZ P., MILLMAN R., LANGROD J. (Eds.): Substance methadone treatment in primary care medical abuse: a comprehensive textbook. Williams and Wilkins, practices: review of the Scottish experience and Baltimore. pp. 550-561. implications for US policy. Jama. 283:(10) 1343-1348. 19. LOWINSON J. H., RUIZ P., MILLMAN R. B., LANGROD J. G. (1992): Substance Abuse. A Comprehensive Textbook. Williams & Wilkins, 2.6

Medically Supervised Withdrawal from Methadone I. Maremmani and M. Pacini

The progressive tapering of methadone to gramme. Withdrawal from methadone may reach a level of tolerance may be prescribed for be accomplished through a variable degree of various different reasons and be performed in tapering and by using various different time a range of settings. On medical grounds, meth- terms. adone tapering should only be started when When tapering is quite slow, no withdraw- some rationale is in place with regard to the al-related discomfort is reported. When, on the treatment of opiate addiction. Conversely, ta- other hand, tapering starts after a maintenance pering should not be tried when it is expected phase with no recent dose reduction, discom- to heighten the risk of relapse, or worsen the fort of varying degrees may develop, depend- expected outcome of concurrent medical or ing on how steep the tapering is. MSW is con- psychosocial problems. Also, dose reduction ceptually different from any dose reduction should never be thought of as a ‘step forward’ requested or performed by the patient, against towards an ideal drug-free condition; any such or without medical advice. In either of these view would make treatment seem an unjusti- two cases, the dose may be reduced, but self- fied prolongation of higher dose maintenance. wise dose reductions should never be rated in Any schedule of methadone tapering the same way as a medical prescription, since should be referred to as ‘medically supervised their meaning usually carries an opposite im- withdrawal’ or ‘medically supervised subtrac- plication (craving-related), or leads to an option’ of therapeutic methadone, instead of the posite result (a worse outcome). unjustified and misleading expression ‘detoxi- MSW can be proposed when patients are fication’. stabilized at a 50 mg/day dosage or less. MSW The medically supervised withdrawal of should not be initiated for patients stabilized methadone (MSW) may be the end phase of at blocking dosages: those patients may be- a methadone maintenance treatment pro- come suitable for MSW after a long period of

109 110 · CHAPTER 2.6 medically supervised withdrawal from methadone · 111 stabilization at lower dosages, but should not of the neuronal opiate metabolism. As a rule, pass from a condition of remission at blocking stepping down from higher dosages is more dosages to a high-risk condition like that cor- comfortable than applying reductions from responding to possible sensitivity to opiates lower dosages (with reference to a full block- (no narcotic blockade). As a rule, the risk of re- ade threshold). The last 60 mg are the most lapse should never increase sharply, as it does awkward to taper, unless the tapering schedule when the reduction of anticraving coverage is stretched out so as to last longer, proceeding is coupled with the loss of narcotic blockade, by taking shorter steps. Patients who report no which may turn a slip into a full and fast re- discomfort when quickly tapering from higher lapse due to reinforcement. dosages should therefore be warned that this An acceptable degree of tapering is by 5-10 has no prognostic meaning, and is due to a mg steps down to 20 mg/day, as intervals of non-linear dose-effect relationship between this kind leave time for possible withdrawal dose reduction and withdrawal. In some cen- discomfort to be extinguished before taking tres, the tapering schedule used is 1 mg/day, further steps [8, 9] (Figure 1). An acceptable which is meant to minimize withdrawal-relat- time interval between reduction steps is 15 ed anxiety and objective symptoms. In reality, days. Below 20 mg/day, tapering may proceed this procedure is not reasonable, since it does by taking 5 mg steps. not account for the pharmacological profile During tapering, the relative weight of of methadone, which implies late-onset with- dose gaps should be taken into account, rather drawal, so that the effects of successive 1 mg/ than absolute dose values. In fact, considering day dose reductions accumulate after the first equal dose gaps between different tapering week, when ‘unexpected’ discomfort starts to steps, withdrawal discomfort varies according rise. Usually, patients undergoing a tapering to the corresponding level of up-regulation schedule like this ask their physician to keep

Figure 1: Methodology of Methadone Maintenance: Reduction of Medication after Maintenan- ce 110 · CHAPTER 2.6 medically supervised withdrawal from methadone · 111

their dose stable for some time before reducing dosage. Likewise, MSW is absolutely unrea- again, or return to an intermediate value. sonable for patients testing positive for sub- A reduction based on 5-10 mg step reduc- stances or alcohol, or if there is any clinical evi- tions makes it possible to challenge the pa- dence of relapse or of a switch to another class tient’s opiate system by applying a significant of drugs [5, 7]. It should be remembered that stress, and verifying the clinical significance of alcohol and benzodiazepine abuse is made the corresponding reaction. If any discomfort more likely by inadequate methadone cover- is experienced, MSW should be discontinued age [3], and that a high proportion of benzo- and the previous dose should be restored. diazepine abuse in narcotic addicts is induced Clinical worsening is a good reason for step- by medical prescriptions. ping back and restoring the latest known sta- Using benzodiazepines to accomplish bilization dosage. MSW more comfortably is, firstly, a concep- The patient’s will, or his/her urgency, tual mistake, since MSW becomes an objective should never be considered a clinical reason rather than a clinically funded procedure. Sec- for applying MSW [1, 2]. If the patient has ondly, the adoption of MSW would result in reduced methadone in a self-wise manner, the subtraction of a relapse-preventing treat- the physician should not resort to MSW as a ment regimen coupled with the induction of resource for proceeding with methadone ta- another addictive syndrome (benzodiazepine pering in a supervised way, since any such or alcohol-related) with poorer treatment out- decision would lack a rationale. Likewise, in comes [7]. the case of a self-managed dose reduction, Actually, MSW should not be thought of treatment should not continue at the dose de- as complete when methadone dose is zero: a cided by the patient; the original stabilization follow-up is needed to discharge the patient dosage should be restored. As already stated from the programme, and this must include above, it is counter-therapeutic to regard self- urinalyses and clinical evaluation. Any degree wise handling of methadone as an acceptable of worsening of the patient’s condition, on any behaviour by proceeding in the same direction grounds, may be a reason for restarting meth- or not stepping back and returning to the latest adone induction, up to the latest stabilization prescribed dosage. dosage [4]. MSW is suitable when patients are in at When MSW is justified in terms of the past least one of the following categories: therapeutic course and the patient’s current - a minimum of two years of maintenance, clinical condition (i.e. prognostic judgment) with a minimum of one year of stable ab- no additional means are needed for it to be ac- stinence from narcotics; complished. Similarly, the need for rapidity or - no substance use during narcotic absti- ultra-rapidity in performing MSW is limited to nence, with special regard to alcohol, conditions in which patients are forced to live benzodiazepines or sedatives; in geographical areas where methadone treat- - global rehabilitation, with a sharp change ment is unavailable, or in situations where it is in the patient’s lifestyle. not even feasible (e.g. under war conditions). MSW carries a certain degree of risk when it is undergone before the rehabilitation process is complete, with major psychosocial problems References still present [4]. 1. Deglon J. J. (1982): Le traitement à long terme des héroînomanes par la Mèthadone, Editions Mèdicine et MSW must be performed without resorting Hygiène, Genève. to anti-withdrawal drugs, including benzodi- 2. Deglon J. J. (1994): Toxicomanie et traitements de substitution par la methadone, l’un des plus azepines [6]. Urinalyses should be performed formidables malentendus de l’histoire de la médicine. weekly during MSW, together with alcohol-re- In: Guffens J. M. (Ed.) Toxicomanie Hépatites SIDA. Les empecheurs de penser en rond, Le Plessis- lated tests. The need to buffer clinically signifi- Robinson. pp. 215-230. cant discomfort is a reason for discontinuing 3. Lubrano S., Pacini M., Giuntoli G., Maremmani I. (2002): Is craving for heroin MSW and restoring the previous stabilization and alcohol related to low methadone dosages in 112 · CHAPTER 2.6

methadone maintenaid patients. Heroin Add & Rel 7. Maremmani I., Shinderman M. S. (1999): Clin Probl. 4:(2) 11-17. Alcohol, benzodiazepines and other drugs use in 4. Maremmani I. (1999): Treating Heroin Addicts i.e. heroin addicts treated with methadone. Polyabuse or ‘Breaking through a Wall of Prejudices”. Heroin Add & undermedication? Heroin Add & Rel Clin Probl. 1:(2) Rel Clin Probl. 1:(1) 1-8. 7-13. 5. Maremmani I., Nardini R., Zolesi O., 8. Newman R. G. (1992): Methadone: simple pharmacology, Castrogiovanni P. (1994): Methadone Dosages complex politics. Lecture: School of Psychiatry, University and Therapeutic Compliance During a Methadone of Pisa, Maintenance Program. Drug Alcohol Depend. 34 163- 9. Newman R. G. (1995): The Pharmacological 166. Rationale for Methadone Treatment of Narcotic 6. Maremmani I., Pacini M., Lovrecic M. (2004): Addiction. In: Tagliamonte A., Maremmani Clinical foundations for the use of methadone in jail. I. (Eds.): Drug Addiction and Related Clinical Problems. Heroin Add & Rel Clin Probl. 6:(2-3) 53-72. Springer-Verlag, Wien New York. pp. 109-118. 2.7

Relapse Prevention and Handling I. Maremmani and M. Pacini

1. Supervised abstinence in a treatment- corresponding to a diagnosis of opiate addic- free regimen tion. Patients may still have a low risk perception, a factor which in itself favours new episodes of narcotic use: unlike what happened In the absence of ongoing effective treat- at the beginning of the disease process, single ment, a diagnosis of heroin addiction carries episodes are enough to trigger immediate, full a lifetime risk of relapse. To date, no evidence involvement in addictive narcotic use, instead has been put forward to attest to a way of pre- of a gradual intensification of narcotic use over dicting future relapses or discriminating be- a period of several months. The outcome is that tween low- and high-risk forms of the disor- periods of latency between single use episodes der. The only useful features are the following and addictive use become shorter and shorter clinical ones: severity of the disease before the through relapses, indicating an increased sen- onset of treatment; the time spent under treat- sitivity to narcotic reinforcement which does ment in a condition of symptom remission; the not tend to dwindle over time. results that have been obtained in response As a result, abstinence in a treatment-free to the ongoing treatment regimen, including regimen needs supervision, which is required the course of psychosocial rehabilitation. The to check whether rehabilitation is proceeding course of rehabilitation to be prescribed after despite treatment withdrawal and to evaluate the withdrawal of treatment must be taken the advisability of restoring some treatment into account, too [1-3, 5-7]. regimen in order to prevent relapse. Patients and significant ones should be Some patients may be in need of mainte- clearly informed about the risk of relapse as nance treatment, as when it is implemented something linked to the lifetime persistence of for psychotropic purposes, beyond any risk a metabolic abnormality of the opiate system, of relapse. Opiate agonists may be useful as

113 114 · CHAPTER 2.7 relapse prevention and handling · 115 alternative therapies for the control of patho- 2. Handling relapse logical anxiety, affective imbalance and painful syndromes, and may prove to be a unique resource for subjects with a history of narcotic Engaging again in narcotic use despite an exposure, who tend to be resistant to standard intention to stay abstinent sums up the clinical psychotropic medications. and prognostic meaning of addiction as a dis- Some patients with a dual diagnosis may ease. Relapsing behaviour is the core feature of stay symptom-free under a methadone-only addictive diseases, and, when never witnessed maintenance regimen, which is a reason for directly at an earlier stage, it brings confirma- thinking of longer-term maintenance as a solution of a diagnostic hypothesis of drug addiction to other psychotropic treatment regimens tion [8, 9]. of undefined effectiveness and tolerability When approaching a relapsing patient who [10]. It follows that, in those dual diagnosis pa- is already under treatment for addiction, dis- tients, agonist treatment should be considered appointment, concern and surprise are unac- as a means of relapse prevention with regard ceptable reactions from any staff member. Re- to the ensemble of neurobiological vulnerabili- lapse is fully consistent with the reason why ties. the patient was considered to be in need of On clinical grounds, the risk of relapse into treatment in the first place, and testifies to the addictive narcotic use should be considered as inadequacy of the ongoing treatment regimen, significant in the following situations: so indicating the need for treatment imple- - the subject has gone back to his/her origi- mentation or dose adjustment. nal environment after a period, no matter On clinical grounds, one can distinguish how long, of residence within a protected between two kinds of relapse: minor relapses environment; or is going through stress- (‘slips’), consisting of single use episodes with ful events or routines (even if with posi- a self-limiting course (without any resumption tive results, subjective satisfaction and of continuous use); and major relapses, which increased productivity) which are harder correspond to renewed use, showing similar to cope with than during treatment; patterns and involving similar amounts as - rehabilitation is incomplete, despite the before treatment. Slips must be accounted for availability of resources in the environ- as potential major relapses which have been ment; shielded by ongoing treatment, and would - single use episodes, even when there is have turned into true relapses in the absence no short-term relapse into addictive nar- of treatment. Major relapses indicate the inad- cotic use; equacy of treatment, and they may simply de- - the patient has a dual diagnosis showing pend on dosage. It is important to question the improvement on psychiatric grounds un- patient about the effects of self-administered der a methadone-only regimen, but has narcotics during relapses: if the patient resorts recently worsened, even if there are no to narcotics, it means no actual narcotic block- signs yet of addictive behaviour; ade is in place, or that it is not yet complete. - the subject is convinced he/she has a sec- However, dose-adjustment is usually required ond chance of becoming a controlled nar- to challenge major relapses and lead them to cotic user. extinction. When these are the circumstances, it is ad- On the whole, relapses of either rank should visable to restore the previous treatment be handled as follows: regimen. a) increasing the dosage in order to pursue a state of narcotic blockade, and a stronger anticraving effect; b) regular urinalyses; c) supervised dose-administration at regular intervals in order to ascertain the level 114 · CHAPTER 2.7 relapse prevention and handling · 115

of tolerance. If necessary, take-home can about a single slip and be unreasonably opti- be suspended. mistic about a relapse, in an attempt to con- Sadly, the most common reason for relapse vince others that relapsing is due to special under treatment is premature dose reduc- circumstances and does not need dose-ad- tion or treatment withdrawal. It is important justment. Alternatively, patients may suggest to bear in mind that relapses following dose that treatment be withdrawn or tapered, since reduction must not be ascribed to acute with- it has proved to be ineffective in controlling drawal symptoms: addicted patients are capa- craving. Attitudes like these simply corre- ble of handling withdrawal symptoms by ask- spond to how addicted patients are likely to ing for dose adjustment or a slower tapering react with respect to treatment in general, and schedule. On the other hand, when a relapse is are attributable to the intrinsic ambivalence of spontaneous, re-emerging addictive symptoms addiction [4]. render patients incapable of asking for help, and lead them to narcotic use. Thereby, relapsing should not be interpreted as a reasonable reaction to withdrawal. Addicts who experi- References ence methadone withdrawal tend to handle it 1. Daley D. C., Marlatt G. A. (1993): Relapse by resorting to non-opiate drugs, rather than Prevention: cognitive and behavioral interventions. In: Lowinson J. H., Ruiz P., Millman B. R., Langrod stepping back on their methadone tapering. J. C. (Eds.): Substance abuse, a comprehensive textbook Narcotic use by former heroin addicts must al- Williams & Wilkins, Baltimore. pp. 533-543. 2. Dole V. P. (1972): Narcotic addiction, physical ways be rated as a sign of addiction. dependence and relapse. N Engl J Med. 286 988-992. Hence, physicians should not retry taper- 3. Gorelick D. A. (1993): Overview of pharmacologic treatment approaches for alcohol and other drug ing or medication withdrawal after an initial addiction: Intoxication, withdrawal, and relapse attempt has been followed by relapse. The ra- prevention. Psychiatr Clin North Am. 16:(1) 141-156. 4. Kilpatrick B., Howlett M., Sedgwick P., pidity of tapering just does not matter. Ghodse A. H. (2000): Drug use, self report and Patients who express urgency about ac- urinalysis. Drug Alcohol Depend. 58 111-116. 5. Martin W. R. (1972): Pathophysiology of narcotic complishing the withdrawal of treatment de- addiction: possible role of protracted abstinence in spite their relapsing behaviour should be in- relapse. In: Zarafonetis C. J. D. (Ed.) Drug abuse. Lea and Febiger, Philadelphia. pp. 153-159. formed of the clinical meaning of their present 6. Slater V., Linn M. W., Harris R., Odutola A. condition. Physicians should never evaluate a A. (1981): A retrospective review of relapse. J Psychiatr Treat Eval. 3 515-521. patient’s claimed good intentions to abstain as 7. Stimmel B., Goldberg J., Cohen M., Rotkopf the predictor of a positive outcome. E. (1978): Detoxication from methadone maintenance: Risk factors associated with relapse to narcotic use. Later relapses have the same meaning with Ann N Y Acad Sci. 311 173-180. respect to previous dose reductions of medica- 8. Tagliamonte A. (1999): Heroin Addiction as normal illness. Heroin Add & Rel Clin Probl. 1:(1) 9- tion withdrawal. 12. The patient’s reaction to relapse carries an 9. Tagliamonte A., Maremmani I. (2001): The problem of drug dependence. Heroin Add & Rel Clin important meaning. As a rule, patients will Probl. 3:(2) 7-20. tend to report slips, and minimize or deny 10. U.S. Department of Health and Human Services, Substance Abuse and Mental relapses. Also, they will tend to be concerned Health Services Administration, Center for Substance Abuse Treatment (2003): Medical Assisted Treatment for the 21st Century. Comparison Chart of Heroin Dependence and Agonist Therapies, HHS-SAMHSA, Washington. 116 · CHAPTER 2.7 2.8

Adverse Events During Methadone Treatment I. Maremmani, A.G.I. Maremmani and M. Pacini

1. Global toxicity There is no scientific evidence to support such attitudes; methadone-treated subjects, unlike narcotic-users, cannot be distinguished from Methadone maintenance treatment is a safe normal subjects. Possible differences depend therapeutic regimen [45, 48, 50, 52, 57, 78]: be- on past narcotic use history, not on ongoing in treatment, even for as long as 18 years, ing treatment. Psychomotor functioning and has never been related to a greater risk of organ readiness show no significant differences with failure, structural or functional damage. High- respect to normal subjects [32]. Methadone- er dosages (over 100 mg/day) are no more maintained subjects, as long as they are not toxic than lower ones [80]. The fact that metha- abusing any other psychotropics, can be con- done has such a low level of toxicity is surely a sidered fit to drive [2 , 17 , 36 , 58 , 82 , 86] great stroke of good luck for a treatment which is meant to last a long time and go through a long maintenance phase. Methadone contin- 2. Side-effects ues to be the most effective and widely used option for narcotic addiction treatment; stated in the simplest terms, it can be agreed that “the Some methadone-related side-effects fade main and most relevant impact of methadone during a course of treatment, once the induc- maintenance treatment upon the health status tion phase has been completed, while the pa- of addicted patients is the transition from im- tient is developing tolerance to the stabilization pairment to well-being [77]”. dosage. Later dose increases may be followed Many believe that methadone-treated sub- by similar effects due to acquired tolerance be- jects should be viewed as if lobotomized, or ing overcome, although this is less probable, as if they behaved like a brain-dead zombie. since the actual impact of dose increases is

117 118 · CHAPTER 2.8 adverse events during methadone treatment · 119 lower when starting from a higher tolerance proved to be useful in treating sexual dysfunc- level. In other words, an increase of 20 mg over tions during methadone maintenance, proba- a tolerance level corresponding to 60 mg/day bly due to its pro-dopaminergic action, which will have a greater impact than a similar 20 mg counterbalances methadone-induced hyper- increase from a 140 mg/day tolerance level. prolactinemia [83]. However, reduced free Somnolence, concentration impairment, testosterone may be the reason for sexual im- poor short-term memory, nausea, dizziness, pairment, regardless of prolactin levels. Other swelling due to water retention simultaneous- dopaminergic drugs or sildenafil-like drugs ly with reduced urine volume, hypotension or may be effective resources, too. (Deglon, per- bradicardia are all possible abnormalities that sonal communication). tend to re-adjust as a course of treatment goes Some patients report insomnia during treat- forward. The pain threshold, which usually ment. First, intoxication (stimulants) or with- rises initially during induction, also tends to drawal (benzodiazepines, alcohol) must be return to the level it had before treatment, or ruled out. Apart from that, one cause may be a with treatment at lower dosages [39 , 40, 48 ]. fast methadone metabolism, so that the night- Other expected side-effects, such as exces- time fall in methadone blood levels is greater sive sweating, constipation, irregular men- than expected, even when no full-blown with- strual patterns, sexual dysfunctions, increased drawal develops: in that case, split-dosing appetite and weight gain, do improve as a may be a solution. Sleep-inducing drugs may rule, although more slowly, and sometimes be used, preferably excluding fast-acting ben- persist in the long-term at stable dosages. zodiazepines, and resorting to anti-histaminic Excessive sweating is reported by as many agents, or antidepressants with sedative prop- as 50% of methadone-maintained patients: it erties (trimipramine, mirtazapine). Neurolep- corresponds to normotonic sweating, with- tic drugs may be a good choice for psychotic out abnormalities of serum electrolyte levels or excited patients, but they do tend to have a [1]. Dosage reduction is one simple way of negative impact on mood [65]. reversing excessive sweating. Also, a multiple Weight gain is variable and is unrelated to case-report article suggests the effectiveness of dosage. Food restriction and/or physical ac- biperidene, an anticholinergic drug, to coun- tivity are, presumably, just as effective. Weight teract methadone-induced sweating [6]. gain is quite likely during the induction phase, Constipation affects about one third of and is partly due to the swelling caused by methadone-maintained patients [49 , 61], water retention. Slow-acting diuretics may be depending on reduced bowel motility. Diet a temporary solution. supplements (fibres) or variations (food with high amounts of unabsorbed remnants which increase bowel motility and/or the water con- 3. Intolerance to methadone tent of feces), oil to soften fecal clots, laxative agents with a variety of action mechanisms can be tried. Severe constipation justifies limi- As with any other therapeutic drug, idio- tations on the containment of dosage. Meth- syncratic intolerance to methadone is a pos- ylnaltrexone, a peripheric opioid-antagonist, sible outcome. Some individuals may turn out may be used to counteract opiate agonism on to be intolerant regardless of dosage, that is, the bowels without antagonizing methadone’s at starting doses in the earliest phase of treat- action on the central nervous system [4, 30, 38, ment. Intolerance may comprise dysphoria, 56, 74, 81]. bowel subocclusion or occlusion due to the Reduced sexual drive is rather common suppression of bowel motility, pancreatic in- [61]; it is one major factor influencing compli- jury due to the spasm of end-coledochus and ance with the maintenance regimen and the subsequent elevated biliar duct pressure, se- use of functional antagonists such as cocaine vere impairment of sexual functioning or a [11 , 12, 29, 35 , 85 , 89 ]. Bromocryptine has neuroleptic-like state of sedation and the slow- 118 · CHAPTER 2.8 adverse events during methadone treatment · 119

ing of cognitive and motor functions. medical needs, methadone should be started General ’discomfort’ while the dose is be- alone, without any association with other po- ing increased usually indicates the addicted tentially interacting drugs, while the patient’s brain’s reaction to the establishment of an opi- tolerance is being heightened to allow narcotic oid blockade, and must be challenged by plan- blockade to be achieved. Methadone itself has ning a schedule of dose increases to achieve a a favourable impact on a variety of psychiat- satisfactory anti-craving effect. ric symptoms, so that additional psychotropic Addicted patients may also amplify the treatment can be safely postponed. psychological discomfort caused by side-ef- As the patient’s tolerance increases, the defects and a slight neuroleptic-like effect during crease in numbers of available receptor sites the induction phase, which may be no more causes a fall in the risk of overdose [37]. The than a way of inducing case managers to step concurrent consumption of heroin during back from a dose-increasing schedule or per- methadone treatment does not carry with it suading them to allow patients to decide how a heightened risk of opiate overdosing; con- much methadone should be administered to versely, it is safer than heroin consumption them. alone at equal doses, because of the competi- Patients should be reassured about the tive effect of methadone and a higher level of biphasic effects of methadone on mood and cross-tolerance to opiates. cognitive functioning, with an early phase Methadone intoxication is characterized by characterized by a neuroleptic-like effect of the slow onset of the general symptoms of opi- variable weight (conversely, some patients ate intoxication, with dizziness, somnolence may experience an analeptic effect), followed and sleep, possibly followed by coma, accom- by a later phase with a neutral or favourable panied by miosis and respiratory depression, effect on vigilance, memory and psychomotor in some cases leading to respiratory failure, functioning. which may be the cause of death. Unlike heroin overdose, methadone overdose is a late-onset phenomenon, so a few hours are available 4. Methadone overdose in which a lethal evolution can be avoided. As- ymptomatic patients must, in any case, be kept under observation for several hours. The risk of methadone overdosing must be When intoxication symptoms are displayed, rated with reference to the current level of a the following measures must be adopted: patient’s tolerance to opiates. Patients with an – in the case of respiratory depression, car- unknown – presumably low or zero – toler- diopulmonary support; ance must use caution in starting methadone – intravenous administration of a rapid-on- treatment. Subjects who have discontinued set opioid antagonist (naloxone) in cases methadone a short time before must be re- of respiratory depression or coma [84], at started on methadone very gradually, possibly single charge doses of 0.4-2 mg, to be re- as naive patients if more than two days have peated at 3-5’ intervals, and to be contin- passed (see the chapter on phases of treat- ued intravenously by infusion for up to ment and induction). A patient’s sensitivity 24 hours, due to methadone’s longer half- to opiates may be enhanced by drugs which life. If naloxone is discontinued too early, decrease the metabolism of methadone by the re-overdosing is expected due to the per- liver or compete for the same metabolic path- sistence of methadone in the body fluids ways, or by synergic compounds such as al- that ‘lie behind’ naloxone’s antagonism, cohol and benzodiazepines. Dose increases in which fades rapidly. Flumazenil may be polyabusers of gaba-ergic drugs and alcohol administered to treat possible polyintoxi- must be introduced very cautiously and under cation by benzodiazepines, which is fre- strict supervision, preferably in an in-patient quently involved in methadone-related setting. Apart from cases comprising urgent deaths and opiate overdoses in general. 120 · CHAPTER 2.8 adverse events during methadone treatment · 121

In fact, morphine overdoses in the pres- [16]. In a 1999 study, 185 case files of metha- ence of benzodiazepines develop at lower done-maintained transplanted patients were morphine blood levels, indicating a syn- reviewed: their life expectancy was similar to ergic action between the two classes of other categories of transplanted patients [42 , compound [3 , 10 , 33 , 34 , 53 , 54 , 55]. 60]. The relapse rate after transplantation was In subjects who are not tolerant to opiates 12%, which is, in any case, lower than that and take much higher doses accidentally, nal- among transplanted abusers who were not on oxone may be started in correspondence with methadone treatment [16]. methadone’s expected peak blood level (2-6 hrs) while naltrexone may be administered immediately, orally or by intramuscular injec- 6. Cardiac safety during methadone tion. This procedure allows the patient both maintenance acute and long-lasting protection, by naloxone and naltrexone, respectively [5]. The quantity of naloxone needed to reverse the overdose Major concerns about the cardiac safety of symptoms makes it possible to estimate the opiate agonists have already resulted in the excess of opiate over the patient’s tolerance withdrawal of LAAM [27, 28], due to a sup- level (i.e. in the case of non-tolerant patients, posedly considerable risk of fatal arrhythmias. the entire methadone amount). On that basis Following a few case-reports and a small size the physician can decide how much long-act- sample study conducted on methadone-treating antagonist to use to prevent re-overdosing ed subjects who had experienced critical ar- in the next 24-36 hrs. rhythmic episodes, similar concerns have been Patients who throw up within one hour af- extended to methadone [44, 46]. ter taking methadone orally are at lower risk, Methadone administration causes the QTc and do not need preventive treatment. Nalox- interval to increase in length as a trend, by one should be administered in cases of wors- an estimated 8% in a sample of 132 treatment ening symptoms of intoxication. Also, patients starters. The effect is reported as dose-depen- who report having taken less than 1 mg/kg dent up to 150 mg/die, at least in healthy pro- methadone, without any consumption of ben- bands. The length of QTc in methadone-main- zodiazepines and/or alcohol, can be managed tained heroin addicts, at effective and stable in the same way. Observation should, howev- dose levels, tends to be higher than expected er, continue for 8 hours, and parameters of opi- as for the general population. On the other ate intoxication must be registered at regular hand, the evidence does not show QTc reach- intervals. ing its highest value at the methadone peak time in treatment-starting subjects. Actually, the relationships between QTc length and ad- 5. Methadone and liver function ministered dosage have been determined both in asymptomatic treated addicts [66] and for a small group of treated subjects undergoing Methadone is not toxic to the liver, either arrhythmic crises [44, 46], but were not found acutely or in the long term. It can be safely in the group of 83 heroin addicts followed by used, with appropriate dose adjustments, in Maremmani and colleagues on a methadone- patients with severe liver impairment and liv- only maintenance schedule, at variable dosag- er failure, unless hepatic functions are worsen- es averaging about 90 mg/day[64]. Moreover, ing [47 , 51 , 78]. HCV-positive patients require other authors, who had initally reported that higher dosages in cases with active hepatitis, the length of QTc length is dose-dependent, due to an increased metabolic elimination of eventually rectified that by stating that the methadone by the cytochromal system [71]. weight of the methadone administered is just Liver transplantation can be performed a partial consideration, even if a specific cor- safely in patients maintained on methadone relation is left standing [44, 46], 120 · CHAPTER 2.8 adverse events during methadone treatment · 121

Within a dosage range that is representa- is any causal link with the investigated fea- tive of treatment samples, methadone has been ture, methadone, because of the impossibility proved to induce ECG abnormalities leading of ruling out other known risk factors for the to no arrhythmic accidents. Cases reported in same kind of arrhythmias. These latter authors studying methadone-related arrhythmias are themselves point out that the methadone dose characterized by far higher dosages. In partic- only carries a 25% weight in determining the ular, subjects receiving prescribed methadone QTc length as measured during index arrhyth- for chronic pain control are those who take the mias, though its role is statistically significant: highest daily dosages [31, 44, 46]. In the field in other words, it appears to be a co-factor rath- of opiate addiction treatment, higher metha- er than the cause. The mean age of the sample done dosages are often needed in response to subjects was 49 years, which is quite a high fig- an accelerated methadone metabolism, and ure if compared to the average age of addicts, a correspond to normal methadone serum lev- consideration which applies to Walker’s three els, as was demonstrated for HCV-positive cases, too. Differences that depend on age may subjects and primarily fast-metabolizers [70]. also mirror a difference in the reasons that de- On the other hand, daily oral dosages of over termine methadone prescription, especially 200 mg, which had been raised to that level to pain control instead of opiate addiction. meet the need to buffer re-emerging chronic Taking a comprehensive view, it can be pain, could actually correspond to metha- stated that the prevalence of QTc values above done serum levels that are higher than usual. the risk threshold (> 500 msec) is lower among In fact, the methadone serum values reported treated heroin addicts [64, 66 ], while arrhyth- by Krantz and colleagues were higher than av- mia is exceptional (no cases reported). erage, in a sample half of whose participants On speculative grounds, some authors sup- were patients with chronic, painful syndromes port the idea of a correlation between metha- [44, 46]. done and arrhythmic accidents by observing Needless to say, no single case-report is that rhythm parameters (rate and QTc length) able to provide conclusive data because the change in response to methadone dose re- isolated figures involved cannot, by them- duction or withdrawal: patients admitted for selves, possess statistical significance. More- cardiac arrest or potentially lethal arrhythmia over, in one case there was earlier evidence show a higher heart rate and a shorter QTc af- of a normal QTc, at the same dose level; this ter their methadone is partly or totally with- patient had taken cocaine shortly before the drawn. First, specific anti-arrhythmic therapy onset of the cardiac arrhythmia (arrest), while had been started. However, the withdrawal of in treatment with fluoxetine, olanzapine and an agent from tolerant individuals, which tends trazodone [14]. In another case [73], data con- to modify cardiac rhythm when administered, cerning ongoing therapies are missing, and can reasonably be expected to be followed by methadone consumption had taken place in- modifications of the same parameters in the dependently of any prescription. Of the three opposite direction, so displaying a ‘rebound’ cases described by Walker and colleagues [90], swing. A single fact of that kind cannot consti- one also displayed hypokaliemia, another had tute a strict proof of any causal link between a history of atrial tachi-arrhythmia, and all methadone and the scope or degree of baseline three were taking other agents, too. The HIV- rhythm features. Similarly, a patient who pres- positive patients studied by Gil et al. [31] were ents for a hyperglycemic crisis and is treated at risk of QTc lengthening precisely because of over a long period by cortisone maintenance, their viral disease [43], apart from displaying would display lower blood sugar values dur- further risk features favouring QTc lengthening cortisone tapering, without that constituting (electrolyte balance disturbances, abnor- ing a clear proof of a causal role for cortisone malities of cardiac motility, ongoing pharma- in the current hyperglycemic episode. cotherapies). Nor does Krantz and colleagues’ Patients suitable for methadone treatment 17-subject study authorize the view that there should undergo a cardiologic assessment in- 122 · CHAPTER 2.8 adverse events during methadone treatment · 123 cluding a basal ECG, in order to ascertain pos- an apparently normal brain persist for years sible risk conditions, such as a congenitally in a narcotic-free condition. Detoxification is longer QTc or an intoxication-related longer followed by a relapse after an interval of vari- QTc, before any methadone is administered, able length. A drug-free condition following or at least before the methadone dose is raised detoxification is equivalent to waiting for a above the individually acquired tolerance relapse without any preventive resource. Re- level. Medical assessment should also include habilitation after detoxification is possible, but electrolyte dosage, so that possible distur- is likely to be interrupted by relapses. bances can be counteracted. As far as poly- Methadone treatment is best for the vast abuse is concerned, anticraving therapies may majority of narcotic addicts, in terms of narcot- be the way to achieve satisfactory results, in ic use reduction/extinction and rehabilitation. cases where any are attainable. Enduring co- Despite that, principles of successful metha- caine or stimulant use is an independent risk done treatment are seldom applied [18-20, 21, condition, to be treated as a separate problem. 22, 23, 24-26, 79]. The corpus of research on No combination is advisable, apart from criti- methadone treatment comprises thousands of cal need responses, between methadone and papers, which makes it one of the most stud- other psychotropics, before methadone dos- ied drugs in the history of medicine [15, 62]. ages has been raised to average effective dos- Nevertheless, prejudice is common among ages. Above such values, a further increase politicians, the general population, street-ad- in methadone dosages without resorting to dicts, patients and even physicians and staff a combination regimen may actually offer a members. safer solution. Adequate dosing is important One major misconception is that of ascrib- in reducing cardiac risk: it should be borne in ing chronicity to therapy rather than to the dis- mind that electrocardiographic abnormalities ease itself: one result is that methadone treat- are even more common among treated sub- ment is seen as the source of chronicity. jects with uncovered cravings than among un- An unsustainable way of interpreting the treated street addicts [59]. concept of ‘dependence’ is another important point to discuss. It is often said that it is unethical to maintain a state of dependence by 6. Stigma, prejudice and misconceptions replacing one narcotic with another. By playing with words, the difference between a state of dependence brought about by a therapeutic Cultural factors play an important role in drug and an addictive involvement in the use conditioning the course of heroin addiction of a toxic substance is totally lost. Many people and effective treatment [7, 8 , 9 , 72 , 75]. Igno- depend on therapeutic drugs for a variety of rance, prejudice and misconceptions, together reasons, which means they can be symptom- with dogmatic thought, have always limited free as long as they are taking a drug at stable the spread and application of scientific prin- doses in a maintenance regimen: chronic psy- ciples to the treatment of addictive disorders chotics taking neuroleptics, bipolar subjects by agonist drugs [87]. taking antimanic drugs, transplant-receivers Evidence about narcotic addiction can be taking immunodepressant agents, sufferers summarized as follows: from heart diseases taking antiarrhythmics or Narcotic addiction is a severe chronic dis- anti-coagulants or vasoactive drugs, diabetics order, whose development depends on a vari- taking insulin or oral antidiabetic drugs. In all ety of factors; despite this, it has the feature of these cases relapse (not to mention the worsen- being self-maintaining, independently of any ing of symptoms) can be expected after drug single factor. discontinuation; a rebound is possible, too. On The exposure to some opiate drugs produc- official diagnostic grounds, methadone depen- es persistent damage to the brain opioidergic dence cannot be classified as addiction, either: pathways [88]. The conditioned reactions of DSM-IV TR defines addiction as characterized 122 · CHAPTER 2.8 adverse events during methadone treatment · 123

by : tion during the maintenance phase. - the reckless use of a substance despite in- - involvement in substance use is a cause dividual suffering or damage comprising of social, work and leisure-time impair- at least three of the following within a 12- ment. Methadone treatment is effective month period: just because it promotes the opposite - acquired tolerance, defined as the need to process, leading from impairment to re- increase dosages in order to reproduce a habilitation. pleasurable effect, together with a fall in - subjects endure in substance use though sensitivity to the substance after regular they are aware of being damaged and im- use. Methadone treatment does not cor- paired by the substance. Actually, addicts respond to any such condition. Being sta- continue to think methadone is harmful, bilized means being able to stably obtain despite the evidence of positive effects a therapeutic effect without the need to on their behaviours, because of cultural keep on increasing dosage. prejudice. - withdrawal, which is defined as the Some think of methadone as a pleasurable emergence of specific symptoms when drug, that is, a legal narcotic. The truth is that exposure to the substance is abruptly dis- methadone does not induce any heroin-like continued, and the renewal of exposure ‘high’ and cannot replace a heroin-induced in order to prevent or buffer withdrawal high: addicts who take blocking dosages be- symptoms. Methadone treatment implies fore stabilization is reached experience dis- withdrawal in cases of abrupt discontin- comfort as a rule and would rather reduce their uation, but two points should be made: methadone dose so to be able to sense heroin. first, somatic dependence is crucial to in- Methadone has no analgesic effects, either, in creasing compliance with treatment, since tolerant individuals. Obviously, methadone’s it makes the premature discontinuation action over the individual’s tolerance level can of treatment quite awkward. Second, in produce favourable effects, but no trend to- cases of treatment discontinuation, most wards methadone ‘addiction’ has been report- addicts resort to street narcotics and do ed, and even illegal methadone use among not ‘relapse’ into methadone use, but re- heroin addicts does not usually correspond apply for treatment as fast-narcotic re- to abuse. Narcotic addicts resort to the lowest lapsers. effective dosages; they do so in order to buf- - the substance is administered at higher fer withdrawal-related discomfort, and only dosages and for longer periods than those when other street-drugs (narcotics but also expected by patients. On the other hand, non-narcotic agents such as benzodiazepines addicts tend to limit their methadone use or alcohol) are unavailable. In narcotic-toler- in terms of dose and duration. ant individuals, methadone has a normalizing - a persistent intention to control the drive effect when compensating for the individual’s to use the substance, with recurrent fail- acquired level of tolerance [76]. ures to do so. Conversely, addicts dislike, The mass administration of methadone to and have no interest in, methadone: even treatment-seeking addicts is sometimes de- when in possession of sufficient supplies, scribed as ‘honey attracting flies’, as if treat- there is not one who fails to discontinue ment with methadone actually meant that pa- and abstain from it, despite withdrawal tients receiving it lose an opportunity to enter symptoms. therapeutic communities or undergo detoxifi- - plenty of time is spent supplying oneself cation, or are held back from such options by with the substance, taking it and wearing methadone treatment. The fact is that metha- off intoxication. Apart from the problem done-treated subjects are more likely to attend of having to spend time in reaching treat- other facilities (medical, psychosocial, psycho- ment centres, methadone-treated addicts logical), and are more likely to rehabilitate [13, do not experience any narcotic intoxica- 41]. Methadone treatment, far from implying 124 · CHAPTER 2.8 adverse events during methadone treatment · 125

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AL-ADWANI A., BASU N. (2004): Methadone and JAMA. 235 2117-2119. excessive sweating. Addiction. 99:(2) 259. 23. DOLE V. P., NYSWANDER M. E. (1983): Behavioral 2. APPEL P. W., GORDON N. B. (1976): Digit-symbol pharmacology and treatment of human drug abuse: performance in methadone-treated ex-heroin addicts. methadone maintenance of narcotic addicts. In: Am J Psychiatry. 133:(11) 1337-1340. SMITH J. E., LANE J. D. (Eds.): The Neurobiology of 3. BENTLEY A. J., BUSUTTIL A. (1996): Deaths among opiate reward processes. Elsevier Biomedical Press, drug abusers in south-east Scotland (1989-1994). Med Amsterdam. pp. 211-233. 24. DOLE V. P., NYSWANDER M. E., DE JERLAIS D., 124 · CHAPTER 2.8 adverse events during methadone treatment · 125

JOSEPH H. (1982): Sounding board: Performance- methadone on QT prolongation in a series of patients based rating of methadone maintenance programs. N with torsade de pointes. Pharmacotherapy. 23:(6) 802- Engl J Med. 306 169-172. 805. 25. DOLE V. P., NYSWANDER M. E., KREEK M. J. (1966): 45. KRANTZ M. J., LEWKOWICZ L., HAYS H., Narcotic Blockade. Arch Intern Med. 118 304-309. WOODROFFE M. A., ROBERTSON A. D., MEHLER 26. DOLE V. P., NYSWANDER M. E., WARNER A. (1968): P. S. (2002): Torsade de pointes associated with very- Successful treatment of 750 criminal addicts. JAMA. high-dose methadone. Ann Intern Med. 137 501-504. 206 2708-2711. 46. KRANTZ M. J., MEHLER P. S. (2003): Synthetic opioids 27. EMEA (1999): EMEA Public Statement on and QT prolongation. Arch Intern Med. 163:(13) 1615. Levacetylmethadol (ORLAAM)- Life threatening 47. KREEK M. J. (1973): Medical safety and side effects cardiac rhythm disorders. N° 38436/99 EMEA, of methadone in tolerant individuals. JAMA. 223:(6) London. 665-668. 28. EMEA (2001): EMEA Public Statement on the 48. KREEK M. J. (1978): Medical complications in reccomendation to suspend the marketing methadone patients. Ann NY Acad Sci. 322 110-134. authorization for Orlaam (levoacetylmethadol) in the 49. KREEK M. J. (1979): Methadone in treatment: European Union. N°8776/01. EMEA, London. Psychological and pharmacological issues. In: 29. ESPEJO R., HOGBEN G., STIMMEL B. (1973): Sexual DUPONT R. I., GOLDSTEIN A., O’DONNELL J. (Eds.): performance of men on methadone maintenance. Proc Handbook on Drug Abuse. NIDA U.S. Department of Natl Conf Methadone Treat. 1 490-493. Health and Human Services, Rockville, MD. pp. 30. FOSS J. (2008): How safe and effective is 50. KREEK M. J. (1991): Immunological Function in Active methylnaltrexone for the treatment of opioid-induced Heroin Addicts and Methadone Maintained Former constipation in advanced illness? Nat Clin Pract Addicts: Observations and Possible Mechanisms Gastroenterol Hepatol. In: HARRIS L. S. (Ed.) Problems of drug dependence, 31. GIL M., SALA M., ANGUERA I., CHAPINAL O., 1990: Procedings of the 52th Annual Scientific Meeting CERVANTES M., GUMA J. R., SEGURA F. (2003): of the committee on problems of drug dependence. NIDA, QT prolongation and Torsades de Pointes in patients Rockville,MD. pp. infected with human immunodeficiency virus and 51. KREEK M. J., DODES L., KANE S., KNOBLER treated with methadone. Am J Cardiol. 92:(8) 995-997. J., MARTIN R. (1972): Long-term methadone 32. GORDON N. B., WARNER A., HENDERSON A. maintenance therapy: Effects on liver function. Ann (1967): Psychomotor and intellectual performance Intern Med. 77 598-602. under Methadone Maintenance. National Academy 52. KREEK M. J., KHURI E., FAHEY L., MIESCHER A., of Sciences, National Research Council, Committee ARNS P., SPAGNOLI D., CRAIG J., MILLMAN R., on Problems of Drug Dependence, Washington, DC. HARTE E. H. (1986): Long-term followup studies 33. GRASS H., BEHNSEN S., KIMONT H. G., STAAK M., of the medical status of adolescent former heroin KAFERSTEIN H. (2003): Methadone and its role in addicts in chronic methadone maintenance treatment: drug-related fatalities in Cologne 1989-2000. Forensic liver disease and immune status. NIDA Res Monogr. Sci Int. 132:(3) 195-200. 67 307-309. 34. GREENE M. H., LUKE J. L., DUPONT R. L. (1974): 53. KRINGSHOLM B. (1988): Deaths among drug addicts Opiate overdose deaths in the District of Columbia. II. in Denmark in 1968-1986. Forensic Sci Int. 38:(1-2) 139- Methadone-related fatalities. J Forensic Sci. 19:(3) 575- 149. 584. 54. KRINGSHOLM B., KAA E., STEENTOFT A., WORM 35. HANBURY R., COHEN M., STIMMEL B. (1977): K., SIMONSEN K. W. (1994): Deaths among drug Adequacy of sexual performance in men maintained addicts in Denmark in 1987-1991. Forensic Sci Int. on methadone. Am J Drug Alcohol Abuse. 4:(1) 13-20. 67:(3) 185-195. 36. HAURI-BIONDA R., BAR W., FRIEDRICH-KOCH A. 55. LA HARPE R., FRYC O. (1995): Fatalities associated (1998): [Driving fitness/driving capacity of patients with methadone administration in the Geneva canton treated with methadone]. Schweiz Med Wochenschr. (1987-1993). Arch Kriminol. 196:(1-2) 24-29. 128:(41) 1538-1547. 56. LANG L. (2008): The Food and Drug Administration 37. HEINEMANN A., IWERSEN-BERGMANN S., STEIN approves methylnaltrexone bromide for opioid- S., SCHMOLDT A., PUSCHEL K. (2000): Methadone- induced constipation. Gastroenterology. 135:(1) 6. related fatalities in Hamburg 1990-1999: implications 57. LEAVITT S. B. (2001): The safety of methadone, for quality standards in maintenance treatment? LAAM, buprenorfine in the treatment of opioid Forensic Sci Int. 113:(1-3) 449-455. dependency. Addiction Treatment Forum. 10:(2) 1-22. 38. HOLZER P. (2008): New approaches to the treatment 58. LENNE M. G., DIETZE P., RUMBOLD G. R., of opioid-induced constipation. Eur Rev Med Pharmacol REDMAN J. R., TRIGGS T. J. (2003): The effects of Sci. 12 Suppl 1 119-127. the opioid pharmacotherapies methadone, LAAM 39. JAGE J. (1990): Actions and side effects of methadone. and buprenorphine, alone and in combination with Dtsch Med Wochensch. 115:(14) 552-555. alcohol, on simulated driving. Drug Alcohol Depend. 40. JUDSON B. A., HORNS W. H., GOLDSTEIN A. 72:(3) 271-278. (1976): Side effects of levomethadone and racemic 59. LIPSKI J., STIMMEL B., DONOSO E. (1973): The methadone in a maintenance program. Clin Pharmacol effect of heroin and multiple drug abuse on the Ther. 20:(4) 445-449. electrocardiogram. Am Heart J. 86:(5) 663-668. 41. KAHN R. B. (1992): Methadone maintenance 60. LIU L. U., SCHIANO T. D., LAU N., O’ROURKE treatment: impact of its politics on staff and patients. J M., MIN A. D., SIGAL S. H., DROOKER M., Psychoactive Drugs. 24:(3) 281-283. BODENHEIMER H. C. J. (2003): Survival and risk 42. KANCHANA T. P., KAUL V., MANZARBEITIA C., of recidivism in methadone-dependent patients REICH D. J., HAILS K. C., MUNOZ S. J., ROTHSTEIN undergoing liver transplantation. AJT. 3:(10) 1273- K. D. (2002): Liver transplantation for patients on 1277. methadone maintenance. Liver Transpl Surg. 8:(9) 778- 61. LONGWELL B., KESTLER R. J., COX T. J. (1979): 782. Side effects in methadone patients: a survey of self- 43. KOCHERIL A. G., BOKHARI S. A., BATSFORD W. reported complaints. Int J Addict. 14:(4) 485-494. P., SINUSAS A. J. (1997): Long QTc and torsades de 62. MAREMMANI I., BARRA M., BIGNAMINI E., pointes in human immunodeficiency virus disease. CONSOLI A., DELL’AERA S., DERUVO G., FANTINI Pacing Clin Electrophysiol. 20:(11) 2810-2816. F., FASOLI M. G., GATTI R., GESSA G. L., GUELFI 44. KRANTZ M. J., KUTINSKY I. B., ROBERTSON A. G. P., JARRE P., MICHELAZZI A., MOLLICA R., D., MEHLER P. S. (2003): Dose-related effects of NARDINI R., PANI P. P., POLIDORI E., SIRAGUSA 126 · CHAPTER 2.8

C., SPAZZAPAN B., STARACE F., TAGLIAMONTE 77. NOVICK D. M., JOSEPH H., CROXSON T. S., SALSITZ A., TIDONE L., VENDRAMIN A. (2002): Clinical E. A., WANG G., RICHMAN B. L., PORETSKY foundations for the use of methadone. Italian L., KEEFE J. B., WHIMBEY E. (1990): Absence of Consensus Panel on Methadone Treatment. Heroin antibody to human immunodeficiency virus in long- Addict Relat Clin Probl. 4:(2) 19-31. term, socially rehabilitated methadone maintenance 63. MAREMMANI I., CANONIERO S., PACINI M. patients. Arch Intern Med. 150:(1) 97-99. (2002): Psico(pato)logia dell’’addiction’. Un’ipotesi 78. NOVICK D. M., KREEK M. J., FANIZZA A. M., interpretativa. Ann Ist Super Sanita. 38:(3) 241-257. YANCOVITZ S. R., GELB A. M., STENGER R. J. (1981): 64. MAREMMANI I., PACINI M., CESARONI C., Methadone disposition in patients with chronic liver LOVRECIC M., PERUGI G., TAGLIAMONTE A. disease. Clin Pharmacol Ther. 30:(3) 353-362. (2005): QTc interval prolungation in patients on long- 79. NOVICK D. M., PASCARELLI E. F., JOSEPH H., term methadone maintenance therapy. Eur Addict Res. SALSITZ E. A., RICHMAN B. L., DES JARLAIS D. 11:(1) 44-49. C., ANDERSON M., DOLE V. P., NYSWANDER M. 65. MAREMMANI I., PACINI M., LUBRANO S., E. (1988): Methadone maintenance patients in general LOVRECIC M., PERUGI G. (2003): Dual diagnosis medical practice: A preliminary report. JAMA. 259(22) heroin addicts. The clinical and therapeutic aspects. 3299-3302. Heroin Addict Relat Clin Probl. 5:(2) 7-98. 80. NOVICK D. M., RICHMAN B. L., FRIEDMAN 66. MARTELL B. A., ARNSTEN J. H., RAY B., J. M., FRIEDMAN J. E., FRIED C., WILSON J. P., GOUREVITCH M. N. (2003): The impact of methadone TOWNLEY A., KREEK M. J. (1993): The medical induction on cardiac conduction in opiate users. Ann status of methadone maintained patients in treatment Intern Med. 139:(2) 154-155. for 11-18 years. Drug Alcohol Depend. 33 235-245. 67. MARTIN W. R. (1972): Pathophysiology of narcotic 81. RANGNEKAR A. S., CHEY W. D. (2008): addiction: possible role of protracted abstinence in Methylnaltrexone: a new treatment for an old relapse. In: ZARAFONETIS C. J. D. (Ed.) Drug abuse. problem. Gastroenterology. 135:(5) 1792-1794. Lea and Febiger, Philadelphia. pp. 153-159. 82. SCHINDLER S. D., ORTNER R., PETERNELL A., 68. MARTIN W. R. (1980): Emerging concepts concerning EDER H., OPGENOORTH E., FISCHER G. (2004): drug abuse. In: LETTIERI D. J., SAYERS M., Maintenance therapy with synthetic opioids and PEARSON H. W. (Eds.): Theories on Drug Abuse: driving aptitude. Eur Addict Res. 10:(2) 80-87. Selected Contemporary Perspectives. Rockville,Md: 83. SHINDERMAN M. S., MAXWELL S. (2000): Sexual NIDA Research Monograph 30, Washington,D.C.: dysfunction associated with methadone maintenance: Supt. of Docs.,U.S. Govt. Print. Off. pp. 278-285. Treatment with bromocryptine. Heroin Addict Relat 69. MARTIN W. R., HEWETT B. B., BAKEN A. Clin Probl. 2:(1) 9-14. J., HEARTZEN C. A. (1977): Aspects of the 84. SMITH D. A., LEAKE L., LOFLIN J. R., YEALY D. M. psychopathology and pathophysiology of addiction. (1992): Is admission after intravenous heroin overdose Drug Alcohol Depend. 2 185-202. necessary? Ann Emerg Med. 21:(11) 1326-1330. 70. MAXWELL S., SHINDERMAN M. S. (2002): 85. SPRING W. D. J., WILLENBRING M. L., MADDUX Optimizing long-term response to methadone T. L. (1992): Sexual dysfunction and psychological maintenance treatment: a 152-week follow-up using distress in methadone maintenance. Int J Addict. higher-dose methadone. J Addict Dis. 21:(3) 1-12. 27:(11) 1325-1334. 71. MAXWELL S., SHINDERMAN M. S., MINER A., 86. STAAK M., BERGHAUS G., GLAZINSKI R., HOHER BENNET A. (2002): Correlation between hepatitis C K., JOO S., FRIEDEL B. (1993): [Empirical studies of serostatus and methadone dose requirement in 1.163 automobile driving fitness of patients treated with methadone-maintained patients. Heroin Addict Relat methadone-substitution]. Blutalkohol. 30:(6) 321-333. Clin Probl. 4:(2) 5-9. 87. STIMMEL B. (1999): Heroin addiction and methadone 72. MCGONAGLE D. (1994): Methadone anonymous: a maintenance: when will we ever learn. J Addict Dis. 12-step program. Reducing the stigma of methadone 18:(2) 1-4. use. J Psychosoc Nurs Ment Health Serv. 32:(10) 5-12. 88. STIMMEL B., KREEK M. (1975): Pharmacologic 73. MOKWE E. O., OSITADINMA O. (2003): Torsade de actions of heroin. In: STIMMEL B. (Ed.) Heroin pointes due to methadone. Ann Intern Med. 139:(4) dependency: Medical, economic and social aspects. Stratton W64. Intercontinental Medical Book Corp, New York, NY. 74. MOSS J., ROSOW C. E. (2008): Development of pp. 71-87. peripheral opioid antagonists’ new insights into 89. TEUSCH L., SCHERBAUM N., BOHME H., opioid effects. Mayo Clin Proc. 83:(10) 1116-1130. BENDER S., ESCHMANN-MEHL G., GASTPAR 75. MURPHY S., IRWIN J. (1992): “Living with the M. (1995): Different patterns of sexual dysfunctions dirty secret”: problems of disclosure for methadone associated with psychiatric disorders and maintenance clients. J Psychoactive Drugs. 24:(3) 257- psychopharmacological treatment. Results of 264. an investigation by semistructured interview of 76. NEWMAN R. G. (1995): The Pharmacological schizophrenic and neurotic patients and methadone- Rationale for Methadone Treatment of Narcotic substituted opiate addicts. Pharmacopsychiatry. 28:(3) Addiction. In: TAGLIAMONTE A., MAREMMANI 84-92. I. (Eds.): Drug Addiction and Related Clinical Problems. 90. WALKER G., WILCOCK A., CAREY A. M., Springer-Verlag, Wien New York. pp. 109-118. MANDERSON C., WELLER R., CROSBY V. (2003): Prolongation of the QT interval in palliative care patients. J Pain Symptom Manage. 26:(3) 855-859. 2.9

Clinical Meaning of Urinalyses I. Maremmani, F. Lamanna, B. Capovani and M. Pacini

Drug-screening plays a major role in the regard to the patient’s behaviour and underly- pursuit of rehabilitation within an integrated ing addictive symptoms. When patients refuse programme. Urinalyses provide important in- to deliver samples, or miss an appointment formation about the course of treatment. The for delivery, the reason presumably has to do information that is acquired must be interpret- with core addictive symptoms, so a failure to ed in relation to patients’ behaviours and their deliver can be interpreted as a positive result psychosocial performance [2, 3]. for narcotic use. Likewise, if patients refuse to collect their urine sample in the way requested by staff (so 1. The clinical use of urinalyses as a as to guarantee the reliability of results), addic- “behavioural challenge” tion is the presumable cause, and the results can be assumed to be positive. It may be of interest to ask the patient about Urinalyses are complementary to clinical results before the sample has been collected. judgement in ascertaining a patient’s current Patients who claim negative results despite condition and is crucial in making therapeu- knowing they will turn out to be positive are tic decisions. Basically, urinalyses give direct still overwhelmed by addictive symptoms, and information about the use of a variety of sub- follow an addictive cognitive and behavioural stances, and make it possible to check whether style. This style includes the attitude that any- methadone is present. No precise information thing can be tried to convince others that noth- can, however, be gathered about the amount ing is going on: denying substance use may consumed or the level of tolerance to metha- lead physicians not to collect the sample; it is done. Even so, important information can be possible, too, that positive results will be not acquired when performing urinalyses with be considered to be reliable if patients insist

127 128 · CHAPTER 2.9 clinical meaning of urinalyses · 129 on claiming the opposite. A counter-addictive addictive symptoms or to a fall in the level of style would be that of declaring substance use psychosocial adjustment. in order to have treatment enhanced or, if nec- Some suggestions can be reported to mini- essary, one’s dosage increased, which is just mize false negatives for morphine metabolites. what addicted patients tend to avoid. First, the sample should also be tested for other In conclusion, urinalyses provide informa- possible therapeutic substances the patient is tion about substance use and methadone con- known to have taken (e.g. methadone, antiepi- sumption, whereas a patient’s behaviour in the leptic drugs, lithium, tryciclic antidepressants, context of urinalyses is a source of important phenothiazines). clinical information about the state of his/her The urine that is collected should be enough addictive symptoms. for two different analyses, one testing for substances and the other for general chemical and physical features, in order to make sure that 2. Collection of samples and ensuring the sample consists of normal urine; the pa- the reliability of results tient may deliver altered urines (by dilution, for example), or a similar liquid (tea, for example). The collecting staff should check that the Biological (urine) samples should be col- sample is warm (collected on the spot). Urine lected on a regular basis, although it is better samples become opalescent and irregularly to ask patients to deliver samples at random dense within 48 hours, which does not under- rather than on predetermined days, so as to mine the qualitative reliability of substance- reduce the likelihood of cheating, which be- screening tests. Otherwise, patients can be left comes more difficult and is, usually, awkward alone in a closed room to collect the sample, when it is tried ‘on the spot’. A random pattern if they are warned that they will be video-re- of sample collection also discourages sporadic corded and requested to perform the sample substance use, as long as it happens in a non- collection in such a way as to be clearly visible addictive mode. A reasonable compromise be- to the camera. In our view, it is better to control tween the automatic nature of regularly sched- patients in that way, rather than supervising uled urinalyses and the usefulness of random the delivery of samples and collecting them di- collection is to perform urinalyses on a clinical rectly. In fact, direct control may leave no room basis, that is, when the patient’s behaviour and for cheating, while the same patients may clinical conditions indicate possible substance cheat if left on their own to collect the sample; use. the outcome is that indirect control measures If patients refuse to deliver samples or are allow more information to be collected about caught cheating during sample collection, the patient’s clinical condition. there is no need for actual urinalyses results, According to Mark Parrino, president of because a positive result can be recorded in AATOD, the best way to minimize cheating is any case (at least for the substance to which to exclude the possibility that patients feel that the patient is addicted). the results of urinalyses will be the basis of any The need for detailed and reliable urinal- punishment against them. yses also varies according to the treatment As for positive results, the only clinical ex- stage: during earlier phases, for example, the ception is speedball injecting; in this case the evidence related to the patient’s behaviour patient will test positive for both cocaine and may be enough to justify therapeutic deci- morphine metabolites, without displaying sions, whereas reliable results are needed at any signs of relapse into the use of narcotics a stage when symptoms have been absent for or a craving for them. In these circumstances, years. In fact, urinalyses become more useful narcotics may be not craved for, but they are when the patient has been abstinent recently, coupled with stimulants to amplify the eu- and a single episode of use does not automati- phorizing effect and neutralize symptoms of cally correspond to the re-emergence of severe intoxication by a counterpolar action. 128 · CHAPTER 2.9 clinical meaning of urinalyses · 129

3. Therapeutic implications When dosages are reduced, the frequency of urinalyses should be increased, since the risk of relapse is supposed to increase. The aim of urinalysis is to provide an ob- Positive results after a period of negativity jective check on a patient’s condition in rela- of any length is a reason for increasing the dos- tion to their substance use behaviour. How- age. In no case should the use of any substance, ever, a clinical interpretation of behaviours is especially narcotics, demonstrated by urinaly- far more useful in gaining an understanding sis, be followed by compulsory discharge from of how things are evolving during the course treatment or dose reduction [1, 2]. of treatment. Also, the clinical meaning of urinalyses needs to be interpreted in relation to the stage of treatment: the persistent positivity References of urinalyses during the first weeks is normal, 1. Maremmani I., Barra M., Bignamini E., Consoli A., Dell’Aera S., Deruvo G., Fantini whereas an early negativization of urinalyses F., Fasoli M. G., Gatti R., Gessa G. L., Guelfi does not exclude the likelihood of relapse, and G. P., Jarre P., Michelazzi A., Mollica R., Nardini R., Pani P. P., Polidori E., Siragusa does not ensure that a given dosage will be ad- C., Spazzapan B., Starace F., Tagliamonte equate in the medium term. A., Tidone L., Vendramin A. (2002): Clinical foundations for the use of methadone. Italian Persistently negative urinalyses give a rea- Consensus Panel on Methadone Treatment. Heroin son for not decreasing the dosage. Dwindling Add & Rel Clin Probl. 4:(2) 19-31. positive results, in the best cases tending to- 2. Marion I. J. (1993): Urinalysis as a clinical tool. In: Parrino M. W. (Ed.) State Methadone Treatment wards zero, along with constant psychosocial Guidelines. U.S. Department of Health & Human Services, Rockville,MD. pp. 59-66. improvement, define a condition of stabiliza- 3, NIDA (1986): Urine testing for Drugs of Abuse. NIDA tion. Research Monograph 73, NIDA, Washington, DC. 130 · CHAPTER 2.9 2.10

The Take-Home as a Clinical Tool P.P. Pani and I. Maremmani

The effectiveness of methadone mainte- lary facilities, and cultural attitudes towards nance treatment is based on its capacity to addiction and treatment) [12, 18, 20, 23]. keep craving and addictive behaviour under A large body of research provides infor- control; as a consequence, drug-related con- mation about the appeal of methadone and cerns (crime, psychological and health issues) its side-effects, showing that addicts are more become less pressing and psychosocial param- likely to be willing to enter methadone pro- eters show gradual improvement [4-7]. grammes than other treatment options, such Nevertheless, the quality of results does as therapy with naltrexone [2, 11]. not depend only on the direct impact of the As regards the issue of methadone’s non- pharmacological regimen on core addictive therapeutic use, it must be understood that a symptoms. The first factor for any treatment long-term treatment regimen cannot be con- to be effective is that a patient agrees to follow ceived to continue on a daily administration it and finds it compatible with a normal life. It basis. Treatment must proceed in parallel with is crucial, in other words, that an effective regi- the process of rehabilitation, without ever men should be made sufficiently liveable for coming to constitute an obstacle. When pa- patients to follow it in the long term. tients start their programme, they attend the The patient’s compliance with treatment is centre daily for supervised administration, but influenced by a variety of factors, partly relat- this level of control may be excessive for stabi- ed to the drug (appeal, side-effects), and part- lized patients, who have a real need to attend ly to the limitations and requirements of the less frequently in order to be able to work and programme (frequency of administration, fre- lead a normal life. A lot of patients complain quency of control evaluations), and also by the about the fact that ongoing treatment inter- way in which treatment is delivered (distance feres to an increasing extent with the task of from treatment centres, availability of ancil- handling their job and life opportunities, side

131 132 · CHAPTER 2.10 the take-home as a clinical tool · 133 by side with the general improvement in their availability of illegal methadone may there- state of health and the remission of addictive fore be in direct contrast with the purposes of symptoms. It should also be remembered that, methadone maintenance programmes. apart from work, leisure time and pleasurable On the whole, stabilized patients should activities there are other important elements in generally be allowed take-home privileges, the process of rehabilitation and social adjust- in accordance with the priority of favouring ment. For some patients, bad health may be the process of rehabilitation, but this option a valid reason for asking to attend the centre should be limited to reliable patients. Reliabil- less frequently. One reasonable solution is to ity should be based on a state of clinical remis- allow reliable patients (those with stably nega- sion of core addictive symptoms, rather than tive urinalyses and signs of progressive so- any judgement on the patient’s personality or cial readjustment) to self-administer the drug criminal history. As a result, when rehabilita- at home. On the other hand, take-home pro- tion has been made viable by the ongoing anti- grammes may become a source of illegal street craving treatment, patients are empowered to methadone. On scientific grounds, the option arrange their lives according to social, family of take-home has been indicated as effective and work requirements. in increasing enrolment rates and the level of Significant ones or external staff may be compliance with other treatment rules. More involved in the supervision of methadone ad- recently, it has been shown that programmes ministration, in order to allow take-home and allowing take-home for eligible patients have be a source of reliable information about the higher retention rates [1, 15-17]. patient’s compliance and his/her adequate level of tolerance to opiates. Take-home may sometimes be justified by 1. Guidelines for take-home the need to keep the patient away from a street environment close to the centre location, as long as some reliable significant one can su- The original ‘methadone clinic’ programme pervise methadone administration in place of was based on the daily supervised administra- the staff. In urban areas with addiction treat- tion of the drug, which was the only reliable ment units practising harm reduction together way to reach anti-craving dosages and main- with methadone programmes, younger ad- tain a state of narcotic blockade. Delivering dicts with short addictive histories may, for ex- methadone to drug-using addicts is likely to ample, be allowed take-home in order to avoid result in a diversion of amounts of methadone daily attendance of a high-risk environment. to the black market, where it is sold or trad- Take-home amounts vary from single daily ed for other substances. Apart from any legal to weekly supplies. Clinical and toxicological concerns, from a physician’s point of view evaluations must be maintained and not be al- any case of diversion basically means that the lowed to dwindle once take-home has been al- patient will be deprived of the programme’s lowed in order to prevent diversion. On days therapeutic potential, since the drug will not when patients take delivery of their take-home be taken in the prescribed amounts and symp- supplies, they must take their daily dosage in toms will not be controlled. Moreover, the self- front of the staff, in order to be considered reli- determined use of methadone keeps addicts able. away from structured treatment, since it has no impact of core addictive symptoms: street methadone is mostly resorted to as way of 2. Effectiveness of take-home buffering withdrawal, at low dosages and oc- programmes casionally when heroin is not available at all. Also, unsupervised methadone may be managed in order to reverse acquired tolerance to The earliest data about take-home metha- opiates, either heroin or methadone itself. The done became available in the ‘70s, with the 132 · CHAPTER 2.10 the take-home as a clinical tool · 133

aim of investigating the factors which influ- 3. Conclusions ence compliance. Stitzer and coll. showed that allowing take-home renders patients compliant with the delivery of addictive counselling, Among psychotropics employed in long- as long as take-home is selectively allowed term treatment regimens, methadone is cer- to those attending counselling sessions, by tainly an exception: other psychiatric patients applying a mechanism of positive reinforce- are not requested to attend any treatment cen- ment. Giving patients a privilege like that of tre systematically, let alone daily during the take-home dosages also proved effective in first few years. For psychiatric patients, such a enhancing abstinence rates from a variety of request would be considered as a way to make substances (opiates, cocaine, benzodiazepines, treatment incompatible with the patient’s pro- cannabis) and increasing the likelihood of reductive, social duties and private life. For intention in treatment [3, 9, 13, 14, 21, 24, 25]. It stance, were bipolar patients asked to attend should, however, be noted that only patients the clinic daily to receive lithium under the who have already decreased their opiate use staff’s supervision, they would hardly comply to a certain extent are positively influenced by with such a rule. admission to take-home regimens, whereas Therefore, on one hand it may happen that other patients are not expected to benefit from addicted patients give up job and life oppor- the same privilege, and are at risk of becoming tunities in order to maintain their treatment involved in diversion. status and avoid relapse. Hence, both patients Michael Kidorf showed that take-home is under treatment and people who witness their linked with a higher proneness of patients to condition from the outside may come to think attend psychoeducational interventions that that a narcotic-free life is not any better than aim to consolidate and enhance the motivation before, even if it is longer and healthier. On the to undergo treatment itself. This strategy may other hand, the nature of addiction is such as turn out to have a major impact on patients to make it necessary that treatment is strictly with addictive psychological and psychiatric supervised at least until stabilization has been problems, and polyabusers (cocaine, benzodi- achieved. Unsupervised addicts, to a greater azepines) [10]. extent than other psychiatric patients, tend to Research data from studies carried out in be a rule unto themselves and instinctively re- the 90s confirmed that take-home programmes ject any rule that may be experienced as a limi- are characterized by higher retention rates tation on their access to narcotics, and contin- (19); vice versa, revoking the privilege of take- ue to reason around the priority of controlled home without any clinical basis can have a drug use for months while on treatment. Take- major influence on the likelihood of dropout home without selection would probably re- and relapse into substance use [17]. sult in low retention rates, since some addicts A later, end-stage extension of take-home would prove to be incapable of respecting programmes is what is called ‘medical mainte- the few rules for the maintenance of a take- nance’, where patients take delivery of monthly home privilege. Obviously, ‘wild’ take-home methadone supplies from their general practi- coupled with no control over patients’ toler- tioner, or a dedicated physician. As long as this ance to opiates would decrease the likelihood option is restricted to patients who have been of stabilization for enrolled patients, decrease stabilized for years, studies show encouraging the probability of future enrolment for street results in terms of relapse prevention, feasibil- patients supplied with illegal methadone out- ity and safety [22]. side therapeutic rules, and increase the risk of Diversion from take-home programmes breaking the rules. One major reason which may be a source of street methadone availabil- justifies theprejudice against methadone treat- ity: cases of overdose of untreated addicts who ment in the general population and among ad- bought it or were supplied with it illegally dicts themselves is the identification of metha- have been reported [8, 26]. done treatment and its results with whatever 134 · CHAPTER 2.10

14. McCaul M. E., Stitzer M. L., Bigelow G. E., derives from its improper and unsupervised Liebson I. A. (1984): Contingency management use. interventions: effects on treatment outcome during methadone detoxification. J Appl Behav Anal. 17:(1) 35-43. 15. Pani P. P., Pirastu R. (2000): Take-home and compliance References with methadone maintenance treatment. Heroin Add & Rel Clin Probl. 2:(1) 33-38. 1. Brown L. J. (1993): Responsible take-home 16. Pani P. P., Pirastu R., Musio A., Solinas P., Gessa G. medication practices. In: Parrino M. W. (Ed.) State L. (1994): Compliance and social adjustment during Methadone Treatment Guidelines. U.S. Department take-home treatment with methadone. Addictive of Health & Human Services, Rockville,MD. pp. 67- Drugs and Addictive States: The State of The Art. . 72. 237-241. 2. Buckalew L. W., Sallis R. E. (1986): Patient 17. Pani P. P., Pirastu R., Ricci A., Gessa G. L. compliance and medication perception. J Clin Psychol. (1996): Prohibition of take-home dosages: negative 42 49-53. consequences on methadone maintenance treatment. 3. Chutuape M. A., Silverman K., Stitzer M. L. Drug Alcohol Depend. 41 81-84. (1998): Survey assessment of methadone treatment 18. Phillips C. D., Hubbard R. L., Dunteman services as reinforcers. Am J Drug Alcohol Abuse. G., Fountain D. L., Czechowicz D., Cooper 24:(1) 1-16. J. R. (1995): Measuring program performance in 4. Dole V. P. (1994): What have we learned from three methadone treatment using in-treatment outcomes: decades of methadone maintenance treatment. Drug an illustration. J Ment Health Adm. 22:(3) 214-225. and Alcohol Review. 13:(3) 330-338. 19. Rhoades H. M., Creson D., Elk R., Schmitz J., 5. Dole V. P. (1999): Methadone Maintenance. Comes Grabowski J. (1998): Retention, HIV risk, and illicit of age. Heroin Add & Rel Clin Probl. 1:(1) 13-17. drug use during treatment: methadone dose and visit 6. Dole V. P., Joseph H. (1978): Long term outcome of frequency. Am J Public Health. 88:(1) 34-39. patients treated with methadone maintenance. Ann N 20. Saxon A. J., E.A. W., Fleming C., Jackson T. R., Y Acad Sci. 311 181-189. Calsyn D. A. (1996): Pre-treatment characteristics, 7. Dole V. P., Nyswander M. E. (1966): Rehabilitation program philosophy and level of ancillary services of heroin addicts after blockade with methadone. as predictors of methadone maintenance treatment New York State Medical Journal. 66(15) 2011-2017. outcome. Addiction. 91:(8) 1197-1209. 8. Heinemann A., Iwersen-Bergmann S., Stein 21. Schmits J. M., Rhoades H. M., Elk R., Creson S., Schmoldt A., Puschel K. (2000): Methadone- D., Hussein I., Grabowski J. (1998): Medication related fatalities in Hamburg 1990-1999: implications take-home doses and contigency management. Exp for quality standards in maintenance treatment? Clin Psychopharmacol. 6:(2) 162-168. Forensic Sci Int. 113:(1-3) 449-455. 22. Schwartz R. P., Brooner R. K., Montoya I. D., 9. Iguchi M. Y., Stitzer M. L., Bigelow G. E., Currens M., Hayes M. (1999): A 12-year follow-up Liebson, I.A. (1988): Contingency management in of a methadone medical maintenance program. Am J methadone maintenance: effects of reinforcing and Addict. 8:(4) 293-299. aversive consequences on illicit polydrug use. Drug 23. Stitzer M., Bigelow G. (1978): Contigency Alcohol Depend. 22 17-23. management in a methadone maintenance program: 10. Kidorf M., Stitzer M. L., Brooner R. K., availability of reinforcers. Int J Addict. 13(5): 737-746, Goldberg J. (1994): Contigent methadone take- 1978. International Journal of Addictions. 13:(5) 737- home doses reinforce adjunct therapy attendance 746. of methadone maintenance patients. Drug Alcohol 24. Stitzer M. L., Bigelow G. E., Liebson I. A., Depend. 36:(3) 221-226. Hawthorne J. W. (1982): Contingent reinforcement 11. Kosten T. R., Kleber H. D. (1984): Strategies to for benzodiazepine-free urines: evaluation of a drug improve compliance with narcotic antagonists. Am J abuse treatment intervention. J Appl Behav Anal. Drug Alcohol Abuse. 10 249-266. 15:(4) 493-503. 12. Maddux J. F., Prihoda T. J., Vogtsberger K. N. 25. Stitzer M. L., Iguchi M. Y., Felch L. J. (1992): (1997): The relationship of methadone dose and other Contingent take-home incentive: effects on drug use variables to outcomes of methadone maintenance. of methadone maintenance patients. J Consult Clin Am J Addict. 6:(3) 246-255. Psychol. 60:(6) 927-934. 13. Magura S., Casriel C., Goldsmith D. S., Stug 26. Vormfelde S. V., Poser W. (2001): Death attributed D. L., Lipton D. S. (1988): Contigency contracting to methadone. Pharmacopsychiatry. 34:(6) 217-222. with polydrug-abusing methadone patients. Addict Behav. 13:(1) 113-118. 2.11

Resistance to Treatment I. Maremmani and M. Pacini

Based on the explanations given in the efit from available treatments, or only show previous chapters about the theoretical and partial improvement, without ever acquiring practical aspects of methadone maintenance, spontaneous control over narcotic use or stable the definition formulated for therapeutic re- abstinence. This may be due to clinical, toxico- sistance should account for the failure of all logical and psychosocial features which have viable and potentially effective therapeutic a negative impact on retention in a methadone attempts made on behalf of a patient. Most programme. Moreover, polyabuse often ham- of the addicts who were once labelled ‘hard- pers the achievement of satisfactory social ad- core’, as long as pre-methadone therapeutic justment, despite stable abstinence from nar- standards were applied, would nowadays fit cotics. Lastly, some subjects may fail to reach the stereotype of the potential methadone-re- satisfactory outcomes because of an intrinsic sponder. Relapsing behaviour after the rever- severity of the metabolic impairment underly- sal of tolerance (so-called ‘detoxification’), the ing their addictive symptoms, despite the use dependence of good outcomes on ongoing of highest dose methadone for several months agonist treatment, the need for a long-term in a maintenance regimen [1-4, 6, 7, 10-12]. stable-dose regimen (maintenance), and the The issue of resistance is of major interest, need for higher methadone dosages (over 100 though it looms as a problem of smaller pro- mg/day) have become expected features for portions than it had not long ago, since agonist the vast majority of addicts [5]. None of what drugs are now available and standard treat- has just been said above should ever be taken ment rules have been established. Resistance to refer to an exceptional severity of addiction, may be classified, in a chronological order that nor should recidivism be considered a sign of takes account of the phases of methadone treat- greater severity. ment, as a) ‘absolute’ resistance; b) early attri- Some patients, however, simply fail to ben- tion; c) dropping-out; d) relative resistance.

135 136 · CHAPTER 2.11 resistance to treatment· 137

From a different viewpoint, it can be classified tance indicates a situation in which patients in pathophysiological terms as: a) addictive; b) stay in treatment without achieving a satisfac- polyaddictive; c) dual diagnosis-related. tory response in terms of rehabilitation, due to Absolute resistance means never being able persistent drug use or polyabuse (table 1). to enter any specific treatment programme, Some addicts, during some periods of their even when all types of programme were avail- addictive histories, reject any hypothesis of able and enrolments were correctly managed. long-term structured treatment; or, even if Early attrition indicates the situation of pa- when they do apply for treatment, claim to be tients who leave treatment during the induc- able to decide for themselves what is best for tion phase, that is, before reaching a blocking them, and refuse to submit to treatment rules. dosage. Dropping out refers to a failure to re- With such premises in place, patients of main in treatment as long as would have been this kind cannot follow any potentially effec- required to reach stabilization. Relative resis- tive treatment programme, and so remain un-

Table 1. Clinical phenomenology of “apparent” resistance and its meaning

Clinical Pictures Meaning Relapse after detoxification Malpractice: detoxification is non a specific intervention Relapse after more than one attempt of deto- Malpractice: persistent therapeutical omission xification Narcotic use in the absence of withdrawal Diagnosis of addiction symptoms Narcotic use upon blocking dosages Diagnosis of addiction Possible fast metabolism if narcotics are still fully sensed Narcotic use at higher doses in order to over- Diagnosis of addiction come blockade Relapse after a long abstinence period Diagnosis of addiction Relapse after discharge from a MM lasting about Diagnosis of addiction one year Relapse after dose reduction Diagnosis of addiction Refusal to reduce the stabilisation dosage Good insight Relapse after discharge from a Therapeutic Diagnosis of addiction Community Malpractice: residential treatment in non specific unless anticraving treatment has been performed in the protected environment Relapse after a long period of pharmacologic Diagnosis of addiction stabilisation Relapse when psychosocial condtion are fa- Diagnosis of addiction vourable Claiming to be able to handle narcotic use in Diagnosis of addiction (no insight as a rule) favourable conditions Disapproving of the increasing dose procedu- Diagnosis of addiction (no insight as a rule). re Possible cultural conditioning Poly-intoxication Diagnosis of poly-abuse/addiction. Dosages may be inadequate (undermedication) 136 · CHAPTER 2.11 resistance to treatment· 137

able to receive protection from the chronic, repression is that the most commonly featured lapsing course of their disease. In other words, reasons for ‘early dropout’ are no more than these patients show that they are completely an expression of addictive symptoms, in other resistant to treatment (absolute resistance) as words, are an aspect of an uncontrolled drive long as their therapeutic career fails to proceed to stay ‘somewhere else’ rather than in treat- beyond enrolment. ment, based on a twisted but automatic in- Far more commonly, addicts may apply for terpretation of ‘being in treatment’ as ‘losing treatment, only to leave earlier than planned, one’s freedom to find and sense narcotics’. during the induction or stabilization phase. Most patients fall into the categories de- This tendency dwindles through time, so that scribed above. On the other hand, a minority dropping out is less likely among those who can correctly be classified as ‘relatively resis- have stayed in treatment at least to up to a tant’. To qualify as a condition divergent from certain point in time. Dropping out is excep- ‘absolute resistance’, ‘relative resistance’ has tional for patients who have been in treatment to be understood as resistance despite ongoing for years, and, as a rule, is caused by the loss adequate treatment and satisfactory adherence of stabilization and the re-emergence of addic- to treatment rules. Relatively resistant patients tive symptoms. Dropping out always comes may continue to be prone to: a) relapse into use, ‘earlier’ than stabilization, but we use the though less frequently than before, and with a term ‘early dropout’ to indicate dropout cases self-limiting pattern; b) regular use, at lower that occur ‘very early’, during the induction levels but without ever reaching abstinence; c) phase. Early dropout is liable to occur in any regular use at levels no lower than before, with programme, even if that programme is high- a little improvement due to the prevention of ly effective and employs adequate dosages withdrawal and the curtailment of criminal with those who have stayed in treatment long acts. Obviously, this kind of resistance can be enough to be stabilized. On the other hand, distinguished from latency of response after ‘late’ cases of dropout depend on the adequa- several months of adequate treatment. cy of treatment standards and the quality of As for other diseases, partial response patient-staff relationships, and may vary over (points a) and b) of the previous paragraph) a wide range. is not a good reason for discharging patients When using average effective (around 100 from treatment, which would mean restoring mg/day) or higher dosage, and adjusting dos- a higher grade of disease severity. In addition, ages on a clinical basis, it is possible to maxi- a late-onset response should not be excluded mize retention rates among populations of in any case. To date, no standard index or ret- subjects who have survived a 2-3 month period rospective evaluation can be resorted to in an of early attrition. Conversely, the correct man- attempt to label patients as ‘resistant’ to meth- agement of cases by pharmacological means is adone treatment for life. Nor should patients not enough to avoid some patients dropping be shifted to treatment options which are gen- out within the first 2-3 months. Therefore, a erally less effective and only suitable for low- correctly planned methadone programme is severity addicts. still not viable for some patients, and does not ensure major improvement in insight and compliance in the short-term. Reasons for cases of 1. Addictive resistance ‘early dropout’ apparently belong to different spheres: practical difficulties in attending, daily survival, psychiatric impairment, behav- Addictive resistance is always a feature, ioural instability and disruptiveness (such as just like any other core symptom of addiction, that displayed by polyabusers). It should be since it expresses the way an average addict noted that patients usually find a way to at- interacts with the therapeutic system (table 2). tend, despite unfavourable conditions and the Addicts are specifically resistant to effective presence of psychiatric symptoms. Our im- treatments (long-term, structured) and handle 138 · CHAPTER 2.11 resistance to treatment· 139

Table 1. Clinical phenomenology of resistance and its meaning

Clinical Pictures Meaning Not accepting treatment No insight. Absolute Resistance. Not admitting to have a disorder No insight. Absolute Resistance. Poor compliance to the program rules Severely ill (likely to drop-out). Discotinuing treatment without consulting the Severely ill (likely to drop-out). staff Trying to dictate therapeutic rules or decisions No insight. Absolute Resistance. Violence against the staff or other patients, Severely ill. Absolute Resistance. Dual Diagnosis with no compliance to treat- No insight. Absolute Resistance ment Being late and missing appointments Severely ill (likely to drop out). Satisfactory compliance, but ongoing narcotic Relative Resistance. use to a variable extent

the elements of treatment, when allowed to do happens with addicts enrolled in a condition so in a self-wise way, in order to be ‘free to find of acute psychiatric impairment or polyintoxi- and sense narcotics’. For addicts who have cation, or as detainees: their apparent compli- short addictive histories and low levels of use, ance turns out to be transient and related to this attitude may be due to naivety and shared a particular condition (e.g. imprisonment). cultural misbeliefs about the nature of addic- Others may be interested in starting some tion. Conversely, in most cases resistance acts treatment, with no precise intention about as an equivalent of ambivalence towards the stable adherence. Others again may drop out use of narcotics: on one hand, the request to after being abstinent for a short time and then have the craving for narcotics suppressed due claiming to have ‘turned over a new leaf” with to the impossibility of dealing with it; on the no risk-perception of possible relapse. The im- other hand, the subtle thought of being able pact of treatment on a patient’s insight is not to reach some reasonable level of control and itself favourable: in fact, when subjects enter so becoming able to use narcotics in a more treatment, they usually think they can no lon- comfortable way. The expectation that treat- ger cope with narcotic use and are dependent ment may be a short-term resource capable of on environmental resources (an external locus favouring the onset of controlled narcotic use of control). Soon after withdrawal has been does not vanish, but often consolidates in a resolved, they will change their attitude to paradoxical way, after years of relapses. an ‘internal locus of control’ position, judg- Addicts are therefore likely to appear to ing they can stay off drugs as a result of their collaborate with physicians, while aiming to own will-power. Thus the ‘locus of control’ exploit the therapeutic setting to regain con- fluctuates between two mistaken views, ina trol over the use of narcotics. When treatment way dependent on mood states and the level happens to interfere directly with that use (as of opioid activity, and it never corresponds to in a narcotic blockade), the patient will try to any deeper insight. oppose the treatment rules and his/her am- Addictive resistance can be overcome by bivalence will become evident in terms of be- repeating therapeutic attempts, implementing haviour patterns. pharmacological treatment together with psy- Some addicts soon become incapable of choeducation, or resorting to practical limita- complying with treatment rules. Usually, that tions on freedom (e.g. imprisonment) as a way 138 · CHAPTER 2.11 resistance to treatment· 139

of replacing spontaneous compliance. In these a known reason for resistance. Nevertheless, circumstances, physicians should not negotiate Axis I mood disorders, for example, are often with the patient about treatment rules, which a reason for early dropout. Interference of this would mean following his/her tendency to kind is mostly due to states of mania or hy- steer treatment towards substance use. pomania, in which subjects display superficial A patient who is currently resistant to treat- behaviour and have unreasonable expecta- ment may be capable of attending a harm-re- tions about their ability to control narcotic use. duction setting. If we consider different kinds States of mood elation may actually be a rea- of resistance in a hierarchical order, overcoming son for sustained abstinence after the interrup- absolute resistance will come first, followed by tion of treatment. Also, the quick withdrawal overcoming relative resistance. In this way, pa- of methadone may result in phases of mood tients who are absolutely resistant may be ap- excitement, giving a short-lived impression of proached by harm reduction, in the hope that satisfactory craving control [9]. Since a manic they will become more compliant while still phase is unstable by definition, any such bal- relatively resistant. Patients can move up from ance cannot last long [8]. the lower level of a non-specific treatment to Depressive phases carry a lower risk of more and more structured forms of treatment, relapse, and often raise a need for assistance, until they show resistance to a higher level, but which results in apparent compliance with – a crucial factor for such dynamics – the selec- rules and stable adherence. tion must be made from a top-down basis. In Table 1 and 2 display the clinical types of other words, patients can be referred to harm resistance and pseudo-resistance, with corre- reduction only after they have shown their responding explanations. sistance to agonist treatment. Otherwise, if all patients are directed to harm reduction first, and agonist treatment is References left as a side-issue to be proposed later, resis- 1. CACCIOLA S. J., ALTERMAN A. I., RUTHERFORD M. J., MCKAY J. R., MULVANEY F. D. (2001): The tance to treatment will be reinforced as a result. relationship of psychiatric comorbidity to treatment Harm-reduction, which is a non-specific treat- outcomes in methadone maintained patients. Drug Alcohol Depend. 61 271-280. ment, is the least selective (and is therefore 2. DOLE V. P., JOSEPH H. (1978): Long term outcome suitable for anyone), but needs to be applied of patients treated with methadone maintenance. Ann NY Acad Sci. 311 181-189. at a higher level of selection (only to those who 3. DRAKE R. E., MUESER K. T., CLARK R. E., are resistant to everything else). WALLACH M. A. (1996): The course, treatment and outcome of substance use disorder in person with A multi-level architecture for the organi- severe mental illness. Am J Orthopsychiatry. 66 42-51. zation of addiction treatment should account 4. FRYKHOLM B., GUNNE L. M., HUITFELDT B. (1976): Prediction of outcome in drug addiction. for resistance as being due to the dynamics of Addict Behav. 1 103-110. addiction itself, so that the prevailing strategy 5. HARGREAVES W. A. (1983): Methadone dosage and duration for maintenance treatment. In: COOPER J. should consist in overcoming it, rather than R., ALTMAN F., BROWN B. S., CZECHOWICZ D. adapting to it. (Eds.): Research on the treatment of narcotic addiction State of the art Treatment Research Monograph Series. NIDA, Rockville, Maryland. pp. 19-79. 6. KOSTEN T. R., ROUNSAVILLE J., KLEBER H. D. (1987): Multidimensionality and prediction of 2. ‘Dual diagnosis-related’ resistance treatment outcome in opioid addicts: 2,5 years follow- up. Compr Psychiatry. 28/1 3-13. 7. MADDUX J. F., PRIHODA T. J., VOGTSBERGER K. N. (1997): The relationship of methadone dose and other Aggressive and dysphoric subjects are un- variables to outcomes of methadone maintenance. Am J Addict. 6:(3) 246-255. likely to be eligible for a structured methadone 8. MAREMMANI I., CANONIERO S., PACINI M. programme. Despite this, sub-effective metha- (2000): Methadone dose and retention in treatment of heroin addicts with Bipolar I Disorder comorbidity. done dosages may allow a reduction in aggres- Preliminary Results. Heroin Addict Relat Clin Probl. siveness and dysphoria and ensure a higher 2:(1) 39-46. 9. MAREMMANI I., ZOLESI O., AGLIETTI M., level of compliance. MARINI G., TAGLIAMONTE A., SHINDERMAN Dual diagnosis should not be regarded as M. S., MAXWELL S. (2000): Methadone Dose and 140 · CHAPTER 2.11

Retention in Treatment of Heroin Addicts with Axis 11. STRAIN E. C., STITZER M. L., LIEBSON I. A., I Psychiatric Comorbidity. J Addict Dis. 19:(2) 29-41. BIGELOW G. E. (1993): Methadone dose and 10. ROUNSAVILLE B. J., TIERNEY T., CRITS- treatment outcome. Drug Alcohol Depend. 33:(2) 105- CHRISTOPH K., WEISSMAN M. M., KLEBER H. B. 117. (1982): Predictors of outcome in treatment of opiate 12. VETERE C. (2000): Is prescribing higher doses of addicts: Evidence for the multidimensional nature of methadone likely to promote elevate drop-out rates? addicts’ problems. Compr Psychiatry. 23 462-478. [Letter]. Heroin Addict Relat Clin Probl. 2:(1) 22-22. 3.1

Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases L. Somaini, M. Pacini and I. Maremmani

The immune system is an organization of of modulating peripheral immune parameters cells and molecules with specialized roles in was presented many years ago following the in providing defence against infection. There are vivo administration of morphine in rats. Since two fundamentally different types of response then, a great deal of effort has gone into de- against infections. However many times an in- termining not only which immune parameters fectious agent is encountered, innate or natural are modulated by the CNS, but also the spe- responses occur to the same degree, whereas cific action sites that mediate these responses, acquired or adaptive responses improve on and how central opioid regulation influences repeated exposure to a given infection. Metha- the immune response. done is a widely used synthetic 3,3-diphenyl- propylamine opioid which acts primarily at the opioid receptor. Its most common use is in 1. Methadone and immune function therapy for opioid dependence, but it is also being increasingly used in the management of chronic pain. Besides their therapeutic efficacy, It is well known that opioids, especially her- opioids can produce several well-known ad- oin and morphine, suppress the immune sys- verse events, and, as has recently been recog- tem and lower resistance to various infections nized, can interfere with the immune response. [83]. Human and animal studies have, in fact, Morphine may decrease the effectiveness of shown that both innate and acquired immu- several functions of both natural and adaptive nity are significantly affected by these drugs immunity, while significantly reducing cellu- [70, 91]. The acute and the chronic administra- lar immunity, too. The first demonstration that tion of opioids both induce inhibitory effects the activation of opioid receptors within the on humoral and cellular immune responses, Central nervous System (CNS) was capable including antibody production, natural killer

141 142 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 143

(NK)-lymphocyte activity, cytochine expres- its analogue, N-methyl-morphine, which can- sion and phagocytic activity. The possible not readily cross the blood-brain barrier [26]. mechanism(s) of morphine-mediated immu- Another mechanism that underlies the opioid- nosuppression may reside in the drug’s ability mediated modulation of the immune system to regulate the immune system either directly, is the ability of these compounds to influence by activating mu opioid receptors located on immunocompetent cell production, as shown immune cells, or through an indirect central by the dose-dependent reduction in the num- pathway, by activating mu opioid receptors bers of T- and B-lymphocytes, NKs and mono- in the CNS [69]. Receptors for opioids are ex- cytes/macrophages observed in the presence pressed on the cell surface of mature lympho- of morphine [72]. Opioids may also influence cytes, and are involved in mediating autocrine the immune function through activation of the or paracrine types of response [13, 35, 53, 58]. descending pathways of the hypothalamus- Since the biochemical and hormonal perturba- pituitary-axis (HPA) and the sympathetic ner- tion that takes place during opioid withdrawal vous system [83]. Activation of the HPA axis or intoxication has been implicated in opioid- elicits the production of immunosuppressive induced immunosuppression [61, 62], it is pos- glucocorticoids in the periphery, while activa- sible that improvements in immune responses tion of the sympathetic nervous system induc- could partly depend on the constant activation es the release of epinephrine, nor-epinephrine of µ Opioid Receptors (MOR) that is present and dopamine from adrenal medulla as well as with methadone in contrast to heroin-injecting from sympathetic nerve terminals innervating subjects. Consistently with this hypothesis, it primary and secondary lymphoid organs [7, was shown in a monkey model of AIDS that 16]. Both nor-epinephrine and glucocorticoids the administration of morphine according to modulate the immune functions negatively an experimental design that prevented intoxi- by their action on leukocytes. In particular, cation or withdrawal conditions, did not exert the glucocorticoids play an important role in any negative impact on immune responses decreasing and regulating cellular immune re- and HIV disease progression. These authors sponses [5]. Studies have shown that morphine also reported that a structured discontinuation treatments suppress immune parameters in of opiate administration precipitated immune mice through the HPA axis [60]. The ability of alteration [14], indicating that the tonic activa- a centrally administered acute dose of mor- tion of the opioid receptors on the lymphocyte phine to inhibit either lymphocyte prolifera- cell surface did not produce any immunosup- tion or NK cell activity appears to be primarily pressive effect [80, 81]. In agreement with these mediated by the sympathetic nervous system, data is the observation that short-acting opioid whereas a more prolonged exposure to opi- drugs such as morphine and heroin produce oids alters the immune system predominantly severe changes in the immune system [55], by activating the HPA axis. In this respect it is while long-acting opioid drugs such as metha- interesting to note that long-lasting treatment done are able to progressively restore immune with methadone can normalize the HPA axis function and cytochine concentrations [46]. – the axis that is altered in heroin abusers – as The significant decrease in NK cell activity ob- demonstrated in various clinical studies [21]. served after the administration of morphine The normalization of HPA after prolonged directly into the rat right lateral ventricle treatment with methadone could play an ad- was blocked by the central administration of ditional role in restoring the altered immune the opioid antagonist, naltrexone, suggesting function observed in heroin abusers. A recep- that the opioid agonist suppressed the NK tor-mediated increase in the production of the cell function primarily through opioid recep- transforming growth factor, an immunosup- tors located in the CNS [26]. In addition, the pressive cytokine, is another possible indirect suppression of mitogen-induced whole blood mechanism which may account for the ability lymphocyte proliferation in rats was demon- of opiates to suppress immunity [11]. strated in the presence of morphine, but not of A variety of changes induced by chronic ex- 142 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 143

posure to opioids have also been observed in volunteers. This may suggest that methadone, the human immune system, by means of stud- unlike heroin, has a stimulatory effect due to ies carried out in heroin addicts and in heroin the immunologic hyperactivation of an im- withdrawal subjects. Govitrapong and col- mune system that was formerly inhibited by leagues documented a decrease in the immune heroin. Recently, our group has investigated system functions of both heroin addicts and the immune system function in former heroin subjects undergoing a short period of heroin addicts who have been in maintenance ther- withdrawal (between 15 to 21 days and 6 to 24 apy with methadone for at least six months, months). On the other hand, longer withdraw- comparing them with untreated heroin ad- al periods, lasting over two years, were associ- dicts who are still injecting heroin, and with ated with a gradual return of some immuno- healthy controls [71]. The proliferation rate of logical parameters, such as the CD4/CD8 ratio peripheral blood monocytes induced by phy- and the absolute number of NK cell count, to tohemoaglutinin in untreated heroin addicts normal levels [22]. From a pathophysiological was significantly lower than that observed viewpoint, the ability of heroin to induce im- in methadone-treated patients. Further, al- munosuppression may have some bearing on terations of the Th1/Th2 balance and reduced the higher rates of infectious diseases that are levels of IL-4, TNF-, interferon were reported observed in heroin addicts, although the high in untreated heroin addicts, with respect to percentage of infections among injecting drug methadone-treated patients. users is probably related to drug injection pro- Because of the AIDS epidemic, interest in in- cedures and life-style practices [18, 82]. In this vestigations on how drugs of abuse, especially connection, one interesting issue is how long- opiates, affect the immune system has greatly acting opioids are able to restore the immune increased. Clinical studies that aim to evaluate system. In fact, both preclinical and clinical the immune function of HIV+ subjects have studies appear to indicate that not all opioid shown that MMTs prevent the progression of receptor agonists share the same immunosup- HIV, which, however, does take place in those pressive properties [70]. The hypothesis that who continue to use substances of abuse such significant abnormalities of cellular immunity as heroin, cocaine and morphine [67, 77]; in in heroin abusers can be normalized by using fact, the relative risk ratio (RR) of developing long-term methadone treatment was formu- AIDS is higher in HIV+ drug users who do not lated many years ago, in a pivotal paper that take methadone (RR of 1.78) than in patients analyzed the T cell genetic damage induced by in treatment with methadone. Remission from various opioids [40]. Follow-up studies evalu- drug use is in itself a protective condition, ated several immune parameters, such as NK even in the absence of pharmacological treat- activity, T lymphocyte subset numbers and ment (in this case RR is 0.66, much lower than function and phagocytic physiology, in metha- that of active drug users) [87], but still greater done-maintained patients in comparison with protection is provided by MMT (RR 0.44). heroin abusers [52]. More recently, further Against the background of these epidemio- studies attempted to find out whether the im- logical data, which are enough by themselves provements observed in immune responses in to justify the elective indication of MMTPs for the course of methadone treatment were due to HIV-positive drug users, in this kind of popu- the drug profile or to the lifestyle changes that lation some issues are left open in connection take place in maintenance treatment [1]. Ac- with certain alterations in lymphocyte func- cordingly, a randomized clinical trial recently tions during MMTPs. MMTPs make it pos- reported that methadone was able to activate sible to improve some immune system func- the immune systems that had formerly been tions, but a number of dysregulations that are inhibited by heroin in addicted patients [47]. hard to interpret are observed in the immune The most surprising result was that cyto- parameters of these patients. In particular, chine levels in subjects on methadone treatment the lymphocyte subsets CD2, CD3, CD4, CD8 were higher than those observed in healthy and NK cells are better represented in patients 144 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 145 during MMTP than in heroin addicts who are related to addiction, such as HBV and HIV still injecting heroin [52]; furthermore, dur- [6]. The major risk factors that are the basis ing MMT there is an increase in lymphocyte of infectiousness in patients in MMT are the subpopulations – in particular, of CD4 CD26, frequent inadequacy of methadone doses, re- CD2, CD26 and CD8 – which are also func- sulting in the continuation of the use of heroin, tionally hypoactive [28]. These abnormalities and the intravenous use of cocaine. Retrospec- of the immune system are most likely a result tive studies have pointed out that seropositiv- of acquired immunopathy due to chronic liver ity for HCV is associated with elements of the disease or to other infectious diseases that oc- clinical picture that reflect both the duration cur in this population [29] and, as such, have and the severity of addiction [24]. In fact, in a tendency to decrease with the time spent in many heroin addicts, especially those who ex- treatment [30]. perience intravenous addiction, there is the co- The immune abnormalities which may be presence of one or more viral infections, such present in HIV+ subjects during their MMTP as HCV and HBV [24]. This finding in particu- are probably associated with HIV infection it- lar suggests that during the active phase of the self, rather than with an immunosuppressive/ disease, sources of infection associated with immunodysregulatory effect of the drug. How- drug abuse practices are the main channels of ever, some aspects related to the management infection for different pathogens. In HCV in- of therapy in patients moving towards AIDS fection, cellular and humoral immunological as well as to humoral anti-methadone immu- mechanisms participate in viral clearance in nity (88% of HIV+ patients in MMTP have an- the liver, peripheral blood and lymphatic or- timethadone antibodies [19, 20]), are points of gans. However, the role played by the immune interest that should be investigated further. In system in the progression of chronic hepatitis the current state of knowledge we can say that in not completely clear and the mechanisms MMTP is able to improve the immune system responsible for the persistence or viral clear- functions in heroin-addicted patients who are ance are still largely unknown. The activation not users of other substances and are not af- of T cell responses is considered one crucial fected by other causes of immunodeficiency, mechanism in the antiviral immune response such as HIV infection. Therefore any alteration against viruses [9, 15]. It is generally accepted in the immune system observed in this kind that opioids may facilitate the outbreak of in- of patient during an MMTP deserves further fections through marked immunomodulating clinical investigation [31, 50, 54]. effects on the immune response against a virus. Conversely, opioids seem to exert a biphasic action on cytokine production, as this 2. Methadone maintenance and HCV action is mediated by endogenous opioids. infection In any case, opioid receptor overexpression or deficiency would predispose aberrant defensive mechanisms [57, 68]. Interferon in Hepatitis C virus infection (HCV) is a clini- combination with ribavirine is currently the cal disease often (64-88%) associated with her- most effective therapy for patients with HCV oin addiction [12, 24, 54, 59]. The chronic char- infection, and the positive effects of this com- acter of hepatitis C and its evolution towards bination therapy may not be directly antiviral hepatic insufficiency causes 9% of all deaths but mainly immunomodulatory [9, 15]. In this associated with methadone maintenance treat- connection it is important to note that opioids ment (MMT) [2]. The increased infectiveness are able to interact with the immune system, of the virus and the existence of modes of and different types of opioid receptors have transmission that cannot be neutralized by the been detected on various cell types, includ- clinical control of drug addiction most probing blood mononuclear elements which dif- ably underlie the increased infectiousness of ferentiate as macrophages in tissue. In fact, HCV, compared to other infectious diseases suppressed NK activity was demonstrated in 144 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 145

heroin and in polydrug abusers and NK an- ness, with or without the presence of specific tibody dependent cell-mediated cytoxicity or non-specific symptoms. In any case, the (ADCC) was present in injecting drug users. presence of severe chronic hepatopathy is Conversely, some experimental data have not a clinical counterindication for beginning shown that the opioid effects on the immune and/or continuing a pharmacological treat- system are not necessarily deleterious; in fact, ment with methadone [51]. The belief that the endogenous opioid metenkephalin was people suffering from hepatitis C are intoler- seen to determine immunostimulatory activ- ant to methadone and/or are more sensitive to ity on T cells. These different effects (inhibitory unspecified hepatotoxic effects of methadone or stimulatory) of opioids on immune system itself, is unmotivated. In any case, pharmaco- functions could be explained by the method or logical treatment with methadone has a posi- duration of chronic drug use [56, 88]. Howev- tive impact on the liver function of patients er, it has been observed that the immune func- with HCV-related liver disease; in fact, plasma tions that become normalized in drug abusers transaminase levels are higher in non-treat- on long-term methadone maintenance as a ment than in cases of methadone treatment result of methadone’s long-lasting action com- [39]. The lowering of plasma transaminases prise the normalization of the HPA axis, the is probably related to the clinical remission of consequent persistence of the drug level, and drug behaviours, and any direct hepatotoxic the greater endurance of receptor stimulation damage from a drug (as in the case of naltrex- [32, 45, 71]. Heroin addicts presented signifi- one) appears to be clinically less significant for cantly low levels of NK cell activity, whereas the liver as compared with a clinical addiction patients treated with methadone over a long not treated pharmacologically. Furthermore, period, from 5 to 8 years, showed a progressive long-acting opioids seem to improve the out- and constant normalization of NK cell activity. come of the viral infection, as suggested by Likewise, data presented in the literature sug- the ability of methadone to significantly re- gest that IL-2 and TNF-alpha production is a duce the relapse rate of patients undergoing predictive index of a good response to IFN-al- interferon and ribavirine treatment [48]. With pha treatment in patients affected by a chronic hepatopathic patients, the choice of using a hepatitis C virus, even in non-drug users. The daily dosage of methadone below the levels plasma levels of TNF-alpha, IL-2 and IFN- recommended in the international literature gamma in patients affected by chronic active has a clinical rationale only when there is a virus C hepatitis rose significantly in patients rapid progression of liver disease towards a during methadone treatment [48]. Because of form of cirrhosis. This clinical attitude has a their poor compliance, drug users with HCV pharmacological rationale, considering that in are usually treated for only a few months after such situations, the sudden reduction of liver the end of methadone therapy. Nevertheless, function resulting in a reduction of the he- specific IFN therapy may be recommended patic absorption of methadone, will gradually in drug addicts during methadone treatment, develop tolerance to the amount given, with since this period is immunologically favour- a subsequent increase in plasma concentra- able for antiviral treatment. tion, when the quantities being administered remain constant. Normally, in a patient who has cirrhosis ab initio, the best recommenda- 2.1 Methadone maintenance for HCV-position is to use appropriately reduced posology tive patients and patterns of introduction [49, 51], whereas in patients undergoing active hepatitis, an increase in daily dosage may be required, since Chronic Hepatitis C, in its natural history, the activation of C infection can actually lead alternates between periods of persistence of to an increase in the enzymatic activities that the virus without clinical evidence of hepatic are responsible for the hepatic metabolism suffering, and periods of increased infective- of methadone [42]. After all, the inclusion of 146 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 147

HCV+ subjects in methadone maintenance most effective therapeutic strategy for drug- programmes appears to be a priority, not only addicted patients to get anti-HCV treatment. for the remission of the underlying disease but The incidence of mood disorders, states of especially since the progression rate of hepa- anxiety and depressive symptoms in patients titis C is lower in these treatment conditions. secondary to treatment with interferon and The clinical measures to be taken in manag- ribavirine in patients in MMT is similar to that ing drug addicts suffering from HCV, should seen in non-addicted patients, but the severity include: (1) the enrolment of the patient in an of the sequence of symptoms is less marked in MMT as quickly as possible; (2) the initiation patients treated with methadone [73]. In order of a parallel treatment to reduce the possible to reduce the side-effects of antiviral treat- consumption of alcohol and cocaine; (3) veri- ments on mood, the following are effective: a) fication of the presence of antibodies to HAV an increase in the daily dosage of methadone and HBV and possibly an immunoprophylaxis during antiviral treatments; b) the preventive treatment through vaccination; (3) an assess- use of antidepressant drugs (SSRIs). In pa- ment of the desirability/feasibility of starting tients in MMT, cases of drop-out from antiviral a specific antiviral therapy for HCV [85]. treatments are not correlated with therapeutic status nor with the presence of mood disturbances, depression in particular. 2.2 Antiviral therapy in MMT patients 3. Methadone maintenance and HIV The treatment of HCV infection with inter- infection feron and ribavirin proved feasible in patients who had good compliance with methadone treatment, regardless of the presence of a dual diagnosis (62% of the sample) or the continued 3.1 Methadone and prevention of serocon- use of alcohol (21%) and drugs (31%) during version the antiviral therapy itself [79]. The data reported in the literature indicate the presence of a satisfactory and stable clinical response The enrolment of heroin patients in MMT to the antiviral therapy among heroin addicts programmes is a particularly effective mea- in MMT – a response which is quite similar to sure for the prevention of HIV virus transmis- that observed in non-addicted patients treated sion [4, 17, 84]. Indeed, several retrospective for HCV infection (40%) [79]. In a population epidemiological studies have provided evi- of non-selected patients, a number of factors dence that in a population of people addicted such as older age, prevalence of significant to heroin, those who had been enrolled in psychiatric disorders, a more advanced hepa- MMT before 1981 showed a lower incidence topathic stage and the use of opioid drugs have of death caused by AIDS than those who re- a negative impact on the response to antiviral ceived pharmacological treatment after 1981 therapy (29%) [12, 79]. In the selection of pa- [75]. During the period corresponding to the tients to be directed to an antiviral treatment, it epidemic diffusion of HIV infection, the termi- should be borne in mind that a priority should nal phase of the viral infection was the most be given to those for whom methadone thera- important cause of death among those treated py is not only able to determine the remission with MMT, in spite of the decline in the impor- of drug addiction, but also control over the use tance of other causes of death related to drug of other drugs, so avoiding any indication of addiction [2]. In this sense, MMT seems to have suitability for the treatment of patients with a played a protective role, especially in patients low probability of clinical response to antiviral who were enrolled before the epidemic diffu- treatment. From this perspective, pharmaco- sion of HIV and who presented a condition of logical treatment with methadone offers the serum negativity to the HIV virus. Those pa- 146 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 147

tients have consequently maintained a nega- end of their pharmacological treatment, with tive serological status as a result of their phar- the consequent adoption of risk behaviours for macological treatment in the years when the the transmission of infectious diseases related HIV epidemic was spreading. The hypothesis to dependence. From a clinical viewpoint, the of protective action from MMT is strengthened real evaluation of MMT efficacy in preventing by the observation that some patients who had HIV from spreading among people addicted been enrolled in MMT before 1981 and left the to heroin is correlated with the efficacy of this treatment for 1 year during the period when treatment in controlling possible relapses into the epidemic was active, after which they re- any recourse to drugs of abuse. Short-lasting enrolled in MMT, died of AIDS [75]. In order pharmacological treatments or those carried to reduce the spread of HIV among addicted out with inadequate and/or sub-therapeutic people, optimization of the strategy should dosages fail to provide satisfactory protec- aim to achieve early enrolment in the treat- tion from the risks of contracting the infec- ment, so reducing their exposure time to risks tion. Lack of protection may become evident of infection. Once enrolled in an MMT treat- both during the treatment, in the case of sub- ment, the protective role of these agents tends therapeutic dosages, and after the end of the to persist in proportion to the rate at which treatment, in the case of unduly short-lasting good therapeutic results, especially withdraw- programmes – those carried out below the al from the endovenous use of drugs of abuse, “security limits” [34]. Furthermore, the use of are achieved. Indeed, when starting MMTs, subtherapeutic treatments, based on dosages HIV-negative subjects maintain serum nega- that are ineffective in reducing heroin crav- tivity both in the short [27], medium [92], and ing, must itself be considered a negative fea- the long term, providing that the treatment is ture that weakens retention in treatment [25, carried out uninterruptedly [50]. As already 74] and predisposes the subject to a relapses stated, continuity in treatment is the main into heroin use. Reduction of the risks of infec- feature on which the protective role towards tion in subjects addicted to heroin with unsafe serum conversion for HIV is based: subjects behaviours is extremely important, especially suspending the treatment tend to show a high- for the kind of population being considered, er degree of serum conversion [3, 10, 90] with since the subjects who are a target for the in- respect to those who remain for longer periods fection also represent the ‘reservoir’ of the in- in pharmacological treatment. This effect is al- fection itself. Consequently, in this population ready clear-cut as little as 18 months after the the probability of transmission of the disease interruption of methadone treatment, (3.5% vs is quick to show the typical features of an epi- 22% of serum conversions for HIV among sub- demic diffusion. In this regard, a study carried jects treated with respect to those who have out in Vienna has shown that all the subjects interrupted the treatment) [43]: any relapse in entering an MMTP from the second half of the use of abuse substances is thus readily fol- the 1980s onwards displayed a progressive in- lowed by the reappearance of the use behav- crease in the rate of positivity to the infection iours that facilitate the spread of the HIV virus. (from 8.5 to 29.7%); this increase abated in con- However, one noteworthy underlying factor is junction with the growing use in the district of that, even in MMT-treated subjects, rates of se- Vienna of methadone treatment, which led to rum conversion are not completely suppressed a reduction, even if modest, of the rates of in- [44, 76]: indeed, an epidemiological investiga- fection (from 29.7% to 26.9%) [36]. This reduction carried out in the United States showed tion does not seem to be exclusively due to fall a serum conversion rate of 1.3% even among in the availability of subjects who might have patients who were treated for at least one year been infected, since one distinctive feature of during the epidemic diffusion of HIV infection the addicted population is the high turnover between 1985 and 1990. In this connection, it of subjects. This observation is confirmed by a can be presumed that some of these subjects comparative analysis carried out in several Eu- have relapsed into using drugs of abuse at the ropean countries, which reported that the high 148 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 149 percentage of intravenous drug users (IDU) preventing the spread of HIV infection. MMT treated with MMT is inversely proportional to subjects reported having had fewer partners in the prevalence of HIV infection. In addition, the period preceding the interview [23, 37, 38, countries with a low prevalence of HIV infec- 86, 90], even if, from this standpoint, there are tion are characterized by a rise in the number conflicting data in the literature [3, 33, 78]. Fur- of cases between 1987 and 1992. During that thermore, the number of partners in the year time lag period, the European countries which preceding the interview proved to be inversely had both a low prevalence and a low incidence proportional to MMTP duration [38], confirm- of the infection were further distinguished ing the importance of treatment retention as a from the other European countries by having stabilizing factor. Viewed as an isolated factor, a much higher percentage of drug addicts en- retention in treatment seems to be directly pro- rolled in MMTs [63-65, 86, 92]. portional to the daily dosage of methadone. The sexual activity of subjects undergoing treatment persists as a result of the search for 3.2 Behavioural targets in methadone main- personal satisfaction, while prostitution tends tenance to become less common. Although there is no general consensus on the possibly higher attention displayed by MMTP patients to condom The appearance of a full response to metha- use [23, 37, 41, 86], the concept of sexuality for done therapy, as a consequence of withdrawal these patients is mostly oriented towards the from taking drugs of abuse, induces a reduc- search for personal satisfaction, with the con- tion in risky behaviours [75, 90]. However, a sequent exhaustion of a series of phenomena beneficial effect on the risk of contracting infec- which favour promiscuity, such as prostitu- tious diseases related to dependence can also tion [86]. An indirect, but significant, demon- be recognized in heroin addicts who respond, stration of the usefulness of methadone treat- even if partially, to treatments. Even if these ment as a tool for the prevention of the spread individuals do not stop taking heroin during of HIV infection is the fall observed in serum MMTP treatment, it is well documented that conversion between sexual partners in MMTP in these cases patients who are still heroin- patients [76]. A possible explanation for the addicted at least reduce syringe interchange discrepancies in the data on risky sexual prac- significantly [78, 89]; from a behavioural view- tices is based on the presence, among MMTP point this is interpretable as an increase in at- patients, of subgroups of patients with unsafe tention towards their own safety (the tendency behaviours, which are not directly related to “to borrow a syringe” is, indeed, weaker than the use of heroin, but to the use of other drugs the tendency “to loan a syringe”) [78]. It is of abuse, such as cocaine and/or patients with also evident that a reduction in the frequency mental diseases unrelated to dependence [10]. of taking drugs of abuse is paralleled by a re- There is, however, a common consensus on the duced tendency to interchange syringes [8]. evidence that MMTP treatments are effective This last phenomenon can be partly related to in reducing the risks of HIV infection risk that a higher tendency to take drugs occasionally derive from risky behaviours [65]. and on their own, with a less recurrent use of drugs taken together with those who are defined as “needle mates” [23, 33, 90]. However, 3.3 Methadone and the reduction of infection some data in the literature suggest that even risk in low threshold programmes when greater attention is given to rules on hygiene, such as the washing of used syringes, this may not be accompanied by behavioural Harm Reduction (HR) traditionally sets a changes in the habit of interchanging syring- premium on handling the contingencies of a es [3]. A limitation of sexual promiscuity is specific case or of an illness by adopting mea- another important issue to be considered in sures that aim to prevent and/or reduce risks 148 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 149

deriving from drugs of abuse, rather than what can be learned on these occasions. The planning a specific therapeutic programme utility of prevention campaigns, which is al- that aims for a clinical resolution of the illness ready evident in the absence of pharmacologi- itself. By contrast, when the path chosen is that cal adjuvants [6], might therefore be enhanced, of a specific intervention on drug dependence, even in the absence of any drastic reduction in the dominant idea is that the use of sub-thera- the chronic use of drugs of abuse. When the peutic dosages of methadone or of non-con- impact of MMTP is reduced, that is undoubt- tinuous cycles of methadone therapy are use- edly linked to a significant increase in the risks less, since these interventions will not lead to and the damage associated with drug depen- recovery from the illness. One outcome of this dence [23, 66]. dichotomy has been that the tool ‘methadone’ has been segregated exclusively for use in specific, structured programmes. Furthermore, 4. Conclusions “HR” programmes are prevalently based on non-pharmacological interventions, such as the distribution of condoms, contingent sup- Although many advances have been made port, or, when intervention is pharmacological, in understanding the effects of opioid drugs on it is exclusively carried out with symptomatic immune response, the real clinical relevance drugs. In our opinion the true intrinsic differ- of these effects has only emerged recently. It ence in HR does not depend on the means to has been definitively shown that not all opioid be used, but on the need to use both pharmaco- drugs share the same immune profile. Chronic logical and non-pharmacological approaches, morphine administration in animals and long- in relation to the therapeutic needs of a target term heroin in humans have consistently been patient who displays poor compliance and/ associated with immunosuppression and a or is characterized by having to face degrad- higher rate of infection. Conversely, it has now ing psychosocial conditions. In any case, HR become clear from human and animal studies programmes should refrain from excluding a that methadone is not only devoid of any in- pharmacological tool such as methadone. In- trinsic immunosuppressive effect but that it is deed, even in subtherapeutic dosages, besides able to progressively restore immune system its contingent usefulness in combating the functions. This effect may partly depend on anti-withdrawal syndrome, pharmacological the ability of methadone to restore the HPA treatment with methadone could be particu- axis function, which is altered in heroin-de- larly useful in reducing some risky behaviours pendent patients, or by the long-lasting acti- that may lead to a rise in the transmission of vation of opioid receptors both in the central infections. In general, infections transmitted in nervous system and on immune competent this way are a consequence both of a partial cells. The immunorestoring properties of effect on craving, and of a ‘cooling’ effect on methadone are key factors in the treatment of peaks of psychopathological distress, which concurrent infections, such as HCV, which are are often associated with impulsive behav- frequently associated with heroin addiction. iours that themselves lead to leading to risky In fact, evaluation prior to, during and after behaviours. In most cases such behaviours are methadone treatment has revealed that heroin not under the patient’s control and therefore addicts with HCV can be successfully treated place him/her in a condition of higher vulner- with pegylated interferons and ribavirine, sug- ability to the transmission of infectious dis- gesting that therapy should be initiated dur- eases related to dependence. In addition, any ing the MMT to achieve a more sustained re- reduction in the need to consume drugs of sponse. Indeed, it is evident that the objective abuse, as well as in ideation in their favour, al- of achieving adequate control of addiction and lows the ‘on the road’ drug abuser not only to of concomitant infectious diseases by choos- participate more advantageously and directly ing either immunosuppressive drugs or drugs in informative campaigns, but also to take in characterized by immunoneutral or immunos- 150 · CHAPTER 3.1 Clinical Foundation for the Use of Methadone in Patients with Infectious Diseases · 151

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Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients I. Maremmani, M. Pacini, S. Lubrano, S. Canoniero, M. Lovrecic and G. Perugi

1. Introduction

The first step in structuring an effective versely, mentally ill individuals may resort treatment for dual diagnosis patients is the to substances in order to soothe psychiatric definition of a correct psychiatric diagnosis; symptoms or to counter the side-effects of ad- this is not always easy, because there is an ministered agents. Withdrawal of substances overlap area between outbursts of primary can be another cause of psychopathology. Ad- psychiatric disorders and drug- or alcohol-re- dictive disorders may also coexist side by side lated psychopathology. with independent psychiatric disorders, as au- Psychiatric illness and substance use share tonomous entities. several features: substance use may elicit or Lastly, there is significant overlap between else mask a concurrent but independent psy- the behaviours that accompany some types of chiatric symptomatology, thus making it dif- psychiatric disorder and drug-related behav- ficult to discriminate between them. iours. The clinical severity, duration, and typol- When two independent medical disorders ogy of psychiatric features has been shown affect the same subject, the term ‘Dual Diag- to be correlated with the quantity and dura- nosis’ can be used. In the fields of psychiatry tion of underlying substance abuse. The use and addictive diseases, the term has taken on of alcohol or other drugs may bring forward the meaning of “the coexistence of a psychi- the onset of psychiatric disorders for which an atric disorder with a substance use disorder”. independent proneness already exists, exacer- From now on, we will use the acronym ‘DD’ to bate symptoms of current psychopathology or indicate dual diagnosis. favour relapses into major syndromes. Con-

153 154 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 155

2. Treatment of personality disorder ages depend on the grade of psychopathol- during methadone maintenance ogy and aggressiveness at treatment entrance [113]. A sample of 20 subjects was divided into two clusters according to the baseline SCL90- Treece and Nicholson verified that some score (high psychopathology vs. low psycho- personality features (according DSM manu- pathology). All subjects had been abstinent al [1]) indicate a need for higher methadone from various substances for a long time and stabilization dosages, whereas others tend to had achieved a satisfactory level of psycho- lower methadone dosages. Methadone-treated social adaptation, after a treatment period of patients and street addicts were classified in variable length (1-96 months). Stabilization three groups, according to the cluster of their dosages ranged from 7 to 80, averaging 39±23 personality disorder, plus a fourth category for mg/day. A higher degree of psychopathology addicts with a non-pathological personality. corresponded to higher stabilization dosages Street addicts had been enrolled by means of (60 mg/day vs. 30 mg/day on average, the lat- a newspaper ad. The A-cluster featured schiz- ter corresponding to a lower degree of psycho- oid, schizotypical and paranoid personalities pathology); similarly, higher aggressiveness characterized by loneliness, isolation and odd- accounted for higher stabilization dosages (50 ity. The B-cluster comprised borderline, nar- mg/day vs. 30 mg/day for mildly aggressive cissistic, histrionic and antisocial personalities, subjects). Neither psychopathology nor ag- which were regarded as displaying dramatic, gressiveness appeared to vary with treatment overemotional, eccentric styles. Antisocial per- duration. Methadone-sensitive psychopathol- sonality disorder was displayed by 75% of the ogy appeared to comprise depression, phobic subjects. The C-Cluster was actually excluded, anxiety, paranoia, somatic features and psy- because it featured only two subjects. Metha- chotic symptoms, the latter two showing the done dosages turned out to be higher in the strongest correlations. As regards aggressive- A- and B-cluster groups than in the non-patho- ness, methadone dosage seemed to be related logical group [170]. to unexpressed aggression, irritability and A case can be illustrated as an example of violence, the strongest correlations emerging a dual diagnosis of personality disorder and for the latter two. In conclusion, the higher the heroin addiction: it was that of a 29-year-old level of psychopathology and aggressiveness white male addict, of middle class origins, at treatment entrance, the higher the metha- diagnosed as suffering from chronic depres- done dosage required for stabilization. sion and schizotypical personality disorder, and treated with 100 mg/day methadone. At the age of 18 he started displaying depressive 3. Treatment of mood disorders during features, isolation and antisocial behaviour. methadone maintenance He first tried narcotics during his military service. He used marijuana, hallucinogenic drugs, amphetamines and barbiturates occasionally, but in high amounts; his use of heroin 3.1 Heroin addiction and its consequences on quickly became massive and regular. He un- mood derwent methadone maintenance at 23, after four unsuccessful detoxification programmes, but continued to abuse alcohol and anxiolytic Opiates usually produce mood disorders drugs even after 14 months of treatment, while during intoxication, while chronic opiate use displaying low self-esteem, flattening of emo- induces a fall in CNS noradrenergic firing. Un- tions and stereotypical speech, thought incon- like other abused substances, opiates are very sistency, lateness, repetitiveness, and lying unlikely to cause psychotic symptoms. Sub- [170]. stance use during manic episodes may depend Our group verified that methadone - dos on loss of inhibition, impulsiveness, impair- 154 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 155

ment of judgment or lack of caution. Patients 3.2 Treatment of mood disorders in heroin with mixed episodes are twice as likely to use addicts substances than normal subjects. The switching phase can be intensely unpleasant and lead to substance use as a form of self-medication. The reduction of opiate use may itself in- Taking the opposite view, some authors duce the onset of psychiatric disorders (mania, judge that mood liability develops as a con- depression, psychosis) that put the subject at sequence of CNS neuroadaptation to chronic risk of a relapse into heroin use. When mood exposure to heroin. The leading hypothesis disorders are unrelated to substance abuse, is that heroin-induced depression stems from psychiatrists should be careful about using functional alterations in the endorphinergic, agents associated with abuse liability, and take noradrenergic and hypophysis-adrenal gland into account possible interactions with other system. Adaptation to the protracted use of psychotropics (e.g. benzodiazepines). MAOIs heroin may continue for several months af- (Monoamine Oxidase Inhibitors) should be ter detoxification, and come to underlie what avoided, so as to prevent interactions with is clinically described as hypophoria [117]. cocaine, heroin or other psychotropic drugs Since 1942, detoxified heroin addicts have [79, 82, 181]. Generally speaking, rapidly act- been described as showing a “protracted with- ing benzodiazepines (diazepam, alprazolam) drawal syndrome”, or a “post-withdrawal should be avoided, as they have a high addic- syndrome”, which features chronic residual tive potential. Slowly acting benzodiazepines and often invalidating withdrawal symptoms (oxazepam, clorazepate), which ensure a low- [115, 116, 118, 129]. The clinical picture is domi- er abuse liability, are safer to use, at least in se- nated by an organic mood syndrome, which lected patients and under medical supervision. is sensitive to methadone and represents the Any other psychotropic should be evaluated crucial risk factor for relapse into heroin use. by urinalysis. In methadone-maintained pa- Dysphoria, in fact, is usually associated with tients who are dependent on heroin and BDZ, an increase in craving and substance-seeking clonazepam, a long-lasting, potent and slow- behaviours. Relapse into heroin use followed acting benzodiazepine, which is therefore free by a soothing of dysphoria works to refuel the of addictive properties, can be resorted to as a vicious circle of addiction, even when other replacement for other compounds [62, 150]. features of early or protracted withdrawal One frequent complication of opiate addic- are absent. Mood disorders also develop dur- tion is dependence on alcohol, cocaine or other ing opiate detoxification. Depression seems substances. 60% of methadone-maintained pa- to occur more frequently among addicts who tients were abusing cocaine when they entered have gone through methadone tapering (60%) treatment. Cocaine abuse is found in as many than among those entering methadone treat- as 40% of heroin addicts, alcohol abuse is prob- ment after heroin discontinuation (25%) [34]. lematic in 15% to 30% of cases, and BDZ abuse This can easily be explained by considering is quite common [5, 9, 12, 163]. No comparable that addicts with mood disorders tend to join data on naltrexone-maintained patients are methadone treatment programmes, as this is available. Even so, it does seem that polyabuse the only treatment that has proved effective in is common among patients who enter naltrex- restoring the heroin-related opioid imbalance one treatment without fitting it, but who re- and controlling the associated psychopathol- fuse or are denied better-fitting options due to ogy. So it is quite likely that mood alterations, environmental pressure or cultural bias [97]. which led subjects to undergo methadone Special care is required when treating ad- treatments, will re-emerge after therapeutic dicts suffering from additional psychiatric stabilization has been achieved. disorders, as intervention on heroin addiction alone, even when successful, cannot be expected to resolve the abuse of other substances. Such patients require closer monitoring (daily 156 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 157 alcohol test, twice-a-week urinalyses), more pressive symptoms after methadone initiation frequent counselling sessions, direct access to is marked by a gradual decrease in severity self-help groups (e.g. Alcoholics Anonymous) that continues through the first eight months and specific pharmacotherapy (e.g. disulfi- [42, 142, 158, 166, 176]. Tricyclic agents should ram) [165]. therefore be resorted to only when depres- Two studies have shown that high dose sion shows no significant improvement in methadone treatment, when combined with response to methadone treatment, and when, frequent medical controls, is likely to favour consequently, the estimated risk of relapse a decrease in cocaine use. As a rule, patients stays high [42, 142, 158, 166, 176]. Caution is addicted either to heroin or other substances, also needed in the light of several cases of tri- CNS depressants in particular, should be stabi- cyclic abuse that have been documented in the lized on methadone and gradually detoxified literature [30, 164]. According to the PISA-SIA from other substances. Attempts to treat all Group, a dose of 150 mg/day is effective in different kinds of abuse at once are bound to treating most of the cases of depression in her- fail. The recommendation is that abuse issues oin addicts. Tricyclics can be used alongside should be faced one by one [165]. methadone tapering, at the end of a successful programme, or to favour abstinence in drug- 3.2.1 Antidepressants free subjects in the first six months after the successful accomplishment of a programme, Despite the frequency of depressive dis- due to their property of controlling mild with- orders among heroin addicts, few reports are drawal symptoms (enduring insomnia or pro- available in the literature on the use of tricy- tracted withdrawal states). clic antidepressants in these patients. When On the whole, clinical trials on the effec- doxepine was administered at doses ranging tiveness of tricyclic antidepressants have pro- between 25 and 150 mg once a day in the eve- vided ambiguous results. This may be partly ning, an improvement in the data on anxiety, attributed to the difficulty of retaining abstain- depressive features and anxiety-related in- ing addicted patients in any unspecific treat- somnia [162] was documented. Amitryptiline ment. To sum up, it may be said that trials on partly controls withdrawal symptoms in ab- doxepine have agreed in showing its efficacy staining volunteers [162]. In a double-blind, in methadone-maintained patients, at doses placebo-controlled study of doxepine in de- ranging between 25 and 100 mg. Otherwise no pressed addicts, a significant improvement significant efficacy has been ascertained for ei- was documented along the Zung and Beck ther imipramine or desimipramine. However, Hamilton rating scales. Although a lot of pro- desimipramine blood levels are higher than bands dropped out, retained subjects showed expected in methadone-maintained subjects. a decrease in craving [183]. Later studies per- As regards SSRIs (Serotonergic System formed on methadone-treated subjects failed Reuptake Inhibitors), their effectiveness and to show any greater improvement for imipra- safety have been documented by the PISA-SIA mine-treated subjects (doses ranging between Group on subjects displaying intermittent de- 150 and 225 mg/day) vs. placebo, but a gen- pression while maintained at average metha- eral decrease in depressive symptoms was done doses of 100 mg/day. It must be remem- documented [82]. The conclusion could be bered, though, that SSRI bioavailability rises in drawn that methadone treatment accounts for methadone-maintained patients. In fact, both the improvement of depressive symptoms, no fluoxetine and fluvoxamine may cause metha- further advantage being provided by imipra- done blood levels to increase significantly (by mine. In cases of severe depression, the paren- up to 200%, in the case of fluvoxamine) [71]. theral administration of clomipramine (25-50 Sertraline increases methadone blood lev- mg) ensures fast and significant improvement, els during the first two weeks of administra- showing impressive results after just one week tion [124]. Methadone doses should therefore of treatment [39]. The natural course of de- be pondered carefully, especially if SSRIs are 156 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 157

added on during the induction phase. Inter- can be expected if anticonvulsants, especially estingly, fluvoxamine has proved useful in valproate, are used. However, lithium may improving the bioavailability of methadone reasonably be attempted in bipolar cocaine ad- over a 24-hour period, in high dose-treated dicts [32, 52, 128]. patients, who report withdrawal symptoms Lithium-methadone interaction have been before each new administration (probably due suggested on an experimental basis, but has to a fast metabolism). Patients who show an not yet been clinically confirmed [73, 74]. Fe- unsatisfactory response to 100-150 mg/day nythoin, carbamazepine and phenobarbital methadone can definitely benefit from the ad- strongly decrease the bioavailability of metha- dition of fluvoxamine [17, 38]. done, so causing opiate withdrawal [124]. Val- MAOIs’ stimulating properties, which proic acid and the latest anticonvulsants do have been documented in depressed non-ad- not seem to have this effect. dicts too, make them unfit for use with heroin addicts, due to their abuse proneness. More- 3.2.3 Opioidergic agents over, the likelihood of cheese-effect accidents is supposedly too high in patients such as addicts, who are known to have hardly any con- 3.2.3.1 Agonists trol over their consumption of chemicals, food or alcohol. In prognostic terms, the presence Antidepressant properties have been re- of affective symptoms predicts poorer control ported for opiates, so suggesting that opioid over abuse conducts, heavier psychosocial im- use may develop as a form of self-medication pairment, and a greater suicidal risk. for depressive symptoms, on one hand, and to support the endorphinergic hypothesis of 3.2.2 Mood-stabilizing drugs dysthymic disorders, on the other. The administration of opioids to depressed patients has Bipolar syndromes are probably the most showed some efficacy, though failures have frequent psychiatric disorders among heroin been reported too. In two trials, beta-endor- addicts. As mentioned above, 39 out of 40 con- phins were successful in treating depression secutive heroin addicts entering methadone in a few non-addicted depressed patients treatment were diagnosed as suffering from (there were 2 responders in one trial and 3 bipolar I or bipolar II disorder, or displayed — out of 6 — in another) [6, 83]. The efficacy hyperthymic temperament, or else had a fam- of beta-endorphins was confirmed vs. placebo, ily history of bipolarity [99]. The use of mood whereas no greater efficacy over placebo was stabilizers is appropriate in patients with bi- documented for morphine or methadone, on polar disorders or borderline personality dis- non-addicted depressed patients [54]. In opi- order, which are both categories that often ate addicts, higher methadone doses (over 100 involve substance abuse. However, neither mg/day) are needed to stabilize patients with lithium nor carbamazepine has been clearly prominent features of depression and aggres- shown to be suitable for heroin addicts with siveness at programme entrance [113]. In a bipolar disorders [124]. Moreover, it should be two-year follow-up, methadone maintenance recalled that the normalization of basal mood seemed successful in achieving major mood does not ensure control over true addiction, stabilization in bipolar I patients [98]. Though once the revolving door phase has been en- contrasting data do exist [43, 134], some neu- tered. Mood stabilization may be crucial for robiological observations are consistent with the control of substance use in the honeymoon that orientation. Opioid receptors and endor- phase, or in subjects who can stay persistently phins are highly concentrated in hypothalamic abstinent after the accomplishment of detoxifi- and limbic areas, as both are involved in the cation. Bipolar abusers have a poorer outcome physiology of affective states; and opioid sys- than non-abusing peers. Their response to lith- tems have been shown to interact with cate- ium is predictably poor, whereas better results cholaminergic systems, which are themselves 158 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 159 involved in the pathophysiology of depressive 3.2.3.2 Antagonists disorders. This is in agreement with Extein’s hypothesis that “a decrease in endorphinergic Although opiates are known to produce activity may be the pathophysiological basis of euphoric states, and spontaneous states of ela- depression” [44]. tion are associated with high CNS levels of en- Table 1 shows pharmacological interactions dorphins, a low incidence of manic states has and dosages in heroin addicts with mood dis- been reported among heroin addicts. Nalox- order psychiatric comorbidity as recorded in one, an opiate antagonist which has no appar- the experience of the PISA-SIA Group. ent effect on depressed patients, has proved to have antimanic properties [173]. It has been

Table 1. Pharmacological interactions and dosages in methadone maintained heroin addicts with mood disorder psychiatric comorbidity according to the experience of PISA-SIA Group

Dosages (mg/daily) Min Mean Max Bipolar patients Methadone, stabilization dosage 50 120 320 Carbamazepine§ 400 510 800 Valproic acid 318 480 1000 During depressive phase Fluoxetine§ 10 20 40 Fluvoxamine§ 50 120 200 Paroxetine 20 28 40 Sertraline§ 25 100 200 Citalopram 5 20 60 During manic phase Haloperidol§ 3 7 9 Clozapine 25 50 100 Risperidone§ 1.5 4.5 6 Olanzapine 5 10 20 Quetiapine 100 200 300 Unipolar depressive or dystymic patients Methadone, stabilization dosage 60 120 200 Imipramine 50 80 150 Clorimipramine 25 35 50 Trimipramine 25 75 150 Fluoxetine§ 20 30 40 Fluvoxamine§ 100 150 200 Paroxetine 20 30 40 Sertraline§ 50 100 200 Citalopram 10 20 60 §Use caution during the methadone induction phase. Re-evaluate methadone dosage if patient is already in treatment 158 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 159

hypothesized that naltrexone has a negative are those who seem to benefit from naltrexone influence on basal mood, on the basis of obser- maintenance, as witnessed by the satisfactory vations on addicted or non-addicted patients. retention rate among this subgroup compared One bulimic patient treated with naltrexone with uncomplicated addicts or non-bipolar developed panic attacks [103]. Of 80 naltrex- addicts. The use of fluoxetine as add-on to na- one-maintained patients who were also receiv- ltrexone maintenance has been shown to im- ing psychosocial treatment, 13 experienced an prove patients’ outcome, so suggesting that overdose accident during the first year of treat- naltrexone has an anti-reward property, which ment. Four overdoses were lethal, including is specifically reversible through fluoxetine’s one case of suicide. Of nine non-lethal over- antidepressant effects [100, 114]. dose cases, four were classified as attempted suicide [122]. Unpublished data gathered by the PISA-SIA Group indicate that naltrexone 3.3 Recommendations treatment is less effective on the aggressive behaviour and suicidal thoughts of heroin addicts [107]. This flaw emerges most clearly in Table 2 shows the PISA-SIA (Study and In- long-term treatment programmes. By contrast, tervention on Addictions) Group recommen- bipolar patients with a low craving for opiates dations for patients with mood disorders.

Table 2. Treating mood disorders in heroin addicts. PISA-SIA (Study and Intervention on Addic- tions) Group recommandations

A. Remember that antidepressant pharmacotherapy alone does not extinguish addictive behavior in heroin addicts B. Apply antidepressant properties of long acting opiates C. Use over-standard doses of methadone (over 120 mg/day) D. Remember that antidepressant medications (especially SSRIs) increase methadone blood levels a. Use SSRIs in methadone rapid metabolizer patients b. Use caution during MM induction phase c. Do not use SSRIs during the patients detoxification E. Remember that craving increases during manic phases. Avoid switching antidepressants. Prefer anticraving antidepressants (fluoxetine or sertraline) in depressed heroin addicts F. Avoid IMAOs because of their interaction with cocaine (disulfiram effect) G. Avoid BDZ for treating comorbid anxiety (use anxiolytic properties of long acting opiates) H. Use clorimipramine plus methadone to reduce the latency of antidepressant effect I. Use tricyclic antidepressants after opioid detoxification for at least six months J. Consider the possibility of tricyclic abuse (especially Amitriptiline) and tricyclic withdrawal syndrome K. Use mood stabilizers in Bipolar Heroin Addicts but remember that mood stabilizing therapy alone does not extinguish addictive behavior in heroin addicts L. Use caution with carbamazepine. Increase methadone dosage if carbamazepine is necessary M. Prefer valproic acide N. Use litium in compliant cocaine abuser heroin addicts 160 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 161

4. Treatment of anxiety disorders during to any condition of abuse/dependence makes methadone maintenance a diagnosis of primary anxiety disorder more likely. Apart from conditions of intoxication or Most addicted patients display symptoms withdrawal, the treatment of anxiety in addict- of anxiety at some time during their addictive ed patients does not differ from the treatment of history [35-37, 64, 72, 86, 89, 92]. In alcoholics, simple anxiety syndromes. Anti-anxiety agents as much as 50-70% of that symptomatology are indicated for patients who continue to dis- can be described as generalized anxiety, panic play anxiety even when receiving effective disorder and phobic syndromes. The occur- treatment for their addiction. Target symptoms rence of anxiety features is even more common should be always defined and monitored, and among specific groups of cases featuring with- treatment should not necessarily be thought of drawal or intoxication syndromes, where that as chronic. This is particularly true of benzodi- frequency rises to 80%. From an etiopathoge- azepines, which are useful only to the extent netic viewpoint, a genetic link between anxi- to which they prompt patients’ acceptance of ety and addictive disorders has been postu- other treatments. Agents such as alprazolam, lated; some authors have interpreted that link lorazepam or diazepam should be avoided, as depending on a self-medicating dynamic. because of their strong abuse liability. Diaz- Although it is hard to tell whether anxiety is epam is one of the most popular abused psy- of a primary type, or springs from a substance chotropics among heroin addicts, not only due abuse/addiction course, it can be agreed that to its property of soothing some of the opiate comorbid anxiety disorders in alcoholics or withdrawal symptoms: as addicts themselves drug addicts deserve specific clinical attention report, it is often used to maintain euphoria, or and therapeutic intervention. to reproduce a heroin-like euphoria when tak- Any of the DSM-IV anxiety disorders can ing methadone [80], if heroin itself produces become manifest during a phase of intoxica- few strong sensations, or else to make a sub- tion or withdrawal, whatever the substance ject feel “high” [182, 183]. Clonazepam, on the abused. The most common pictures are those other hand, has proved suitable and safer, and typical of phobias, panic disorders and gener- can be used in dosages of up to 0.50 mg three alized anxiety. DSM-IV indicates syndromes times per day, when required. These findings such as substance-induced anxiety disorders, are consistent with the data provided by ani- and states that prominent symptoms comprise mal studies, in which diazepam has proved to free anxiety, panic attacks, obsessions and com- heighten the effects of opiates [157]. At high pulsions. The onset of symptoms can come less doses, diazepam is mostly used to buffer with- than one month after an episode of intoxication drawal symptoms, or to improve the course of or withdrawal, and may endure for months, so rapid detoxifications, or to prolong abstinence causing significant psychosocial and working after detoxification has been completed. impairment, as well as difficulties in managing During methadone treatment too, diaze- private life. Comorbid anxiety disorders some- pam abuse is a common finding, more so than times represent a true dual diagnosis, but their among alcoholics [24, 80, 82, 91, 147, 162, 182, features are not distinguishable from drug- 183]. The percentage of methadone-maintained induced ones. Despite this, DSM-IV provides subjects using benzodiazepines is as high as useful criteria for drawing a distinction: the 10-20%, reaching a maximum of 30%, as re- likelihood of an anxiety disorder being prima- ported by some authors, if benzodiazepines or ry rises when anxiety symptoms forerun the hypnotics have been used during the previous onset of substance abuse; when symptoms en- week [24, 70, 164] According to the Treatment dure far beyond an episode of intoxication or Outcome Prospective Study, between 5% and withdrawal; or when they exceed what might 16% of methadone-maintained subjects have be expected from the severity of the toxic state. been using benzodiazepines weekly or less of- Lastly, a history of anxiety disorders unrelated ten [75]. Regular diazepam use is common too, 160 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 161

as assessed by random urinalysis: 20% of pa- for engaging in illicit behaviours. tients turned out to be high-rate diazepam us- Dreadful accidents may happen in those ers (with more than three positive urinalyses circumstances, so the prescription of benzo- over a 6-month period) and 46% were defined diazepines to addicts should only be allowed as low-rate users (with at most one positive when strictly necessary, and addicted patients result) [67]. It is doubtful whether benzodi- should never be given free access to them. In azepine use should be read as an attempt to particular, it is harmful to encourage addicts deal with anxiety, or actually looms as a form to decrease their methadone dosage and use of addiction. Lately, the problem of benzodi- benzodiazepines to compensate for the differ- azepine withdrawal has been regarded with ence: not only will patients’ clinical conditions increasing concern, and cases of symptomatic not improve, but they will also be put at risk of withdrawal have been documented for dos- developing a polyaddictive disease [110]. ages even lower than those taken on aver- No matter what the dynamics may be that age by methadone-maintained patients [178]. underlie benzodiazepine use, it can certainly Benzodiazepine-abusing methadone patients be expected to worsen an addict’s already may display oversleeping, ataxia, speech dif- delicate conditions, especially if heavy, regu- ficulties, and even anger attacks [80]. Through lar use is initiated. That is why clinicians agree time, diazepam addiction has partly replaced that the anxiety of agonist-maintained addicts the already recognized phenomenon of depen- should be dealt with first by regulating the ag- dence on hypnotics, which are often carelessly onist dosage, then, if necessary, by counselling prescribed by G.P.s for insomnia. Diazepam facilities, relaxing techniques or environmen- abuse can sometimes produce states of altered, tal intervention. dreamlike states of consciousness, which ad- The findings emerging from the PISA-SIA dicts may experience as optimum conditions Group experience (Table 3) indicate that the

Table 3. Pharmacological interactions and dosages in methadone maintained heroin addicts with anxiety comorbidity according to the experience of PISA-SIA Group

Dosages (mg/daily) Min Mean Max Panic disorder patients Methadone, stabilization dosage 80 85 90 Imipramine 25 30 50 Fluvoxamine§ 50 100 150 Paroxetine 10 20 30 Sertraline§ 50 100 200 Citalopram 10 20 40 OCD patients Methadone, stabilization dosage 80 100 110 Clorimipramine 75 150 300 Fluoxetine§ 20 30 40 Fluvoxamine§ 150 200 250 Sertraline§ 50 100 200 §Use caution during the methadone induction phase. Re-evaluate methadone dosage if patient is already in treatment 162 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 163 average methadone dosage needed to stabilize Some authors [148, 160] speculate that heroin addicts with a dual diagnosis of anxiety schizophrenic patients self-select pro-dopa- disorder is lower (80 mg/day) than the aver- minergic substances, as likely to be effective age required to stabilize other types of dually in alleviating their negative symptoms, com- diagnosed addicts, or even uncomplicated pa- prising spontaneous or iatrogenic depression tients (100 mg/day). Consistently with such and extrapyramidal effects deriving from neu- observations, naltrexone has been shown to roleptic medications. The dopamine-wasting elicit anxiety in non-addicted, as well as ad- effect of psychostimulants may itself lead to dicted patients [103]. the persistence of abuse behaviours, given the The anxiety disorders of heroin addicts can need to maintain a normal dopaminergic fir- also be treated successfully with antidepres- ing level. This mechanism resembles cocaine- sant drugs and buspirone [51]. Tricyclic agents induced dopaminergic stress, through which and SSRIs are effective in controlling both a dopaminergic hypofunction perpetuates the anxiety and depressive symptoms, and are tendency to resort to cocaine. suitable for long-term treatment programmes. A different point can be made regarding Imipramine and nortriptiline may cause seda- other non-therapeutic substances. Mescalin, tion and hypotension. psylocibine and LSD are straightforward psy- chotomimetics and hallucinogenics, because they can bring on psychopathological syn- 5. Treatment of psychotic disorders dromes displaying the same features as those during methadone maintenance of spontaneous psychotic disorders. Amphet- amines and cocaine and, to a lesser extent, cannabinoids may produce a range of thought Previous suggestions [16] about a pos- or sensorial-perceptive alterations which sible causal relationship between the chronic can reach the same degree of severity as full- use of morphine and the onset of a psychotic blown psychotic states [15, 31, 58, 66, 68, 161, picture failed to be confirmed by later studies 167]. These effects are wholly consistent with [84, 132]. Data on the comorbidity of substance the specific action of these substances on the use disorders strengthen the assessment that dopaminergic system, which is known to be the likelihood of a schizophrenic spectrum di- hyperactive in the brain of acute schizophren- agnosis among heroin addicts on methadone ics. Substance-induced acute psychosis is usu- maintenance is low. In the Yale study, only ally short-lasting. It is not uncommon, how- 3.4% of patients were diagnosed as affected ever, to witness the persistence of psychotic by schizophrenia (0.2%) or schizoaffective dis- symptoms, along the course of a schizophren- order (3.2%), so raising doubts about the reli- ic-like prognosis. Different interpretations of ability of previously reported prevalence rates such pictures are plausible: they might apply [141], which ranged between 11% and 19% in to individuals who abuse drugs as a result of different surveys [29, 53]. Moreover, the major their previous psychopathological condition; studies [11, 126, 140, 160] that have investigat- or else, to prone individuals who leap into a ed the prevalence of substance use disorders in full-blown disorder due to an aspecific excit- populations of schizophrenics have reported atory effect of substances — an effect shared heroin use as being found in 2-6.9% of subjects, with stressful events; lastly, the substance a range that falls below its prevalence among could be directly and specifically responsible the USA general population, which is estimat- for the onset of a psychotic picture in low-risk ed to be as high as 9% in the latest NIDA sur- populations. vey [127]. Apart from this, the prevalence of Acute psychosis has been documented in amphetamine and hallucinogenic drug abuse chronic cocaine users with no previous Axis I turned out to be greater among schizophrenics disorder, after an average of three years of con- than in the general population — 25% vs. 15% tinuous use. Such episodes usually achieve res- and 20% vs. 15%, respectively [11, 148]. olution spontaneously as long as cocaine use 162 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 163

does not persist, and is not prolonged after the effective dosages, it has been shown that TAs so-called crash phase, which is distinguished turn off the mesolimbic dopaminergic firing, by psychomotor depression and oversleep- which is the known substrate for the reinforcing. The chronic use of cocaine or amphet- ing effects elicited by many abused substances, amines has also been associated with chronic such as cocaine. Cocaine itself and alcohol are psychotic disorders, which continue along an the two most frequently abused drugs among independent course, displaying chronic psy- psychotics. Several addictive substances in- chotic symptoms with no co-occurring cogni- duce an increase in the levels of omovanillic tive deficiency. The risk of developing chronic acid (OVA), an index of dopaminergic activity, psychosis does not vary with the pattern of co- and enhance the release of dopamine in the caine use. Other factors are therefore likely to nucleus accumbens, which is the terminal of the be involved, such as those associated with the dopaminergic mesolimbic pathway [121]. On premorbid personality [135, 145, 146]. this basis, it is plausible that the use of substances is effective in reversing the dopaminergic blockade induced by TAs. On one hand, 5.1 Antipsychotic agents this is consistent with the relapse-provoking role of drug use; on the other, it suggests that treated psychotics may resort to substances to Both typical and atypical antipsychotics counter the blunting effect on emotional life have been evaluated in dually diagnosed psy- brought about by the mesolimbic antagonism chotics. If it is to be comprehensive, any evalu- of TAs. In a highly tolerant mesolimbic sys- ation of antipsychotics must take into account tem, like that of abusers, which is more sensi- their impact on drug-related issues: on one tive to lack of stimulation than that of normal hand, abused substances may have psychoto- individuals, the administration of TAs is likely mimetic properties; on the other, the persis- to elicit an intense and intolerable hypopho- tence of, or relapses into, drug-taking are both ria, followed by compensatory behavioural predictive of an unfavourable course. activation towards sources of reward. For in- Typical antipsychotics (TAs) offer little help dividuals who have already learned to achieve to dual diagnosis psychotics [19, 22, 41, 159, rewards by substance use before treatment, 184, 185]. Substance use is common among resorting to available substances would au- schizophrenics treated with TAs, and it shows tomatically ensure compensation. The abuse- no reduction during treatment; in fact, a ten- enhancing effect of TAs would be directly re- dency towards an increase in consumption lated to the antidopaminergic potency of the during treatment has emerged for some sub- specific compound. Consistently with that, the stances, such as nicotine [119, 120]. Psychotic use of desimipramine as adjunct to a TA for who are also abusers show a less favourable cocaine-abusing psychotics has been reported response to TAs, presumably due to the pro- to reduce cocaine use, which does not happen psychotic effects of persistently abused sub- with the same agent among non-psychotic stances, which limit the incisiveness of that cocaine abusers. In other words, TAs appear treatment. When substance use foreruns a to enhance drug abuse in a way that is revers- psychotic outburst, agents such as haloperidol ible by desimipramine, which is effective on or perfenazine can be expected to prove less drug abuse to the extent to which it counter- effective than would otherwise be the case. acts the mesolimbic dopaminergic antagonism Since both TAs and abuse substances act achieved by TA. on the CNS dopaminergic system, it can be Clozapine, which possesses low specific- hypothesized that special phenomena may in- ity on dopaminergic receptors, showed a poor tervene in the relationship between the phar- capacity to reduce dopaminergic transmis- macodynamics of the specific agent and its sion in animal models, when compared with impact on the course of psychoses, when sub- TAs. Again in animal models, clozapine, un- stance abuse co-occurs [19, 159]. At clinically like other antipsychotics, has been shown to 164 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 165 decrease cocaine consumption, when a fixed of the dynamics between antipsychotic treat- dose schedule is used, and to lengthen co- ment and the course of concurrent substance caine-free periods, when an increasing dose abuse. The frequency of depressed mood schedule is used. On clinical grounds, clozap- symptoms among TA-treated psychotics and ine has revealed anticraving properties. Firstly, their partial reversal following drug-taking the responsiveness of psychotic patients to clo- are consistent with this explanatory model. zapine is independent of concurrent substance The novelty-seeking dimension of Cloninger’s use, in a way that is not attainable with TAs, Tridimensional Personality Questionnaire, which, as a rule, prove to be less incisive in which implies a higher risk for substance-re- substance-abusing individuals. Some authors lated behaviours, has been recently associated have even suggested that substance-abusing with the D4 receptor subtype. Agents acting psychotics may display a better response to as D4 antagonists may reduce drug-seeking clozapine than non-abusers [4, 23, 94]. behaviour, whereas D2 antagonists (such as In dual diagnosis schizophrenics, clozapine TAs) appear to increase them, especially in treatment reduces nicotine use. In fact, switch- individuals who are highly positive to D4. In ing from haloperidol to clozapine lowered nic- reality, clozapine’s profile is distinguished by otine consumption, whereas haloperidol had its higher specificity for D4 receptors (higher caused it to increase. The clozapine-related D4/D2 ratio) [90]. Risperidone, which has the reduction in nicotine use is dose-related [120]. highest specificity for D4 receptors, has not yet Alcoholics treated with clozapine are likely to been evaluated on this issue. have stayed abstinent (50%) throughout the first year after discharge from hospital. Two psychotics with alcohol dependence, treated 5.2 Methadone and antipsychotics with 500 mg/day clozapine, were shown to have stayed abstinent in the long term [48, 49]. The concurrent use of antipsychotics in The interpretation of clozapine’s effects methadone-maintained psychotics can be con- on drug and alcohol use is not clear, though: sidered acceptable and helpful [28, 81]. When in some contexts, a primary anticraving ef- combined with methadone, low dosages of fect seems to loom, whereas in others it seems TAs such as chlorpromazine, flufenazine and plausible that drug use leads to a reduction haloperidol are needed in controlling psy- because in its case there is no need for self- chotic symptoms [162]. One problem is that medication brought about by an antidopami- antipsychotics are quite likely to be poorly nergic blockade, such as that which has to be tolerated by heroin addicts. Usually, TAs are dealt with in the case of TAs [77, 96]. Abus- not abused, but, if they are, patients should to ing schizophrenics, in fact, report “negative be urged to comply. Depot preparations make symptoms”, anxiety and mood especially, to a it possible to skip the limitations posed by lesser extent, whereas counteraction by dopa- non-compliance and concurrent methadone minergic substances ends up by exacerbating treatment seems to act as a shield against ex- psychotic symptoms, so unfavourably affect- trapyramidal side-effects. Table 4 shows the ing the course of the illness, and impairing the methadone and antipsychotic dosages needed efficacy of antidopaminergic antipsychotics for psychotic heroin addicts. Clinicians should (i.e. TAs). A vicious circle is set up comprising be particularly careful during the induction negative symptoms and treatment by TAs, the phase, in order to minimize the narcotic mu- use of dopaminergic substances, psychotic re- tual potentiation of antipsychotics and opi- lapses, and then the potentiation of TA treat- ates, especially when TAs are used. As a rule, ment to achieve a wider antipsychotic defence the recommendation is to avoid administering spectrum. antipsychotics until the steady state has been In dually diagnosed patients, TA-induced reached with methadone. In the meantime, hypophoria could be the key to an explanation the sedative action of methadone itself can 164 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 165

Table 4. Pharmacological interactions and dosages in methadone maintained heroin addicts with psychosis and violent behaviours according to the experience of PISA-SIA Group

Dosages (mg/daily) Min Mean Max Methadone, stabilization dosage 30 140 290 Typical antypsychotics (Haloperidol equivalent)§ 3 7 9 Clozapine 100 150 300 Olanzapine 10 10 20 Risperidone§ 2 4 6 Quetiapine 25 50 100 Valproic acide 80 100 110 §Use caution during the methadone induction phase. Re-evaluate methadone dosage if patient is already in treatment

be resorted to. In addition, the use of benzo- chotic alcoholics at a dosage of 250 mg/day: diazepines cannot be recommended. In cases at this dosage, the likelihood of an iatrogenic of severe psychomotor excitement requiring worsening of psychotic effects carries less neuroleptic administration, limited amounts weight than the impact of ongoing alcohol use of neuroleptics can be used, as long as they are in causing exacerbation and in harming the under medical control, and as long as neuro- overall course of the illness. leptic doses are not taken late in the evening. Disulfiram has also been shown to be use- Antihistaminic agents are a valid and suitable ful in treating cocaine dependence in metha- alternative option for achieving sedation in done-maintained opioid addicts [131]. psychotic heroin addicts. 5.4 Desimipramine 5.3 Disulfiram

Desimipramine has been used at doses of Disulfiram counteracts alcohol consump- 100-150 mg/day in cocaine-addicted psychot- tion regardless of the presence of psychotic ics, as an adjunct to antipsychotic treatment. symptoms. The reduction of alcohol abuse is In these patients, that combination achieved bound to have a positive impact on the course a good level of control over cocaine craving. of psychosis itself, because alcohol is known The same agent, when tried on non-psychotic to worsen psychotic symptoms. In subjects cocaine-addicts, failed to show any definite ef- treated with high-dose disulfiram, however, ficacy [2, 3]. Anticraving dopaminergic agents psychotic symptoms have been reported to must be avoided during acute psychotic phas- deteriorate [21, 90]. Schizophrenic alcoholics es, because of the risk of exacerbating psy- have been reported to benefit from disulfi- chotic symptoms, as well as the uncertainty of ram treatment to the same extent as non-psy- their impact on substance abuse. In stabilized chotic alcoholics. In particular, alcohol abuse chronic psychotics, our anecdotal evidence in schizophrenics seems to show an excellent suggests that ropinirole, up to 1.5 mg/day, can response to the clozapine-disulfiram combina- lead to a reduction in craving, with no concur- tion [21]. rent psychopathological destabilization. In conclusion, disulfiram is useful in psy- 166 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 167

5.5 Recommendations produces/enhances defence [10, 152, 151]. The peripheral administration of naloxone heightens or elicits defensive behaviour and Table 5 shows the PISA-SIA (Study and In- aggression. On the other hand, naltrexone tervention on Addictions) Group recommen- failed to modulate defence in monkeys, while dations for patients with psychotic disorders its administration to mice caused aggressive

Table 5. Treating Psychosis in Heroin Addicts. PISA-SIA (Study and Intervention on Addictions) Group Recommendations

A. Apply antipsychotic properties of long acting opiates B. Use the patient’s greater compliance during methadone maintenance or buprenorphine maintenance to reduce the risk of psychosis crises C. Add-on low doses of typical or atypical neuroleptics (in combination with mood stabilizers). Take advantage of methadone and/or neuroleptic blood level increases D. Prefer clozapine-like neuroleptics E. Consider the possibility of withdrawal psychosis. Reintroduce methadone or buprenorphine F. Add neuroleptics with caution in low tolerance psychotic MM heroin addicts. Use caution also during the MMTP induction phase. G. Avoid low potency neuroleptics in MM heroin addicts (higher dose = greater metabolic interference = greater blood level increases) H. Consider the use of I.M. antihistaminics for agitated psychotic MM heroin addicts.

6. Treatment of violence during outbursts to dwindle in frequency. Most of the methadone maintenance evidence indicates that the role of opioid modulation differs with the typology of aggression that is being considered [18, 45, 76, 136, 137, Assessment of the role of opioids in modu- 139, 168, 179]. lating aggressive behaviour is no easy matter, Naloxone-challenged cats showed greater as most studies on the subject actually deal proneness to defensive behaviours, in terms of with animal models, where acts of aggression a lowered threshold and a shortened latency result in defensive behaviour (a physiological of reaction. The effects measured depended on form of response to threats from outer) against time and administered dosage. Interestingly, preying. These studies have provided a vari- in the same model preying behaviours showed ety of evidence, allowing the following con- they had acquired a longer period of latency clusions to be drawn [57, 65, 154-156, 175]. after naloxone administration [154]. Several areas of the brain that are related to the production and modulation of defensive behaviour are crowded with opioid receptors 6.1 Opiates as anti-aggressive agents and enkephalin-binding axon terminals. These areas comprise: the nucleus proprius of the terminal stria The top priority of intervention on addict- and the nucleus accumbens, as modulators of ed patients is to control possibly homicidal or defence [7, 59, 60, 63, 125, 138, 153]. suicidal patients, and metabolically impaired the periacqueductal grey substance, which ones. In the first two cases, hospitalization is 166 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 167

required; whereas the latter can sometimes be a cross-over pattern after the first three years, successfully treated with an outpatient regi- so that dual diagnosis addicts are more likely men. to have been retained in treatment after three On therapeutic grounds, antidepressant years. Bipolar patients are an exception to this treatments do buffer the risk of suicide in ad- rule, as they continue to show a lower reten- dicted patients. In our experience this risk ap- tion rate [98]. peared to be higher among naltrexone-treated Further information about the relation- patients, and lower in methadone-maintained ship between opiates and aggression comes ones. A series of studies indicates that opiate from our clinical observations on agonist- or agonists are likely to be effective in control- antagonist-maintained populations [106]. ling concurrent psychopathology and aggres- When addicts were compared in terms of sion in opiate-addicted patients. In our clinical features of aggressive behaviour by repeated practice we examined over 600 street addicts monthly evaluations, significant differences on heroin who asked for treatment. Of these, emerged between methadone and naltrexone- 30% reported suicidal thoughts, though a high treated patients. Methadone-treated patients degree of severity was only recorded in 1% of displayed lower levels of aggression and self- cases. Anger and hostility were found in as injuring behaviour. Subjects did not differ in many as 40%, but were displayed in severe the assessment made of their aggressiveness form in only 4%. Violence occurs most often at the beginning of treatment, but methadone- among non-depressed addicts and phobic ad- maintained patients proved to be less aggres- dicts. Suicidal thoughts and aggression are sive at the end of the observation period. The quite common among street addicts applying unsatisfactory effects of naltrexone in control- for treatment from the PISA methadone treat- ling aggressiveness were also documented in ment programme; our view is that these sub- a sample of bulimic patients, who received jects may have such a highly impaired opioid naltrexone alone or naltrexone plus fluoxetine, function that it can no longer be controlled in a three-month monthly cross-over proto- even by the highest heroin street doses. In fact, col [102]. Within the same study, a case was in our personal experience, most heroin ad- reported of a bulimic patient who developed dicts search for treatment when they cannot panic attacks in the early phase of treatment find enough money to ensure their daily heroin with naltrexone [103]. Naltrexone may also be supply. We suppose that aggression is likely to responsible for the opioid-like discomfort ob- depend on undermedication, consistently with served in naltrexone-maintained patients: in the observation that subjects displaying more fact, the addition of fluoxetine to naltrexone severe psychopathology (depression, anxiety, succeeds in improving the retention rate of paranoia and somatic symptoms) and aggres- naltrexone-maintained subjects. We have sug- sion at treatment entrance turn out to need gested that fluoxetine is effective in overcom- higher stabilization dosages [104]. In particu- ing some of the naltrexone-induced resistance lar, an inverse correlation was found between to retention in naltrexone treatment [114]. violent behaviour and methadone dosage. It In our opinion, then, the opioid system has also been demonstrated that dual diag- may be closely involved in the control of agnosis heroin addicts need higher stabilization gressiveness. Indeed, when addicts who take dosages (150 mg/day on average) than heroin enough heroin are given enough agonist to addicts with no additional psychiatric disor- balance their opioid tolerance, they do not der (whose average dose is 100 mg/day). As display aggressive or suicidal behaviours. Ag- long as adequate dosages are used, retention gressiveness, whether as self-injuring behav- rates do not vary with the presence or absence iour or as outward violence, only characterizes of dual diagnosis [108, 112]. In fact, even if addicts whose opioid tolerance has become there is a trend towards a lower retention rate unbalanced by a high level of opioid stimula- for dually diagnosed subjects during the early tion. Among non-addicts, violent or suicidal period of treatment, this trend seems to show individuals may be marked out by a primary 168 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 169 imbalance of their opioid system. Consis- opioids may be crucial to the modulation of tently with this hypothesis, a higher level of human aggression, which may be essential endorphins was documented in autistic sub- to survival but is also devastating when it be- jects, and was not balanced by a correspond- comes uncontrolled. By studying the role and ing tolerance to opiates [177]. In fact, the ad- function of endorphins in mental activities, a ministration of opioid-antagonists to autistics better understanding can be achieved of how was not followed, as in drug addicts, by any to increase energy and activity without elicit- withdrawal symptoms [85, 130]. Aggressive ing aggression, and about how abnormality subjects may constantly display a subnormal and dysfunction of the opioid system may be functioning of their opioid system, similar to related to destructive expressions of human what addicts end up by suffering from, due to aggressiveness [77]. chronic exposure to toxic opiates. On clinical grounds, the aggressive behaviour of heroin addicts mostly looms as a sign of metabolic 7. Treatment of alcoholism during impairment. Aggressive heroin addicts require methadone maintenance higher methadone dosages than their non-aggressive peers, and if aggressiveness is a problem during agonist-treatment, an increase in Several data from the literature define the dosage is probably needed. relationship between depressive states and Traditionally, drug addicts have been alcohol abuse, though controversy continues thought to be essentially psychopaths — vio- about the dynamics that link different kinds lent individuals who unconsciously long for of depressive syndromes and alcohol-related death. This view appears to be incorrect: ag- problems. Most authors agree in considering gressiveness can best be considered as a sign heavy drinking as an equivalent, or a masked of addictive disease, and deserves more ap- form, of depression [133]. Patients who con- propriate medical intervention than stricter tinue to drink, despite severe or advanced so- repression and social stigma. matic consequences, display a peculiar form of As a fall in levels of aggressiveness follows depression [133]. Alcoholism stems from de- adequate methadone treatment, it can be hy- pressive states, which are mostly of minor se- pothesized that some addicts-to-be resort to verity and a disguised kind [174]. Other stud- heroin as a means of self-medication, rather ies have described a significant association than to seek euphoria. According to Khantzian between bipolar disorders and alcohol abuse. [77], aggressive symptoms are among the fea- According to Kraepelin, as many as 25% of bi- tures that may be found in the habit of self- polar patients abused alcoholic drinks [88]. medication. Several authors conclude that alcohol Opiate agonists display an antiaggressive abuse mostly characterizes depressive states, action both against self-injuring behaviour and is resorted to as a way to elate mood and and against outward violence. Interest has soothe pain, whereas alcohol use during states been raised on this issue because of the lack of mood elation is a sign of excitement and of antiaggressive medicines, on one hand, and impulsiveness [20]. DSM also has suggested the frequency of aggressive syndromes among a close link between cyclothymia and alcohol psychiatric patients, on the other. Apart from abuse. Chronic depression too has been asso- clozapine [27, 172], in fact, antipsychotic ciated with alcohol abuse. It is not surprising, agents show a poor capacity to control ag- therefore, that alcohol use, which can stand as gressiveness outside a psychotic condition. an addictive disease itself in some cases, is of- According to Khantzian, we may state that in ten found combined with substance abuse in normal conditions, and during the course of general. Studies in the literature have increas- development, the brain produces endorphins ingly reported an association between heroin not only to control pain, but also to maintain and alcohol abuse [5, 8, 13, 14, 25, 33, 61, 69, affective balance and well-being. Endogenous 87, 123, 144, 149]. Alcohol abuse seems to be 168 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 169

related to polyabuse, and mainly affects young 7.1 Psychopharmacotherapy of heroin addicts addicts; among these, lifetime rates for alcohol- with alcohol dependence ism range between 10 and 75%. The National Drug Alcohol Collaborative Project (NDACP) reported a rate of 43% for combined alcohol- Alcohol undoubtedly has a negative influ- heroin use in a sample of over 1500 heroin ence on the outcome of a methadone mainte- addicts [25]. Heroin was the first substance nance programme. It implies a more severe to be abused in 99% of cases. Rounsaville re- cognitive and behavioural disturbance, a high- ported a lifetime and index prevalence of alco- er prevalence of psychiatric disorders, and a hol dependence of 13% and 34%, respectively lower degree of compliance, which often con- [143]. Californian addicts have been reported ditions an operator towards a quicker, prema- to abuse alcohol at a rate of 53-75%, and 11% ture tapering of methadone [40, 140]. Moreover, have been admitted to hospitals for alcohol- alcohol dependence has more serious somatic related somatic matters. Alcohol abuse occurs consequences (e.g. chronic hepatic failure), as often as 10-20% among street addicts, and which can lead to premature death or may fa- up to 27% among methadone-maintained sub- vour overdosing accidents, due to interference jects [5, 61]. Some authors have tried to explain with the methadone metabolism [55]. Since the increase in alcohol use during methadone both addictions need to be treated at the same treatment programmes, concluding that meth- time, disulfiram was tried first on methadone- adone-maintained addicts may abuse alcohol maintained patients, but, though the complete in order to counter the opioid-normalizing safety of the combination was ascertained [26, effect of methadone, and to go beyond the 93, 169], its efficacy is still controversial, as di- methadone-heightened opioid threshold [5, sulfiram is mostly equivalent to placebo [93]. 61, 180]. When the correlation between alcohol The decrease in alcohol consumption appears use and heroin use among methadone-main- to depend on a subject’s compliance with the tained addicts was examined in a large sample combined treatment; this depends in its turn of heroin addicts, it was pointed out that alco- on the level of the subject’s awareness of the hol use during methadone treatment seems to severity of the problem [93]. It is awkward to be the result of an automatic behavioural pat- get addicted patients to take disulfiram daily: tern, according to which alcohol use tends to as an alternative, subcutaneous implantations rise as street-opiate use falls, and the reverse can be resorted to, as long as patients consent; [5]. Furthermore, Rounsaville, who supports or else, methadone administration may be al- this theory, also reports that alcohol use is lowed, but only as long as compliance with di- mostly found in addicts who had once abused sulfiram treatment is shown. Another strategy alcohol, so displaying a relapse into a previous is not to provide patients with methadone if alcohol-related disorder [143]. there is a positive result to the screening test On the basis of their clinical experience, for alcohol on the breath (revealing alcohol use Maremmani and Shinderman suggest that during the previous 12 hours) or abnormally the use of alcohol, benzodiazepines and other high alcohol blood levels. This procedure does types of drug in heroin addicts may be corre- not guarantee that patients will abstain from lated with a condition of opiate dependence alcohol after their methadone has been admin- improperly compensated by street heroin or istered. Table 6 reports the feasible combina- by substitution treatment dosages. Thus the tions of psychotropics with methadone, as ob- search for an appropriate methadone dosage served by the PISA-SIA Group. during methadone maintenance is crucial not The combined use of methadone and di- only because it raises the retention rate for pa- sulfiram should be limited to the most severe tients within the treatment group, so allowing cases, or at least to cases in which non-com- an improvement in social rehabilitation, but pliance has hampered the feasibility of other also because it lowers the risk of polydrug treatments. Apart from such cases, different abuse [109, 110]. pharmacotherapies, supportive approaches or 170 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 171

Table 6. Pharmacological interactions and dosages in methadone maintained alcoholics heroin addicts according to the experience of PISA-SIA Group

Dosages (mg/daily) Min Mean Max Methadone, stabilization dosage 240 310 380 GHB 10 27 30 Clonazepam 2 5 9 Trimipramine 50 70 100 §Use caution during the methadone induction phase. Re-evaluate methadone dosage if patient is already in treatment psychosocial treatment should be used. in rats; moreover, it has been proved to de- Naltrexone, though useful in pure alcohol- crease ethanol consumption in alcoholics [50, ics, is unsuitable for alcohol-dependent heroin 56, 101, 111]. Hence, GHB may be used in al- addicts. During naltrexone treatment, in fact, cohol-dependent heroin addicts, and be added substance abuse (like benzodiazepines and on to methadone even when it is administered stimulants) has been reported to increase [97]. at high dosages, like those needed to control One possible explanation is the following: heroin use [105]. heroin is capable of inducing a strong craving, It is worth mentioning the case of a female which reinforces heroin taking. Naltrexone heroin addict displaying alcohol dependence, blocks the heroin-induced reward, so leading who became stabilized on methadone when craving to extinction, but at the same time, it treated at the PISA-SIA Group. F.M. was a 31- ends up by intensifying the hypophoria caused year-old unemployed woman, with a 10-year by lack of opioid stimulation. Naltrexone- history of heroin addiction, at that stage a poly- treated subjects may therefore resort to alcohol abuser and HIV-positive. She had been treated or BDZ to soothe late withdrawal symptoms with 10 mg/day methadone at a Local Service, and naltrexone-enhanced hypophoria and was drunk with alcohol when first observed at the PISA-SIA Group Service. She was judged to be one of the most severe cases ever 7.2 GHB for alcohol-dependent heroin ad- observed. After 24 days of treatment, she had dicts cut down on her alcohol consumption by 70%, and her CGI score of 3 indicated a mild form of disease, so recording a major therapeutic gain GHB is a general anaesthetic drug which is combined with the absence of major side-ef- no longer used for its original purpose. GHB fects. She was given GHB at an average dose has several pharmacological properties: at an- of 27 cc/day (min. 20, max. 30), together with aesthetic dosages, it causes an increase in do- methadone at an average dose of 27 mg/day pamine levels in several cerebral areas, which (min. 10, max. 30) and clonazepam, on average follows a widespread inhibition of CNS neuro- 4.75 mg/day (min. 2, max. 9). Trimipramine, nal activity. Lower dosages seem to selectively 100 mg, was also used in the evening to con- raise dopamine transmission in the mesence- trol insomnia. During the subsequent phases phalic ventral tegmental area [46, 47, 78, 95, of stabilization and maintenance, GHB dose 171]. Some of GHB’s pharmacological prop- was gradually increased up to 60 cc/day, to be erties are particularly interesting: it binds to maintained for at least one year. Maintenance many different sites, none of them associated lasted 7 years, until the patient passed away with GABA-A receptors, whereas, it does bind due to AIDS. At the time she died, she was re- to GABA-B receptors; it substitutes for ethanol ceiving methadone, 40 mg/day, while GHB, 170 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 171

previously given at 10 cc/day, had recently rate brings with it the benefits of a higher rate been tapered off. of retention in treatment. Dually diagnosed subjects display a greater degree of compliance with methadone treatment, which al- 8. Final remarks and recommendations lows them to control their addiction and their psychopathology at the same time. This fact is testified by the high values recorded by them Our chief recommendations include in- on the social adjustment index utilized (DSM- creasing the probability of enrolment, raising IV GAF) and by the absence of hospitalization heroin addicts’ compliance and taking a global episodes throughout the treatment period in approach to the disease. It is very important patients who had previously been hospital- to achieve rapid, complete control of acute ized many times. phases. This becomes possible if the patient In conclusion, we can state that dual di- can be detoxified or if methadone treatment agnosis addicts should in all cases be treated can be initiated in line with the patient’s opi- for their addictive disease by using adequate ate tolerance. After this phase it is necessary to methadone dosages, which can be expected stabilize residual symptoms (in the subacute to be higher than those required to treat un- phase) and maintain achievements in the long complicated addicts, while considering sta- term (case management). It is generally pos- bilization as a medium-term goal. Some dual sible to achieve detoxification in psychostim- diagnosis patients may benefit from the treat- ulant, hallucinogenic drug or cannabis abusers ment that is targeting their addictive problem, before any psychiatric treatment is started, but, thanks to its effects on their mental disorder if concomitant heroin addiction is present, pa- too. Opioid agonists should be reconsidered, tients must been directed towards methadone as not only possessing an anticraving activity, treatment. The prescription of abuse-liable but also as being able to act as psychotropic in- psychotropics, such as BDZs, must be assessed struments in treating mental illness, with spe- with great caution. For heroin addicts with cial reference to mood, anxiety and psychotic multiple drug abuse, it is reasonable to per- syndromes. Lastly, dually diagnosed addicts form detoxification from different substances can be expected to benefit from the facilities one by one, during methadone maintenance. offered within integrated programmes to the Some misconceptions have been spread- same extent as uncomplicated addicts, as long ing among medical operators, who are often as programmes are based on adequate dosag- called to deal with dual diagnosis patients. es that are administered for a sufficient length The first is that dually diagnosed heroin ad- of time. dicts are unresponsive to standard treatments for heroin addiction. The second is that these addicts are, on the whole, non-compliant. The 9. Methadone treatment in dual third is that they are expected to have a less diagnosis patients. The PISA-MMTP satisfactory outcome. During our many years of clinical experience we have observed that the rate of surviv- In this section, we report clinical informa- al-in-treatment is significantly higher among tion about methadone treatment for dual di- dually diagnosed methadone-maintained pa- agnosis patients, on the basis of our personal tients than among uncomplicated heroin ad- experience in the PISA-SIA Group. dicts [108]. The lower dropout rate observed Methadone maintenance took root in the among our dual diagnosis patients cannot be Sixties and continues to be the most wide- interpreted as a difference in the success rate spread treatment solution for opiate addic- for completion of the programme, since this is tion. It starts with an induction phase, through the same regardless of the presence or absence which dosages are gradually increased to reach of dual diagnosis. Rather, the lower dropout an optimum value. Methadone Maintenance 172 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 173 then follows, consisting in the administration guidelines for the treatment of dually diag- of a constant methadone dosage. At the same nosed heroin addicts, as defined by the results time, medical facilities, rehabilitative interven- from our ten-year naturalistic follow-up ex- tions and counselling are available too. When perience at the PISA-SIA Group. Reported in- this technique is properly applied, patients’ dexes include first-day dosage, weekly dosage conditions, which are bound to be displayed during the first month, and average dosage in a critical form at treatment entrance, will over the first four-month interval. Dosages are significantly improve as maintenance goes compared between dual diagnosis heroin ad- forward. dicts and uncomplicated peers. Moreover, sta- Initial methadone dosages are used to bilization dosage and the time taken to reach soothe withdrawal symptoms (early induc- it are also accounted for: the term ’stabilization). As soon as withdrawal has been buff- tion dosage’ is used to refer to the minimum ered, proper induction can be started, with dosage administered for at least four months the aim of identifying a therapeutic dosage with constantly positive results. The outcome value, which is expected to vary between in- is evaluated as positive or negative according dividuals. For non-dual diagnosis patients, to two parameters — level of psychosocial ad- initial dosages range between 20 and 40 mg/ justment, and recent heroin use, as occurring day, and early induction takes no longer than more or less than twice in the previous two 24 hours. Actual induction, which allows a months. therapeutic dosage level to be reached, lasts Table 7 displays first-day and weekly dos- no longer than 5-10 days. The following sta- ages for the first month of treatment. Dual di- bilization phase, during which an optimum agnosis patients need an average of 40 mg on dosage is sought, and after which that dos- the first day, like their uncomplicated peers. age is stably administered as the maintenance Highest first-day dosages for dually diagnosed dosage, is usually complete within a month. addicts, of 80-100 mg/day, are slightly lower During the maintenance phase that follows, than those for uncomplicated peers (up to 200 behavioural and psychosocial readjustment mg). First-day dosages for dual diagnosis ad- are allowed to develop, on the basis of what dicts, then, tend to be lower. During the first has been achieved during the previous phases. month of treatment dosages were increased by At this stage, opiate receptors are stably bound 40% in the first week, by a further 20% in the by the medication, so suppressing craving and second week, by 10% in the third week and, addictive behaviours, on one hand, and com- lastly, by 5% in the fourth week. Again, dosag- pensating for the conditioning due to chronic es for uncomplicated addicts are slightly high- opiate intoxication, on the other. Maintenance er. Nevertheless, stabilization dosage is higher should continue for as long as patients show for dual diagnosis addicts (140 mg/day vs. 100 they are benefiting from it, and for as long as mg/day). In fact, the dosages required for du- patients agree to stay in treatment. The best ally diagnosed patients tend to continue to rise way of evaluating the therapeutic results is, in through the second month, but then stay the fact, the retention rate. same throughout the whole of the rest of the Independently of its essential target, meth- observation period (Figure 1). On the whole, adone maintenance also plays an important it can be said that uncomplicated addicts re- role in social medicine. It can be crucial in quire higher induction dosages, but become limiting the spread of HIV infection among stabilized at lower dosages. The time needed heroin addicts, but it can also improve mental to reach stabilization is longer for dually diag- health among opiate-addicted patients. In fact, nosed patients, an average of seven months vs. dual diagnosis patients who are successfully three among uncomplicated peers (Table 8). treated by methadone maintenance tend to be This gap is not fully justified by the fact that retained in treatment longer than their uncom- eventual stabilization dosages are higher, so plicated peers. dual diagnosis patients can definitely be said In this appendix we have reported the to proceed more slowly towards stabilization. 172 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 173

Table 7. First day, weekly first month dosages in double diagnosed heroin addicts according to the PISA-SIA group experience

Methadone dosage Uncomplicated heroin addicts Double diagnosed heroin addicts 1st day 47±37 40±22 7th day 66±38 53±31 14th day 76±40 67±42 21st day 85±41 76±54 28th day 89±44 80±55

Methadone tapering during treatment accom- age of 80-100 mg when necessary, and as much plishment does not proceed in divergent ways as 200 mg in a few cases. If patients are left in in the two groups, but it does take place more a condition of partial withdrawal, it is quite slowly in dual diagnosis patients. As for reten- unlikely that they will stay in treatment any tion rates, it was noted that dually diagnosed longer. So, what precautions are needed, when patients experience a higher early rate of attri- the dosage exceeds 40 mg on the first day? As tion, but no difference is left after eight months a rule, when withdrawal symptoms are assess- of treatment. First-day dosage is crucial for able, 20 mg should be administered, and eval-

Figure 1. 36-month dosages in dually diagnosed patients in the experience of the PISA-SIA Group

treatment retention: it is important to achieve uation of withdrawal repeated after a couple complete control of withdrawal symptoms of hours. If withdrawal shoots up again or per- within 24 hours, by using a cumulative dos- sists, a further 20 mg should be administered, 174 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 175

Table 8. Double diagnosis methadone-maintained patients. Stabilization dose and time to reach it

Dose Dose (Mg/die) (Mg/die) Diagnosis Min Mean Max Min Mean Max Heroin dependence 20 105 240 1 3 10 Alcohol-related disorders 240 310 380 3 11 20 BDZ addiction 80 163 400 2 8 19 Psychotic disorders 30 140 290 3 13 31 Depressive disorders 60 130 200 3 6 18 Bipolar disorders 50 120 320 3 6 22 Anxious disorders 80 85 90 2 2 3

Presented at American Methadone Treatment Association National Conference, Chicago 1997 and patients should be kept under observation a non-responder. Methadone tapering should for the next two hours. This procedure can be only be considered after at least eight months, repeated until withdrawal is complete. The given that it has to be introduced very slowly eventual cumulative dosage administered on with dual diagnosis patients. However, if ta- the first day will be repeated through the fol- pering results in a worsening of psychosocial lowing days (induction phase), until a steady adjustment or a relapse into substance use, the state is supposedly reached (normally on the previously used dosage should be restored, 3rd or 4th day). No differences due to the pres- whatever the dosage level and whatever the ence of absence of dual diagnosis are expected tapering leap in these stages of treatment. In other words, the presence of dual diagnosis only seems to influence the management of the maintenance References phase. From a clinical point of view, admission 1. A.P.A. (1980): DSM-III Diagnostic and Statistical Manual. 3d ed. American Psychiatric Association, into methadone maintenance programmes Washington,D.C. should not depend on dual diagnosis. How- 2. AA.VV. (1984): Cocaine: Pharmacology, Effects and Treatment of Abuse. NIDA Research Monograph ever, with the criteria currently being applied, Series n° 50. NIDA, Rockville,Ml. dually diagnosed patients are likely not to be 3. AA.VV. (1993): Cocaine Treatment: Research and Clinical Perspectives. NIDA Research Monograph retained in treatment, since there is a trend to Series n° 135. NIDA, Rockville,Ml. administer lower rather than higher metha- 4. ALBANESE M. J., KHANTZIAN E. J., MURPHY S. L., GREEN A. I. (1994): Decreased substance use in done dosages. In fact, it must be recalled that chronically psychotic patients treated with clozapine. dual diagnosis patients require higher dosages Am J Psychiatry. 151 5. 5. ANGLIN M. D., ALMONG I. J., FISHER D. G., PETERS during the stabilization phase. If dually diag- K. R. (1989): Alcohol use by heroin addicts: evidence nosed patients display resistance to standard for an inverse relationship: a study of methadone maintenance and drug-free treatment samples. Am J treatment, they are likely to be considered as Drug Alcohol Abuse. 15 191-207. non-responders, whereas they are simply not 6. ANGST J., AUTENRIETH F., BREM F., KOUKKOU M., MEYER H., STASSEN H. H., STORCK U. (1979): receiving adequate treatment. The time re- Preliminary results of treatment with beta-endorphin quired to reach stabilization is longer for dual in depression. In: UDSIN E., JR. B. W. E., KLINE N. S. (Eds.): Endorphins in Mental Health Research. diagnosis patients, so it is important to moni- Macmillan, London. pp. tor patients through quite a long period, before 7. ATWEH S. F., KUHAR M. (1977): Autoradiographic localization of opiate receptors in rat brain. Brain Res. they can be expected to achieve stabilization. 134 393-405. If these guidelines are applied, it is unlikely 8. BALL J. C., CORTY E., PETROSKI S. P., BOND H., TOMMASELLO A., GRAFF H. (1986): Medical that an under-treated patient will be taken for services provided to 2394 patients at methadone 174 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 175

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TAZI A., DANTZER R., MORMEDE P., LE MOAL M. 178 · CHAPTER 3.2 Clinical Foundation for the Use of Methadone in Dual Diagnosis Patients · 179

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Clinical Foundation for the Use of Methadone in Polyabuse Patients I. Maremmani, F. Lamanna and M. Pacini

1. Handling alcohol abuse during Whatever craving may emerge, as long as methadone maintenance detoxification is proceeding and as long as abstinence continues, addicts may succeed in providing clean urinalyses by switching to The available data are in agreement that it cross-acting substances. Whatever the thera- is quite common for addicts entering a Metha- peutic setting may be, in the addict’s natural done Maintenance Treatment Programmes environment alcohol consumption may com- (MMTP) to have a history of alcohol abuse; pensate for the lack of heroin availability (due the impact of MMTPs on pre-existing alcohol to poverty, somatic impairment, temporary abuse turns out to vary widely, whereas the re- lack of supplies), the outcome being that this sults of MMT in cases of heroin use show close becomes a common means of self-managing similarities [13, 16, 17, 20, 21, 27, 29, 56, 58, 61, opiate craving [50]. 64, 65]. Moreover, the possible increase in al- For heroin addicts, who have strong mo- cohol consumption during MMTP develops tivations to “turn over a new leaf”, whatever alongside dwindling heroin use, which sug- proves to be useful in staying detached from gests a negative correlation between the two, heroin may be resorted to on a regular basis. at least in programmes in which dosages are In the case of other addictive substances, such kept low [1, 26]. as alcohol or cocaine, an apparent state of re- Alcohol use shows as increasing trend mission actually arises from a switch between among self-detoxifying and detoxified heroin forms of addiction. An iatrogenic way of fa- addicts who undergo naltrexone treatment, vouring a course towards involvement with suggesting that alcohol serves as a means of alcohol as a surrogate, would consist in skip- compensation for the unavailability of heroin ping or interrupting effective treatment for [38, 51, 52] heroin addiction. The premature removal of

181 182 · CHAPTER 3.3 Clinical Foundation for the Use of Methadone in Polyabuse Patients · 183 agonist drugs, the easy availability of naltrex- the obvious exception of naltrexone treatment. one programmes as the most suitable solution Disfulfiram can be combined with it [37]. Dis- for addicts whose condition is mild, medically fulfiram should not be introduced into a pro- supervised detoxification programmes, and tected environment, leaving the results to be drug-free regimens are all examples of inter- tested after discharge, since such a procedure ventions which directly favour, or refrain from would make the staff and the patient blind to impeding, a switch away from the evolution the patients’ current craving and the conse- of heroin addiction towards alcoholism. Con- quent risk of severe intoxication. Disulfiram versely, when alcohol-abusing addicts are treatment is not recommended in patients who prompted to try methadone treatment, that are susceptible to binge-drinking episodes. Di- may manage to preclude their consumption sulfiram should never be self-administered by of alcohol in the short-term, so indicating how the patient: one ingenious solution is that of quickly and directly opioid agonism is able to making acceptance of disulfiram administra- act on alcohol craving in this population [10]. tion by the staff a condition for being given Rates of alcohol and heroin use are expected to daily methadone. In this way dependence change in a reciprocal way, according to Ang- on methadone can be used to induce another lin’s compensatory model [1]. therapeutic behaviour from the patient [36]. As the results for heroin use were similar, GHB can be used in combination with metha- higher methadone dosages were related to done (table 1). A partial reduction in craving lower rates of alcohol and benzodiazepine use by GHB may also make combined disulfiram [39, 46, 47]. In our personal experience, we as- treatment possible, until binge-drinking has certained the relationship between methadone been extinguished. dosage and depressant abuse in one single In our personal experience Clonazepam subject over time: an increase in methadone may be useful in treating alcohol abuse associ- dosage was quickly followed by a significant ated with benzodiazepine abuse. High doses decrease in alcohol and benzodiazepine use, of clonazepam reduce the risk of lethal intoxi- whereas stable-dose subjects went on abusing cation by an alcohol-benzodiazepine combi- depressants at the same rate [39, 46]. When nation. It is preferable to arrange for a high programmes are restricted to low dosages, they dose clonazepam induction during a brief are likely to be spoiled by a high incidence of hospitalization until doses around 8-10 mg are alcohol abuse – a situation that reflects the in- reached. complete control these addicts have over cravings, masked by the coupling of methadone and alcohol. As a result, it may even seem that 2. Benzodiazepine (BDZ) abuse during methadone treatment, when no other feature methadone maintenance is specified, somehow favours the development of alcohol abuse [2]. When subjects are abusing cocaine, metha- Benzodiazepines are widely and repeated- done dosage is significantly higher (130 vs. ly prescribed to large populations of patients, 65 mg/day, on average, F 2.89, p = 0.04). By with a trend towards unrecompensed long- contrast, when alcohol use is present in combi- term prescription, beyond actual effectiveness, nation with cocaine, no difference is recorded, which fades as tolerance develops. In this way, which may indicate that alcohol has an opi- high numbers of psychiatric patients, usually ate-boosting function, automatically limiting suffering from mood or anxiety disorders, be- the need for methadone coverage [46]. Other come dependent on low-to-moderate doses authors report that, contrary to their expecta- of benzodiazepines, and fail to break away tions, methadone dosages were higher in non- from them, due to untreated underlying anxi- alcohol-abusing heroin addicts [53]. ety and dysphoric symptoms which worsen Specific treatments for alcoholism are com- sharply when an attempt is made to taper. patible with methadone maintenance, with Actual benzodiazepine abuse is less common, 182 · CHAPTER 3.3 Clinical Foundation for the Use of Methadone in Polyabuse Patients · 183

Table 1. Pharmacological interactions and dosages in methadone maintained alcoholics heroin addicts according to the experience of PISA-SIA Group

meaning by that term ‘ongoing use despite re- opiate-related ‘high’. In accordance with what current intoxication symptoms’ [8]. Abuse is may be expected from BDZ kinetics, the stable, sometimes a consequence of prolonged, unsu- non-euphorizing effect of a slow-acting opiate pervised benzodiazepine prescriptions for an is converted into a fast-acting opiate rush. In anxiolytic purpose, and is sometimes related a laboratory setting, diazepam pre-treatment to recreational use, together with other drugs reduced amounts of methadone that were self- [57]. Benzodiazepine abusers are highly con- administered by a sample of methadone-main- centrated (80%) among current polyabusers tained heroin addicts [63]: the more diazepam [49]. A lifetime comorbidity for any other drug is pre-administered, the lower the amounts of abuse reaches 100%. methadone that are self-administered after- Typically, benzodiazepine abuse is com- wards. No change in expected diazepam or bined with opiate or analgesic abuse (features methadone blood levels was reported, so that found in 77% of all current benzodiazepine the behavioural interaction is thought to take polyabuse pictures and in 67% of cases of life- place at a dynamic level [55]. time polyabuse) [8, 28]. Alcohol abuse seems On this basis, the hypothesis that has been to have an inverse relationship, at least as a tested is that BDZ abuse is related to low-dose current combination, with BDZ abuse: even methadone treatment, below the threshold of so, most current BDZ abusers do have a his- average effectiveness (100 mg/day). In fact, tory of alcohol abuse. Thirteen % of BDZ abus- the craving for both alcohol and BDZ was ers combine BDZ with cocaine, whereas life- inversely related to methadone dose [39, 47]. time comorbidity is less common. Seventeen When higher methadone dosages are em- % abuse two other kinds of drugs, together ployed (over 100 mg/day), BDZ abusers tend with BDZ. BDZ use brings with it poorer so- to stop polyabusing [6]. cial adjustment and higher infective hazards BDZs are characterized by a range of abuse [5, 6, 12]. potentials. Among street addicts, flunitraze- Heroin addicts abuse BDZs for two main pam and diazepam are far more common than reasons. On one hand, they may be resorted to oxazepam, [28]. In fact, flunitrazepam (4 mg) as anti-withdrawal medications. On the other, is euphorizing to methadone-maintained sub- they may even be tried to boost the effect of jects [14]. On therapeutic grounds, we can state opiates, and prolong their effect, as soon as it that methadone treatment at over 100 mg/day starts to fade. Some methadone-maintained is effective in reducing alcohol and BDZ poly- subjects use BDZs habitually too, though rates abuse, along with that of toxic opiates. Lower vary widely (5-45%) [7, 18, 25, 31, 62, 70]. In dosages may produce the extinction of toxic this situation, the combination of therapeutic opiate use but leave room for BDZ and/or al- opiates with BDZs may induce a rapid though cohol use to be initiated or to persist as a result transient boosting effect which produces an of residual craving. 184 · CHAPTER 3.3 Clinical Foundation for the Use of Methadone in Polyabuse Patients · 185

BDZ abuse that persists during a higher- tion cannot be considered secure, since con- dose methadone maintenance programme trol over craving has been partly achieved by can be challenged effectively by clonazepam having replaced heroin with BDZ and alcohol. treatment [6, 69]. Induction into clonazepam The patient should be made aware that dose should be performed cautiously. The principle adjustment is required in order to make re- is the same as that used with methadone treat- habilitation follow abstinence from opiates, ment – the aim should be that of reaching a which cannot be expected to happen if the condition of BDZ-blockade by clonazepam tol- use of BDZ and alcohol is allowed to develop erance (over the 6 mg threshold) and reducing or persist. Moreover, when the use of alcohol levels of craving by residual agonist activity. and/or BDZ does persist during treatment, Also, BDZ-blockade by clonazepam is a pro- even though they are not addictive at the be- tective measure against episodes of fast-acting ginning, this habit may evolve into actual dual BDZ abuse. addiction later on. When clear signs of independent craving for alcohol or BDZ are recognized, specific in- 3. Handling alcohol and BDZ polyabuse terventions should be adopted. during methadone maintenance The omission of correct dose adjustment in cases of BDZ or alcohol use is the basis of actual iatrogenic polyabuse. On one hand, no Physicians may have to challenge different prevention or counteraction against polyabuse patterns of BDZ polyabuse: is being implemented. On the other, the com- 1. patients maintained on ineffective dos- bination of low-methadone dosages with the ages with morphine-positive urinalyses, continuing consumption of BDZ and alcohol who also use BDZ and/or alcohol may directly favour the onset of habitual use 2. patients who have negative urinalyses for in order to boost the effects of methadone it- morphine but use BDZ and/or alcohol self. 3. patients who have negative urinalyses Needless to say, the use of BDZ to favour but have dual addiction to BDZ and/or detachment from methadone means placing alcohol patients in a situation where they are at risk of In patients with positive urinalyses, the developing a liking for BDZ, especially when methadone dosage must be increased to the fast-acting BDZs are resorted to. Discharging effective anticraving dosage. Induction should patients after detoxification with prescrip- be performed rather gradually, considering tions of BDZ but with no specific term must possible interactions with alcohol and BDZ. be viewed as both anti-therapeutic and patho- Hospitalization may be required. Once urinal- genic. yses have turned negative, the use of BDZ and alcohol should be given a second look. BDZ and alcohol may persist even when 4. Handling cocaine abuse during urinalyses are stably negative for morphine. methadone maintenance Methadone dose increase is recommended, until a blocking value is reached, in order to minimize the boosting effects of alcohol and Concurrent substance abuse during Metha- BDZ on methadone. Lethal interactions are done Treatment is a common problem which also reduced in patients with high levels of holds down retention rates and interferes with opiate tolerance. the achievement of satisfactory clinical out- It should be noted that patients who use comes both in terms of relapsing behaviour BDZ and alcohol may tend to oppose dose and as regards general health status and so- increases, claiming that their abstinence from cial adjustment [3, 9, 22, 23, 30, 33, 40, 48, 59]. heroin at lower dosages is a valid reason for As to cocaine, the prevalence of its use among not increasing them further. Such stabiliza- patients in methadone treatment in the USA 184 · CHAPTER 3.3 Clinical Foundation for the Use of Methadone in Polyabuse Patients · 185

increased by three times in the 1980s, with Generally speaking, no standard treatment respect to previous estimates [11, 32, 48], so for cocaine addiction has been developed, that cocaine has become the most frequently whereas a variety of interventions have been abused substance in that context. The preva- shown to be useful in reducing otherwise un- lence of cocaine use in untreated opioid-de- specified cocaine (ab)use. pendent subjects ranges from 30% to 80%, and The administration of higher methadone this phenomenon is still present in patients dosages does neutralize the psychopathologi- after a long period under methadone therapy, cal effects of cocaine, but, just by doing so, one although treatment initiation produces a non- could delay the emergence of cocaine-intoxica- specific trend against any form of polyabuse, tion symptoms, allowing patients to claim they cocaine included [35]. In the 90’s, it was pro- are still quite balanced. On the other hand, posed that cocaine abuse during methadone psychopathological stabilization corresponds treatment might result from an inadequate to greater retention in treatment. On these methadone dose [19, 24, 66, 67]: the theory was grounds, it is not clear whether to let cocaine that patients initiate or increasingly resort to abuse come to a psychopathological breaking cocaine and other non-opiate substances in or- point earlier, without increasing methadone der to achieve a change in their mood or func- dosages, in order to justify earlier intervention that is no longer accessible through opi- tion, though with some risk of dropout; or to ate use, because of the blockade effect or the buffer its psychopathological symptoms by in- heightened tolerance. creasing methadone dosages, with some risk While this theory has not yet been thor- of delaying actual intervention and favouring oughly comprehensively checked out, data the transition from cocaine use to addiction. showed that, when heroin abuse continues Patients who use cocaine should not be in methadone treatment patients, cocaine use allowed to take delivery of high amounts of may be associated with it, over a wider range take-away methadone, which may be traded of methadone doses [15, 41, 54]. for cocaine. If that happened, control over her- Conversely, the counterbalancing effect of oin addiction would be lost, too. a tonic opiate may render individuals more tolerant to cocaine loads. Maremmani and colleagues [46] showed that cocaine abusers re- References quired higher methadone dosages to achieve 1. ANGLIN M. D., ALMONG I. J., FISHER D. G., PETERS K. R. (1989): Alcohol use by heroin addicts: evidence and maintain psychopathological stabilization, for an inverse relationship: a study of methadone while cocaine abuse was not extinguished. maintenance and drug-free treatment samples. Am J Drug Alcohol Abuse. 15 191-207. When alcohol was co-abused, methadone dos- 2. BACKMUND M., SCHUTZ C. G., MEYER K., age was not dissimilar from controls. On the EICHENLAUB D., SOYKA M. (2003): Alcohol comsumption in heroin users, methadone-sobstituted other hand, when heroin was combined with and codeine-substituted patients. Frequency and cocaine before treatment, levels of psychopa- correlates of use. Eur Addict Res. 9:(1) 45-50. 3. BALL J. C., ROSS A., JAFFE J. H. (1989): Cocaine thology, as evaluated by the examiner, were and heroin use by methadone maintenance patients. higher, although individuals tended to rate NIDA Res Monogr. 95 328. 4. BANDETTINI DI POGGIO A., FORNAI F., PAPARELLI themselves as feeling “better” than heroin- A., PACINI M., PERUGI G., MAREMMANI I. (2006): only abusers [4]. Comparison between heroin and heroin-cocaine polyabusers: a psychopathological study. Ann NY On pathogenetic grounds, there is a large Acad Sci. 1074 438-445. body of works that have suggested that a 5. BLEICH A., GELKOPF M., SCHMIDT V., HAYWARD R., BODNER G., ADELSON M. (1999): Correlates of pre-existent psychiatric disorder or even a benzodiazepine abuse in methadone maintenance personality disorder could influence the ad- treatment. A 1 year prospective study in an Israeli clinic. Addiction. 94:(10) 1533-1540. diction process and could determine different 6. BLEICH A., GELKOPF M., WEIZMAN T., ADELSON patterns of drug abuse [34, 42-44, 60, 68, 71]. M. (2002): Benzodiazepine abuse in a methadone maintenance treatment clinic in Israel: characteristics The association between cocaine polyabuse in and a pharmacotherapeutic approach. Isr J Psychiatry heroin addicts and a bipolar disorder has been Relat Sci. 39:(2) 104-112. 7. BUDD R. D., WALKIN E., JAIN N. C., SNEATH T. C. reported recently [45]. (1979): Frequency of use of diazepam in individuals on 186 · CHAPTER 3.3 Clinical Foundation for the Use of Methadone in Polyabuse Patients · 187

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(1989): Personality risk factors for cocaine abusers. methadone. Drug Alcohol Depend. 18:(2) 195-202. Am J Public Health. 79:(7) 891-892. 56. RITTMANSBERGER H., SILVERBAUER C., LEHNER R., RUSKAK M. (2000): Alcohol consumption during methadone maintenance treatment. Eur Addict Res. 6:(1) 2-7. 188 · CHAPTER 3.3 3.4

Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding L. Finnegan, M. Pacini and I. Maremmani

1. Methodological and conceptual issues ed patients who are able to stop using heroin at low doses, the majority receiving less than 80 mg/day will continue abusing practices In some cases, treatment of pregnant ad- combining substances in a struggle against the dicted women is flawed by major omissions blockade. In such settings, these low dose treat- and misconceptions. For example, methadone ed patients may have a worse outcome than treatment is often regarded as substitution, untreated addicts. Since most authors agree on pointing at its withdrawal-preventing use- the global benefit of effective methadone doses fulness, which has little to do with its actual on the course of pregnancy in opiate-addicted employment in an anti-craving and behav- mothers, when evaluating treatment effective- iour-modifying view. The main goal of treat- ness, in addition to receiving adequate doses, ing women with methadone should be that they should be provided with comprehensive of minimizing illicit opiate use throughout services within structured programs especially pregnancy, and to permit them to normalize designed to meet their needs. their health and psychosocial issues. Effective dosages are associated with better outcome. Opiate abusing pregnant women, who are cur- 2. Premises rently receiving methadone treatment, should have their dose increased to control craving. The use of ineffective dosages will produce an Heroin addiction during pregnancy is as- incomplete opiate blockade and can be harm- sociated with increased rates of perinatal ful to the pregnancy, causing an unstable in- morbidity, including spontaneous abortion, trauterine environment and potentially foetal premature delivery, meconium stained liquor, withdrawal. Apart from a minority of addict- neonatal infection and withdrawal syndromes

189 190 · CHAPTER 3.4 Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding · 191 varying according to which substance has been vices without any short-term or monetary ad- abused [18, 53]. Recurrent exposure to fast-act- vantage [67]. Given the combined benefit for ing, short-lasting opiates produces a condition both the mother and the foetus, and the poten- of continuous swinging from states of opiate tial double damage caused by treatment omis- intoxication and withdrawal due to a height- sion or delay, pregnant addicts, who apply for ened tolerance level to their narcotic action. treatment, should be given priority for enroll- Fluctuations of opioid concentrations result in ment in methadone maintenance programs. an irregular blood supply to the utero-placental unit and the foetus suffers from recurrent hypoxia. Such a mechanism is responsible for 3. Teratogenicity and pregnancy delayed foetal development, foetal death and abnormalities. morbidity [18]. Providing opiates equivalent in potency, but characterized by long-lasting, slow-acting kinetics and administered in a No congenital abnormalities have been re- maintenance schedule, will normalize opioid lated to methadone. The widespread exposure metabolism of tolerant individuals and pre- of opioid abusing mothers to methadone in vent foetal damage. therapeutic settings provides an opportunity to As for addiction-related issues, a series of normalize the pregnancy and prevent untow- additive behaviours may imperil pregnancy: ard damage to the foetus. When evaluations lack of use of sterile equipment, sexual proof drug-induced abnormalities are performed miscuity, the involvement in violent acts, de- on neonates of women undergoing treatment, creased hygiene, environmental influences, the role of poly-drug abuse and alcohol abuse poverty, and refusal to comply with the health should be considered [1]. Methadone exposed supporting guidelines of treatment facilities. newborns have been reported to have higher The main goal of effective addiction treatment birth weights and less morbidity than heroin is that of leading addictive behaviour to ex- exposed babies. A trend towards increased tinction and normalizing opioid metabolism. birth weight has been reported by Hagopian et Beyond tolerance/withdrawal related issues, al., 1996 [24]. No delivery abnormalities have the clinical correlates of opioid metabolism are been noted in women who have followed suc- of a behavioural nature, so that increasing dos- cessful methadone maintenance during their ages of therapeutic opiates can override the pregnancy. compulsion to seek illicit opiates. Some opiates, such as methadone, display pharmacological characteristics which allow 4. Methadone management during a health-promoting interaction with the brain pregnancy. due to the possibility of behavioural control and long-term damage reversal, at least in less severe cases. Methadone maintenance Methadone metabolism in pregnancy is has been the standard treatment, and the only different than that of the non-pregnant patient treatment approved for pregnant heroin ad- and is influenced by the increased body fluid dicts [12, 34]. As for non-pregnant addicted of pregnant women, especially during the 3rd individuals, adequate methadone dosing is trimester [68]. Methadone elimination is more crucial to enhance compliance to treatment rapid in pregnant women, so that the half-life guidelines and achieve health objectives [13]. is significantly shorter and methadone absorp- Even at no blocking dosages, pregnant heroin tion may be also reduced [13, 30]. In blood sam- addicts’ behaviour is modified enough to al- pled from the same subjects, peak methadone low attendance at healthcare facilities and to levels after equal oral dose loads are lower in obtain abstinence from cocaine by voucher in- the pre- than in the post-partum phase [43]. centives [19, 32-34, 67]. Methadone treatment When withdrawal symptoms are monitored in may render women capable of attending ser- a population of heroin abusing pregnant wom- 190 · CHAPTER 3.4 Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding · 191

en entering methadone treatment at variable lating pattern. During this period the infant stages of their pregnancy, symptomatic wom- can gradually be stabilized [70]. Duration of en display methadone serum levels below the hospitalization is generally longer for metha- 0.211 mg/l [27], while administered dosages done than for heroin withdrawal. Polydrug are similar. [Also a discrepancy seems to occur abuse further contributes to the duration of between higher methadone dosages and foetal withdrawal symptoms (Johnson et al., 2003). serum levels of the drug: this latter tend to be When morphine is used (as a tincture of opioid similar regardless of increases of oral maternal solution), lower dosages administered more dosages [14]. It should be remembered that dif- frequently are associated with fewer days of ferent oral dosages may actually correspond to hospitalization in comparison with higher dos- similar blood levels: therefore, such discrepan- ages at longer dosing intervals [31]. An earlier cy may have no actual implication as long as (within the first three weeks), transient hyper- the administration of methadone to pregnant phagic picture has been described which does women is rather based on clinical needs than not correspond to an increase in weight and on a scale of absolute oral dosage value [15]. appears to be unrelated to other withdrawal As a consequence, some pregnant heroin ad- symptoms and maternal methadone dosage dicts are provided ineffective medication due [49]. to unjustified cautions by the clinician [20]. The relationship between NAS and maternal methadone dosage is controversial. Some authors have found no association with dose 5. Neonatal abstinence syndrome in [4, 5, 24, 35, 37, 38, 42, 46, 51, 58, 64, 69], while methadone-exposed newborns. other authors ascertained a dose-dependent relationship with regard to incidence and severity of abstinence in their samples [14, 26, Since opiates traverse the placental bar- 41, 47, 48, 50, 52, 53, 62, 63, 66]. Some of the rier and foetal tissues become tolerant to their studies evaluating this relationship used very presence, the sudden deprivation of an opioid low doses, far below average effective dos- source at delivery may result in a withdraw- ages. Such a methodological choice is likely al state, called the neonatal abstinence syn- to correspond to patients being treated at inef- drome (NAS). More than one substance may fective dosages and not representing the level be involved, and one should be aware of the of health and behavioural stability achievable possibility of a combined tolerance to opiates by methadone maintenance. Anti-withdrawal and gabaergic neurodepressants (benzodiaze- and partially blocking dosages, such as those pines). NAS occurrence is variable and is gen- between 20 and 60 mg, do not suppress crav- erally seen in 60 to 90% of exposed neonates [6, ing and favour the combination with other 16, 26, 54, 59]. opiate-boosting or replacing drugs, such as NAS intensity is widely variable. Onset of benzodiazepines, leading to the misinterpreta- abstinence seems to depend on the interaction tion of clinical findings. Patients, for whom a between the newborn’s slow metabolism and 20-30 mg dose is enough are likely to be low- the agents’ own slow dissociation from bind- severity individuals and will not abuse opiates ing sites. Long acting morphine substitution is during pregnancy; on the other hand, average- not preferable to methadone in preventing the to-high-severity patients not provided with occurrence or severity of neonatal withdrawal effective doses will continue abusing drugs [21]. When buprenorphine was evaluated, when provided a 40-60 mg dose. In some stud- withdrawal was rated as milder and hospital- ies, [10, 50], NAS severity is predicted by ben- ization time was consistently shorter [56]. zodiazepine and cocaine abuse, respectively, Symptoms generally occur within 72 while no other opiate-related predictive factors hours. The course of withdrawal traverses are identified. The possibility of a combined a period of a week to several weeks with a withdrawal, (opiate and alcohol-benzodiaze- gradual decrease in intensity within an undu- pines) may also be considered] [57]. 192 · CHAPTER 3.4 Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding · 193

Therefore, NAS will tend to be more severe permanent. for higher dose patients, whose dosage is still Opiate withdrawal can be effectively treat- not enough. However, no difference is reported by following a tapering schedule [2, 56]. ed by Berghella and colleagues, who studied Shorter dosing intervals of opiate-containing NAS in infants exposed to less than 80 mg/day solutions have been found to reduce the du- to those exposed to more than 80 mg/day [3]. ration of withdrawal [9], Morphine solution is Sinha et al [63] report NAS being more often in preferred for the treatment of NAS. need of morphine treatment in women taking Breast feeding of mothers on methadone higher methadone doses, but methadone-only may be helpful in flattening the withdrawal exposed children are at lower risk of NAS than slope to a drug-free state [21, 28, 44]. Breast- heroin-exposed ones. Overall, most results in- feeding alone is not likely to provide the infant dicate NAS is less frequent in infants of metha- with enough methadone supply, and is not done treated mothers than heroin using peers. always viable due to concomitant conditions, Although there is a risk of NAS in methadone such as HIV infection. Barbiturate treatment exposed infants, the syndrome is treatable and may be indicated in addition to morphine not lethal if it is assessed and managed ap- when benzodiazepine withdrawal coexists. propriately. The NAS is overshadowed by the acquired gain in pregnancy and delivery outcomes and the mother and child’s health status as well as many psychosocial aspects that 6. Neonatal thrombocytosis can be ameliorated [29]. Many clinicians still practice medically supervised withdrawal from opioids during Increased platelet count and aggregating pregnancy [45]. Along the stated reasons for function have been reported in newborns of withdrawing pregnant women is to prevent methadone treated mothers [6-8, 25], with an NAS, prejudice or lack of knowledge about estimated prevalence of 3,65% [22]. A similar addiction and its clinical features [55]. Medical finding has been described in the offspring of withdrawal is not indicated during pregnancy opiate-tolerant female mice [7]. Platelet over- except in a few instances where logistics ham- crowding may occur regardless of which opiate per the delivery of methadone maintenance. has been administered, that is both for heroin Some clinicians have tried a fast detoxifica- addicted mothers and opiate treated subjects. tion procedure with the claimed aim of NAS Its timing seems to follow that of neonatal prevention. A twelve-day schedule of metha- opiate withdrawal, with a delayed onset one done withdrawal shortly before birth resulted week after discharge and a protracted course in 29% of relapses just after the schedule com- lasting several weeks [22]. The causes and pletion, and a global short-term abstinence mechanisms of such a phenomenon have not rate of 59%, while 15% of newborns required been reported, however, the parallel evolution treatment for a clinically relevant NAS [11]. concomitant with the abstinence syndrome Safe management of pregnant opioid ad- suggests it may be reversed by cross-tolerant dicted women should start by methadone opiate drug treatment. maintenance at effective dosages. NAS resulting from methadone exposure should be evaluated by clinical surveillance and treatment 7. Strabismus. when needed with an opiate at tapering doses [60]. Moreover, the administration of higher methadone dosages should never be offset Surveillance for the development of stra- by the priority to avoid neonatal withdrawal bismus is needed in children of opiate-depen- since NAS is manageable through adequate dent mothers. Available data do not indicate care and treatment, whereas damage resulting any correlation with either methadone dosage from untreated addictive behaviours can be or altered opiate tolerance (NAS-related fea- 192 · CHAPTER 3.4 Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding · 193

tures) [23]. sible factors which may contribute to developmental abnormalities in a group of children of addicted mothers treated with methadone, no 8. Methadone for pain in pregnant relationship was documented with opiate-re- women lated characteristics, such as methadone dose and duration of exposure to methadone [17].

Chronic pain control may benefit from increased long-acting opiate coverage without employing further analgesic agents. Break- 10. Breast-feeding through pain control needs fast-acting agents. Morphine is suitable to relieve acute pain in methadone maintained patients with its dos- Breast-feeding is possible for methadone age to be established on a subjective basis. As maintained women. The milk contains approx- a rule, methadone tapering during pregnancy imately 2% of daily dose and concentration is not recommended. Pain can be one possible [71]. Values range from 0,05 to 0,57 mg/ml for consequence of lowered opiate coverage. Oth- dosages varying from 10 to 80 mg/day [71]. er combinations with non opiate analgesics Daily methadone exposure is approximately may be considered [61]. 0,02-0,09 mg/die, far below the theoretical le- Women receiving methadone for pain con- thal dose in non tolerant babies. On the other trol during pregnancy deliver earlier, differ- hand, such a dose is not enough to prevent ently from methadone maintained pregnant NAS in opiate-tolerant newborns. However, heroin addicts [23]. Methadone for pain is ad- methadone maintained mothers who breast- ministered for shorter periods and generally feed their babies should not stop abruptly if at lower doses than that used for the addicted dosages are average-to-high [48]. A study link- individual. NAS has been observed in 11% of ing prenatal methadone exposure to delayed the neonates. Wholly, neonatal outcomes of development examined a group of women methadone treated pregnant women differ treated with an average dose around 40 mg, along the reason for methadone administra- which does not shield against poly-drug abuse tion (pain vs. addiction). and addictive behaviours [70].

9. Early child development 11. Psychological aspects

Developmental delays have been reported ‘Pregnancy’, as a life event, is often expe- in methadone-exposed babies [55, 72]. Growth rienced by patients, or suggested from oth- is slower during the first trimester, but no dif- ers, as somehow psychologically linked with ference in achieved dimensions is noted at six the natural history of addiction. Redemption months: a compensatory acceleration of growth themes should never be supported or induced, takes place farther from discharge. Head cir- and pregnancy should never be considered as cumference is normal within one year of age a healing opportunity through a withdrawal [40] while no cognitive delay is documented from therapy. In fact, expectations and moti- during infancy [36, 39, 40, 65]. However, when vational drives have nothing to share with the methadone is provided to pregnant women at destiny of a metabolic disease. On the con- effective dosages within structured programs, trary, patients will have to be provided with newborns tend to weigh more and have a larg- adequate information on treatment opportuni- er head circumference; the latter in proportion ties and feasibility in order to complete preg- with the average dose administered during nancy in the best way. A good counselor could the third trimester [24]. Examining the pos- motivate, through the experience of treatment 194 · CHAPTER 3.4 Clinical Foundation for the Use of Methadone During Pregnancy and Breast-feeding · 195 during pregnancy, a stronger relationship with use. An anti-addiction therapy has to restore the therapeutic program. In this case, pregnan- the mother so that she can maintain a parental cy can really become a motivation to treatment role. 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Ir Med J. 92:(1) 232-236. to plan a coherent, adequate line of conduct. 11. DASHE J. S., JACKSON G. L., OLSCHER D. A., ZANE Drug addicted women, as with most drug ad- E. H., WENDEL G. D. J. (1998): Opioid detoxification in pregnancy. Obstet Gynecol. 92:(5) 854-858. dicted individuals whose addiction is not very 12. DE LANGE E. E. (1979): The effect of heroin and severe, aim to recover control of the substance methadone on pregnancy and the newborn infant. Dutch J Psychedelic Drugs. 11:(3) 191-202. of abuse, in order to continue its use freely, and 13. DEPETRILLO P. B., RICE J. M. (1995): Methadone resort to a treatment able to solve the critical dosing and pregnancy: impact on program compliance. Int J Addict. 30:(2) 207-217. situation of the moment. Questions such as 14. DOBERCZAK T. M., KANDALL S. R., FRIEDMANN home care or resorting to a family collabora- P. 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withdrawal in newborn infants. J Pediatr. 81:(3) 532- 64. STIMMEL B., GOLDBERG J., REISMAN A., MURPHY 534. R. J., TEETS K. (1982): Fetal outcome in narcotic- 55. RAMER C. M., LODGE A. (1975): Neonatal addiction: dependent women: the importance of the type of a two-year study. Part I. Clinical and developmental maternal narcotic used. Am J Drug Alcohol Abuse. 9:(4) characteristics of infants of mothers on methadone 383-395. maintenance. Addict Dis. 2:(1-2) 227-234. 65. STRAUSS M. E., ANDRESKO M., STRYKER J. C., 56. ROHRMEISTER K., BERNERT G., LANGER M., WARDELL J. N., DUNKEL L. D. (1974): Methadone FISCHER G., WENINGER M., POLLAK A. (2001): maintenance during pregnancy: pregnancy, birth, and Opiate addiction in gravidity - consequences for the neonate characteristics. Am J Obstet Gynecol. 120:(7) newborn. Results of an interdisciplinary treatment 895-900. concept. Z Geburtshilfe Neonatol. 205:(6) 224-230. 66. SUFFET F., BROTMAN R. (1984): A comprehensive 57. ROMMELSPACHER H. (1991): The pharmacology care program for pregnant addicts: obstetrical, of drugs (heroin, L-methadone, cocaine, hashish) neonatal, and child development outcomes. Int J and their effects on pregnancy, fetus and neonate. Addict. 19:(2) 199-219. Gynakologe. 24:(6) 315-321. 67. SVIKIS D. S., LEE J. H., HAUG N. A., STITZER M. 58. ROSEN T. S., PIPPENGER C. E. (1975): Disposition L. (1997): Attendance incentives for outpatient of methadone and its relationship to severity of treatment: effects in methadone- and nonmethadone- withdrawal in the newborn. Addict Dis. 2 169-160. maintained pregnant drug dependent women. Drug 59. ROSENKRANTZ H., MILLER A. J., ESBER H. J. Alcohol Depend. 48:(1) 33-41. (1975): delta-9-tetrahydrocannabinol suppression 68. SWIFT R. M., DUDLEY M., DEPETRILLO P. of the primary immune response in rats. Journal of B., CAMARA P., GRIFFITHS W. (1989): Altered Toxicology and Environmental Health. 1:(1) 119-125. methadone pharmacokinetics in pregnancy: 60. SARMAN I. (2000): Methadone treatment during implications for dosing. J Subst Abuse. 1:(4) 453-460. pregnancy and its effect on the child. Better than 69. THAKUR N., KALTENBACH K., PEACOCK J. (1990): continuing drug abuse, should be monitored by a The relationship between maternal methadone dose specialized antenatal care center. Lakartidningen. during pregnancy and infant outcome. Pediatr Res. 28 97:(18) 2182-2190. 227A. 61. SCIMECA M. M., SAVAGE S. R., PORTENOY R., 70. WILSON G. S., DESMOND M. M., WAIT R. B. (1981): LOWINSON J. (2000): Treatment of pain in methadone- Follow-up of methadone-treated and untreated maintained patients. Mt Sinai J Med. 67:(5-6) 412-422. narcotic-dependent women and their infants: health, 62. SHARPE C., KUSCHEL C. (2004): Outcomes of developmental, and social implications. J Pediatr. infants born to mothers receiving methadone for 98:(5) 716-722. pain management in pregnancy. Arch Dis Child Fetal 71. WOJNAR-HORTON R. E., KRISTENSEN J. H., YAPP Neonatal Ed. 89:(1) 33-36. P., ILETT K. F., DUSCI L. J., HACKETT L. P. (1997): 63. SINHA C., OHADIKE P., CARRICK P., PAIRAUDEAU Methadone distribution and excretion into breast milk P., ARMSTRONG D., LINDOW S. W. (2001): Neonatal of clients in a methadone maintenance programme. outcome following maternal opiate use in late Br J Clin Pharmacol. 44:(6) 543-547. pregnancy. Int J Gynaecol Obstet. 74:(3) 241-246. 72. ZAGON I. S., MCLAUGHLIN P. J. (1983): Behavioral effects of prenatal exposure to opiates. Monogr Neural Sci. 9 159-168. 3.5

Clinical Foundation for the Use of Methadone in Jail

I. Maremmani, M. Lovrecic and M. Pacini

1. The rationale of methadone treatment: agonists provide prompt buffering against up- as outside, so inside penitentiaries coming withdrawal. Agonist management that aims to restore the pre-intoxication tolerance threshold can be To date, agonist maintenance has proved ruled out as an effective therapy for heroin ad- to be the most effective means of intervention diction. Moreover, although somatic balance is on the core of opiate addiction. Although oth- restored, psychic toxicity and tolerance to crav- er treatment typologies can play worthwhile ing for heroin are anything but under control. roles within a programme, they still loom as At present, the latter situations are what most side approaches. In correctly structured pro- jailed heroin addicts live in, while there is no grammes of intervention, they either stem from procedure available for reaching out to them the pharmacological core of agonist mainte- through specific agonist (methadone or bu- nance; or, more exactly, function as pathways prenorphine) programmes. Differences in the to bring specific agonist interventions within therapeutic destiny of prisoners do not mirror reach. The key issue of agonist treatment is the any actual difference on pathological grounds, prevention of relapse and recidivism, to be at- as the illness is the same for jailed as for free tained by suppressing craving for heroin. Ago- heroin addicts, and for the same heroin addicts nist treatment has got further beneficial char- before, during and after imprisonment. acteristics: first, doses can be administered that Those who oppose to this view can argue will prevent heroin from being sensed, even if that anticraving therapies are pointless inside patients continue to inject heroin in the early prison walls, because no control over the drive phase of treatment (known as ‘opioid block- towards heroin or blockade of narcotic effects ade’). Eventually, in terms of therapeutic rel- is needed, considering that street drugs are not evance, though firstly in chronological order, available. Leaving aside the long-standing is-

197 198 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 199 sue of drug availability in jail, we prefer to fo- in the dynamics of drug-related phenomena. cus on this question from a medical viewpoint. In line with the new view, imprisonment was Agonist maintenance chiefly aims to prevent a no longer regarded as a means of interven- spontaneously relapsing course. At the same ing specifically against addictions; alternative time, it should bear in mind exactly which ce- measures were needed to allow detainees to rebral functions have suffered damage from benefit from free therapeutic settings. The law chronic heroin exposure. Otherwise, it cannot indicated drug addicts as a category that mer- provide any heroin-like subjective effect, as ited a therapeutic rather than a correctional so- the misleading term “substitution therapy” lution, through what was called “therapeutic suggests. parole”: even if the prison system in itself plays Transforming time spent in jail into thera- no therapeutic role, it may mark a crucial stage peutic time offers advantages that do not in the history of addiction. In fact, not every stand or fall on the basis of whether addicts case is suitable for therapeutic parole. Howev- use drugs or not while imprisoned. As long as er, the health of addicts who cannot be selected the ultimate criterion for assessing treatment as parolees can be preserved in other ways. On effectiveness is the individual’s adjustment one hand, the law states the need to develop in a free setting, a therapeutic regime with a therapeutic programmes while time is being standard dose and scheduling features will served, and on the other the need for conti- work in such as way as to increase the likeli- nuity between therapeutic options inside and hood that prisoners will stay in touch with a outside prison. Generalizing, minor offenders, therapeutic setting after their release. Even if who make up the commonest criminal typol- it is not completely effective, this solution at ogy among drug addicts, are best handled as least allows patients some protection against mentally ill people, so therapeutic needs must drug-related accidents. Supporters of phar- prevail over the need for imprisonment. What- macological intervention [50] and supporters ever their crime, addicts who are unfit for ther- of community-based programmes [9,18] have apeutic parole, show that addiction should both assessed the feasibility and usefulness of continue to be recognized as a medical issue, standard addiction treatment inside prisons, that calls for specific intervention. It has been on the assumption that differences in treat- recommended that medical facilities for drug ment approach did not cancel the shared aim addicts should not differ from those offered to of preventing recidivism. The true promise of their free peers. Moreover, treatment should agonist therapies for addicted detainees is that not be discontinued when passing from free- of building up a subject’s social reliability on dom to detention or the reverse. Correctional scientific bases, while they are kept under con- institutions should then be cooperating with trol in a correctional institution. Otherwise, at the health system for free citizens. Lastly, de- present, released detainees usually reacquire tained drug addicts should be approached their social freedom together with a certainty as subjects who come from the community of relapse. Besides this, as long as pharmaco- and are, hopefully, destined to rejoin it (Old- logical shielding is maintained, the individu- enburg Conference on “Jail and Drug Addic- al’s freedom continue to be linked with a guar- tion”, March 12-14, 1999). A prison, just like a antee of social harmlessness [38]. therapeutic community, can become a useful setting for starting subjects on treatments, the aim being to guarantee their social role in view 2. Towards a prison-based treatment for of their future return to freedom. The control addiction exercised by police within prison walls may help to promote the feasibility of treatments, by overcoming the lack of compliance that The 1950 OMS definition of addiction as would cause treatment failure in a free set- a disease helped to ratify the changed scien- ting. In other words, individuals who would tific awareness of the role of psychopathology be untreatable because of lack of compliance 198 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 199

or would never request any treatment as long the affected individual into a spiral of relapse as they were ill but free, may welcome the op- which can now be expected to spin faster than portunity to receive treatment as long as they in the past. In Italy it has been reported that are deprived of freedom. 75% of imprisoned addicts had stopped their In recent times, changes have been made treatment over 60 days before being arrested, to the prison system in an attempt to organize while only 3% were imprisoned in the short- a special setting for the handling of addicted term after treatment discontinuation [6]. It can inmates. There is, however, a risk that these be said that in Italy the spread and continu- innovations will develop without specific in- ance of methadone maintenance was related struments for curing drug addiction, simply to changes in addiction-related crime between providing environmental, recreational and re- ’86 and ’95, due to changes in the numbers habilitative options which may be out target. of imprisoned subjects who were attending In our opinion an effort should be made to a methadone maintenance programme. The focus on the possibility of exploiting some of number of imprisoned addicts rose from 6,000 the features of prison life, which are needed in 1986 to 13,000 at the end of 1995. On the anyway to ensure security, to enhance the im- other hand, the number of methadone-main- pact and feasibility of therapeutic measures tained subjects among the population of jailed that specifically target drug addiction. When addicts followed a different course: an initial the law leaves no alternative but detention, increase was documented in the late eight- this may create an opportunity to administer ies, while methadone treatment was spread- treatment [38] , and we could then start talking ing nationwide; this was followed by a steep about “prison-based treatment initiation”. fall in the early nineties, when the percentage dwindled from 33% to 3% [4] (See table 1 for details). In France, where agonist treatment 2. Effects of agonist treatment on started spreading in the nineties, the percent- addiction-related crime and handling age of agonist-treated subjects among jailed of addicted detainees addicts gradually fell. Experts at the French Ministry of Health have tried to explain this phenomenon as a preventive effect of the ongoing treatment, which tended to hold addicts 2.1 Specific treatment for addiction and the back from imprisonment as the outcome of prevention of criminal recidivism criminal involvement [21, 49]. Over 40% of all heroin addicts who had drug-related legal problems were imprisoned Agonist-maintained heroin addicts have at some stages over a 20-year follow-up period a 5% likelihood of being imprisoned at some [16]. point during a 7 year follow-up period [35] The criminal career of heroin addicts who or 2% at the end of 12 years 46. To be under enter maintenance treatments shows a strong methadone maintenance implies a low risk of tendency improvement in terms of frequency imprisonment both with respect to untreated of reimprisonment [3, 15, 35], number of de- peers [12, 20, 23, 25, 30-32, 34, 37, 40, 44, 52], tention periods and total time served while and compared with the same subjects when attending the programme [20]. Patients who they were not being treated [3, 13, 15, 39]. agree to take 60 mg/day (the standard thresh- When treatment is discontinued, its protective old for opioid blockade) are less likely to be value is lost as soon as addictive behaviour sent back to prison than those who refuse to re-emerges — a moment that does not neces- take blockade dosages [2, 48]. sarily occur during withdrawal and that often Conversely, unspecific treatments fail to af- follows an early period of abstinence. In fact, fect the natural course of addiction and the ad- it is over the medium to long term that crav- diction-related crime of former detainees [40]. ing and addictive drives re-emerge, pushing 200 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 201

Table 1. Incarcerated methadone-treated addicts in Italy

Survey term Incarcerated addicts Methadone-treated addicts N % 1996-12-21 6.102 252 4.13 1987-12-31 5.221 1.742 33.37 1988-12-31 7.500 750 10.00 1989-06-15 8.790 1.916 21.80 1990-12-31 7.299 184 2.52 1991-06-30 9.623 273 2.84 1991-12-31 11.540 378 3.28 1992-06-30 13.970 237 1.70 1995-12-31 13.448 391 2.90

2.2 The advantages of methadone maintenance tion, and the intensity of craving. A minority for the prison environment of heroin addicts, who stand out as particularly violent, are characterized by extremely severe withdrawal symptoms, together with In Canada a heroin-addicted detainee made a harm-avoidant personality trait, which may the first move by bringing the Kent prison sys- be the behavioural expression of a biological tem to court on a charge of therapeutic omis- predisposition to suffer great damage from sion, because he had been denied the right to chronic heroin exposure. In fact, sensitivity to initiate a methadone maintenance programme heroin’s behavioural toxicity (dysphoria and while in jail [33]. In the Republic of Ireland it aggressiveness) and a disposition to develop was the penitentiary police who proposed the addiction (with a quick transition from experi- extension of methadone maintenance inside mental to regular use) are interrelated, which prisons [24]. suggests that aggressiveness and addiction- These two events should not surprise us if proneness share the same underlying biologi- we consider the fact that detainees and prison cal structure. In the stereotypical heron addict, guards are those closest to what happens in- craving justifies symptoms of aggressiveness, side penitentiaries: between 1989 and 1995 no and thereby mirrors the severity of addiction. drug-related deaths were recorded for metha- In prisons, violent behaviour, suicidal and self- done maintenance addicts: those dying from injuring acts are highly represented among the drug use were not receiving agonist treatment psychopathological events of heroin addicts. [14]. However, suicide and self-injuring behaviours are not most likely during withdrawal [19]. It must be born in mind that the risks increase in the medium term, so that it is malpractice 2.3 Dysphoria, aggressiveness and self-injur- to discontinue agonist treatment by tapering ing behaviour steeply, even if it is apparently safe to do so in the short term. The consequences of an opioidergic malfunctioning become evident over Aggressiveness in heroin addicts has more time, so that recently detoxified, un-medicated than one meaning. In most heavy heroin us- addicts may quite suddenly begin to behave ers it is closely related to the severity of addic- aggressively. Patients benefit most from ago- 200 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 201

nist treatment, even when dosages are in- amongst methadone-maintained heroin ad- adequate. Even so, higher agonist dosages dicts [8, 51]. In a German survey, the risk for are required when aggressiveness is high at HIV seroconversion turned out to be negli- treatment entrance. From another standpoint, gible for methadone-maintained detainees, ongoing naltrexone treatment brings with it in sharp contrast with a 5.9/100 year/person a higher risk of aggressive and suicidal be- rate for the whole prison sample, and 8.9/100 haviours than methadone treatment does, as year/person among methadone-free heroin shown by comparing groups of patients who addicts [45]. did not differ in aggressiveness or suicidal risk It is logical to conclude that a specific ther- at treatment entrance. The need to act vigor- apy — one that aims to prevent relapse by ously and immediately against aggressiveness, craving suppression — should be regarded as while concomitantly reducing craving and ad- first choice for detained, as well as free, heroin dictive behaviours was the objective that the addicts. The data even allow us to state that prison officers had in mind in proposing the addicted detainees are a category of choice for extension of methadone treatment inside pris- methadone maintenance, because of its strik- ons [24]. ing efficacy on severe and high-risk addictive subpopulations. In some cases addiction-targeting treatments are not feasible, due to medical incom- 2.4 Unsafe practices patibility or absolute opposition by the patient, even when the consequence may be a longer prison term. In these cases, the controlled ad- Before talking about possible pharmaco- ministration of heroin is justified on a scien- logical issues, it can reasonably be assumed tific basis, as long as heroin-taking detainees that internal security measures against the are isolated from other prisoners with a heroin spread of drugs are at least partly effective problem [32]. against drug-related events in prisons. On The provision of clean injecting equipment the other hand, given the promiscuity of the does not encourage substance use, while it is prison environment, and the grouping to- effective in reducing infective accidents (such gether of individuals riding the same craving as seroconversion and needle-exchange) [32]. wavelength, drug-related happenings tend to Specific agonist-based intervention is, be uncontrollable, though infrequent [8, 21, therefore, compatible with harm reduction in 27, 42]. Moreover, drug-related risks inside the same context. In fact, harm reduction does prison are heightened by what is, on average, not hamper the spread of effective treatment; the greater severity of addiction of those who on the contrary, it helps to reduce the harm end up in jail — individuals who often display deriving from residual drug-taking activities poor impulse control or antisocial personality that are not covered by the agonist treatment disorders. Methadone maintenance favours an itself. opposite trend for drug-related behaviours: On the whole, substance use inside prisons treated individuals, unlike their untreated can be countered in two separate directions: peers, show greater even while continuing to police controls limit the spread of drugs and, inject, and win a better level of impulse con- therefore, the incidence of drug-using. Specific trol. Conversely, when craving-related urges interventions, on the other hand, should boost coupled with low substance availability are the effectiveness of police control by acting concomitant with a lack of therapeutic cover- from inside the subject, and from within the age, the risk to health rises steeply. By contrast, addict population (by reducing demand). In even when drug-using continues in jail, and this context, agonist treatment helps to prevent returns to pre-incarceration levels soon after leaks within the control system from causing discharge, unhealthy habits (such as needle further damage beyond the mere use of drugs. exchange and unsafe sex) remain uncommon Similarly, in a free setting, agonist treatment is 202 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 203 the simplest and cheapest way of curbing all sence of treatment is chosen, a prison setting drug-related phenomena. may heighten or help to solve drug-related issues, both for the individual and the community [50]. 3. The role of detention in the natural course of addiction and its therapeutic destiny. 3.2 Rationale of agonist maintenance in prison

3.1 A medical or an environmental problem? A prison setting does not curtail the effectiveness of methadone maintenance on narcotic-seeking drives [11]. It follows that Imprisonment necessarily impedes ongo- methadone treatment must be as readily avail- ing substance use. Nevertheless, abstinence, able in jail as it is to free addicts [5]. Several whether self-determined or forced, does not programmes for narcotic addiction, though cause craving to dwindle, especially in the potentially useful for those who stay in treat- case of opiate addiction. This explains why ment, were not complied with from the begin- there is a demand for narcotics from inside ning by the standard heroin addicts [42, 43]. By prisons, and why there is a need to counteract contrast, a clinical trial run by the MTC project the spreading of narcotics inside prisons by team where detainees were started on LAAM police measures. The latter are undoubtedly three months before scheduled discharge, 92% effective in limiting drug using among detain- proved to be compliant in the induction phase ees, but they do not hit the core of addiction. [22]. A methadone maintenance programme The main drive to substance use is not rooted bridging the transition from a prison environ- in the prison environment: in other words, it is ment to a free life outside, despite a notewor- not a habit born inside the prison community, thy dropout rate after discharge (40%), makes but the outcome of the grouping together of it possible to set up a therapeutic relationship, independently ill individuals who became ad- which is likely to be renewed, at least on a dicted while free. Two intervention strategies yearly basis, even when patients have no real should be distinguished: an aspecific one, aim- wish to comply with a structured programme ing at the limitation of drug use behind bars [26]. The coercion implied by a prison-based (supply reduction), which is the task of the po- programme is, in any case, useful in increas- lice system; and a second, more specific one, ing retention rates, without hindering the ef- rooted in medical experience, which aims to fectiveness of a later free setting equivalent. reduce the appeal of drugs inside prisons (de- It must be pointed out that any treatment ef- mand reduction) [47]. Similarly, the issue of sub- fectiveness depends on the type of chemicals stance use initiation within jail is linked with used: methadone itself may possess low effec- drug availability inside, but also with the de- tiveness when administered without specific mand for drugs by addicted habitual users. In rules or objectives, merely to buffer drug-re- fact, when no treatment coverage is provided, lated discomfort. Predictably, the great major- untreated heroin addicts may initiate their jail ity of subjects will discontinue treatment after mates into the use of heroin. A prison setting discharge, if not earlier during the induction may be useful in improving the prisoners’s phase, so missing the chance to bridge the quality of life, but the control of addiction as transition from in-jail therapeutic initiation to a medical problem can only be achieved by outer stabilization. Even so, as many as 60% of a specific, individual-targeting intervention, patients who had gone through the induction which may also prove to be beneficial to the phase by discharge time went on to attend a whole prison community. maintenance programme lasting over the next Depending on whether treatment or ab- 6 months, and a further 30% did so for a shorter 202 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 203

period, at least saving themselves from relapse or at least a standard guarantee (average sta- overdose events, which often occur among bilization dosages). In any case, an average discharged agonist-free individuals. Addicted dosage provides protection against narcotic detainees should be empowered to attend the overdoses after discharge. Dose reduction and ongoing programme at the time of discharge, medically supervised withdrawal carried out so as to accomplish the current phase (wheth- in prison leave discharged patients at high risk er induction or stabilization), and, before that, of behavioural instability and overdose events. they should be given the opportunity to start It follows that these two procedures must be a structured programme while detained. The classified as malpractice. Even worse is the KEEP programme has been set up to implement practice of tapering methadone and adminis- this philosophy, so becoming the first experi- tering benzodiazepines as a means of buffer- mental methadone maintenance programme ing withdrawal; not only are patients deprived for NYC Rykers’ Island’s detained addicts. of their specific therapeutic coverage, but de- One early, major result is that of upgrading depressant polyabuse is favoured [29]. tention time as an opportunity to get detainees Some categories of patients should be started on addiction-specific programmes. As referred to a methadone maintenance pro- many as 85% of untreated detainees is under gramme as a priority, regardless of treatment treatment at discharge and they are referred setting (whether free or prison-based): this is to the local treatment facility [48]. On medical true of all addicts for whom enduring involve- grounds, a prison-based methadone mainte- ment with heroin may worsen or complicate nance programme is conceived to achieve two concurrent somatic, psychic or psychosocial major aims: on one hand, as with all catego- problems. ries of addicts, the prevention of recidivism Methadone-maintained addicts are more and relapse; on the other, the improvement of likely to enrol in anti-tubercular programmes, patients’ quality of life during detention. Fur- and to accomplish the therapeutic schedule of ther, a methadone maintenance programme’s chemotherapy [28]. objectives may be distinguished according Detained addicts who have undergone to scheduled detention time, and therapeutic specific treatment in prison are less likely to status at the time of imprisonment. Already have been sent back to prison or to have re- stabilized patients, whatever their discharge lapsed into substance use six months after re- schedule, should be kept on maintenance. lease [36]. The best protected subjects are those Patients incarcerated while in the induction who are still in treatment long after discharge, phase must reach a blocking dosage. Stabili- while treatment that is started in prison only zation is achievable as an objective even in a to be discontinued soon after discharge is not prison environment; despite this, the return to effective as a means of long-term relapse pre- freedom presents a new challenge for stabili- vention [17]. zation to continue. Methadone dose increase The option of having detention terms and other forms of therapeutic intervention shortened as long as one agrees to attend a may be required when freedom returns. In therapeutic programme might become a trend other cases, the loss of freedom may have been with a scientific basis. A spontaneous request a major stress factor for stabilized individu- for treatment is not predictive of better reten- als, so justifying dose increases or supplemen- tion rates, but it is true that subjects who apply tary interventions in a prison setting. On the for treatment spontaneously have lower re-in- whole, dose increases are often necessary and carceration rates, while treatment discontinua- feasible after release, while dose reductions tion due to lack of compliance is as likely as for or medically supervised withdrawal are to be their coerced peers. As a result, treatment as avoided. In fact, patients should be returned to an alternative to prison may prove effective in their original environment with an individual improving subjects’ compliance and retention guarantee of future stability (i.e. dosage not rates [1, 10]. Given that the effectiveness of lower than the previous stabilization value) treatment is not linked with treatment options, 204 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 205 which depends on a free choice, the motiva- ty; this is true even if some addicts discon- tion to enter treatment should not be consid- tinue when they return to freedom. Protection ered crucial to a positive outcome. In any case, against overdosing is equally effective during an application for treatment is at least partly imprisonment, as it is afterwards, as long as the result of do-or-die psychosocial forks, such treatment proceeds [22]. Discharged addicts as being sent away from home, breaking up should be tolerant to 60 mg/day at least. In no with one’s partner, being parted from one’s case should naltrexone administration be initi- children, or losing one’s job or income. ated, shortly before or shortly after discharge, Some of the advantages of methadone because this constitutes a risk condition for re- treatment are indirect. For instance, it not only lapse, and reliable relapse protection can only reduces the risk of seroconversion among se- be provided by agonist treatment. Similarly, it ronegative addicts, but also among the serone- would be reckless and pointless to start nal- gative non-addicted partners of seropositive trexone medication in prison, as it is suitable addicts. Similarly, the achievement of behav- in only a few cases, and needs to be evaluated ioural control in subjects who entered prisons when heroin is available (outside the jail). as heroin addicts makes it less likely that they will initiate non-abusing cell mates; this is far from being a secondary issue. In fact, as many 3.4 Naltrexone as 3-26% of detained addicts reported trying heroin for the first time during a previous period of detention. Globally speaking, 0.4-21% of Alternative measures are feasible as long addicted heroin injectors started using heroin as subjects are compliant with treatment rules. in jail. When compliance is lost, so is the guarantee that the measures adopted will build up and maintain the subject’s social function, or make 3.3 Safe discharge treated patients suitable for attempts of rehabilitation. The fork leading to social readjustment or Discharge-related overdoses are far more to self-perpetuating dysfunction is closely re- likely soon after discharge (during the first lated to the state of addictive dysfunction as two weeks) than later on [41]. This means that measurable by core addictive symptoms. Un- these events are not the result of a true relapse doubtedly, chronic or repeated acute intoxica- into regular heroin use, but are due to a sud- tion openly hinders social adjustment, but its den increase in craving, without any anticrav- disruptive weight is hierarchically inferior to ing lock, hitting individuals when they are not the addict’s cognitive, affective and behav- tolerant. For some substances, such as cocaine, ioural malfunctioning, all of which bias any a substance-free period may be useful in re- future project for the addict to attempt, by ducing craving. Conversely, heroin-free time shifting any effort towards the substance side. spent without any anticraving treatment is In fact, abstinence from drug-taking does not expected to result in a relapse. The discharge itself lead to the extinction of the addictive dis- of non-tolerant individuals, kept drug-free in ease. On the other hand, anticraving interven- prison after detoxification and not given any tions gradually bring abstinence into being in agonist treatment, is hazardous. Paradoxically, a spontaneous way, though substance use may the risks would be lower for subjects who had be persisted during the early period of treat- been using heroin throughout their detention. ment. Despite all the knowledge acquired so In no case should medical intervention raise far, agonist treatment is often regarded as a risks higher than those made inevitable by the sort of substitution for heroin, and the substi- underlying disease. tution of heroin-derived opioid damage pro- A maintenance programme continuing at vided by therapeutic opiates is mistaken for the time of discharge is best in terms of safe- a legal means for continuing an involvement 204 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 205

with narcotics. In reality, some opiates can be tolerant to opioids and calming their craving used for therapeutical purposes just because, at once. This objective is achievable by induc- for them, no positive reinforcement follows tion on methadone, with a dose of at least 60 exposure, so that they do not share any of the mg/day. rewarding subjective effects experienced with street opiates. In fact, one component of the rationale for their use is that their non-reinforc- 4. Conclusions ing property leads to an anticraving effect on subjects who have become hooked on abus- able street opiates. Addiction itself is likely to cause legal On the other hand, opiate antagonists are problems and confrontations with authorities. suitable for, and accepted by, mildly ill hero- Each legal incident may represent an addi- in addicts only, for whom social respectabil- tional problem, or, conversely, an opportunity ity or general health counts for more than the to start a therapeutic programme, hopefully a strong pleasure provided by the substance. specific one. Whatever the approach adopted, Their awareness that they would no longer we aim to rehabilitate our patients and allow sense heroin because of an opioid blockade them to get back to their natural environment, is enough to make them refrain from using it, bearing in mind that the best therapeutic despite their craving. In behavioural terms, we choice in any setting, prison included, is that can say these addicts are less than severely ill, which has proved most effective in a natural as witnessed by their willingness to adopt a setting. Agonist maintenance is currently the treatment strategy which does not itself con- option which gives the best guarantees in trol craving, while it sharply limits rewards. In terms of rehabilitation, relapse prevention and subjects who comply with naltrexone mainte- social adjustment goals. nance, and agree to undergo urinalyses, treat- Whether in public health or prison settings, ment has proved effective and safe. Retention addicts are sometimes given free access to in successful treatment has allowed naltrex- off-target facilities, which do not even aim to one-maintained detainees to benefit from al- achieve relapse prevention, but only to allow a ternative measures [4]. Heroin-addicted pa- drug-free condition, with no further guarantee rolees who spontaneously attend a naltrexone that abstinence will be maintained. maintenance programme, are more likely to The extension of methadone maintenance stay off heroin and less likely to be re-incarcer- inside prisons, in the form of a multiple phase ated within their first six months on parole [7]. programme, is meant to be a specific thera- These results are similar to those achieved with peutic intervention for addicted detainees [5]. free heroin addicts, but they only fit a small It does, in fact, offer the best way of controlling minority of heroin addicts, who suffer from a the core features of craving and relapse prone- mild form of the disease, and keep to a main- ness regardless of environmental and setting tenance regimen, which is something sharply differences. It is crucial to the aim of integrat- different from taking naltrexone shortly after a ing the prison system in the web of addiction detoxification procedure. treatment services, as heroin addicts are natu- A patient’s determination to take naltrex- rally prone to go through incarceration experi- one in the short term does not ensure a posi- ences. tive outcome. Generally speaking, there is no If we succeed in converting detention time safe conduct in having addicted detainees into therapeutic time, detention may actually discharged while on naltrexone; craving may become meaningful for criminal heroin ad- emerge violently when the substance is avail- dicts. able again after a period of isolation, and this heightens the risk of overdose. By the scheduled term for discharge, a therapy should have References been started that is capable of making addicts 1. Anglin M. D., McGlothlin W. H., Speckart 206 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 207

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Bulletin Stupefiants. 25: 36-47. 208 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 209 Side measures Psychotherapy, coun - Psychotherapy, selling Psychoeducation Counselling Counselling, Psychoeducation Counselling Psychoeducation, counselling Psychoeducation, counselling Psychoeducation Psychoeducation Psychoeducation Malpractice Dose reduction Tapering Quicker tapering Tapering No intervention, other psychotropics, detoxification No intervention Detoxification as non-addict Regard Detoxification only No intervention Dose reduction - - Rationale Maintenance of results Pursuit of stabilization accomplish Programme ment Pursuit of stabilization initiation Treatment Get the opportunity to have addiction treated course relapsing Treat in a relapses Prevent low-risk condition or de - relapse Prevent due pressant-addiction to undermedication abuse and treat Prevent due to undermedication into relapse or indirect heroin Not enough time to oper ate Advisable conduct Confirm maintenance Complete induction and transi - tion to maintenance at stand - dosages (80-120 effective ard mg/die) to schedule on according Taper Clinical monitoring to achieve stabilization dosages - Start or adjust agonist treat ment Start most suitable treatment (agonist maintenance as stand - ard) - Start agonist maintenance pro gramme Monitoring Start agonist maintenance with agonist plus clonazepam Start maintenance programme, cocaine use reevaluate No change in ongoing regimen Addiction phase Maintenance phase Agonist therapy, induction Agonist therapy, phase tapering Agonist therapy, to be Agonist therapy, stabilized under Active user, withdrawal naive addict Drug-free, - trea previously Drug-free, addict ted relapsed - trea previously Drug-free, ted, abstinent addict alcohol/BDZ Drug-free, addict abusing heroin-free cocaine abusing, Drug-free, involve - no major heroin ment at present be detained for days To Appendix 1. Guidelines for imprisoned methadone-treated addicts by addiction phase at incarceration Appendix 1. Guidelines for imprisoned methadone-treated 208 · CHAPTER 3.5 CLINICAL FOUNDATIONS FOR THE USE OF METHADONE IN JAIL · 209 Side measures - Low-potency neuro - leptics (chlorproma zine-like) or atypical antipsychotics Psychoeducation Counselling Valproic acid clonaze - acid Valproic pam, gabapentin - High-potency neuro leptics Psychoeducation. Brief psyshcotherapy Psychotherapy Psychoeducation and Pro-treatment overdose-preventive Psychoeducation Overdose-preventive psychoeducation - Malpractice Antagonists. Bdz admini Chronic stration Antagonists Dose reduction or Dose reduction detoxification Dose reduction, detoxification or nal - trexone Naltrexone Dose reduction and Dose reduction detoxification and Dose reduction detoxification - Rationale Anti-aggressive effect of effect Anti-aggressive agonists Anti-dysphoric proper ties of agonists Anti-catatonic properties of antagonists - Confirm ongoing pro gramme - Confirm ongoing pro gramme, in view of parole - Confirm ongoing pro term- of view in gramme, reduction Positive weighting of child issues custody-related Advisable conduct Agonist Maintenance Agonist Maintenance Antagonists Accomplish the ongoing phase to the next and proceed - Achieve stabilization and pro ceed to maintenance - Achieve stabilization and pro ceed to maintenance Have the detainee induced on blocking dosages (higher than 60 mg/day) by the time of discharge No change Agonist Maintenance Addiction phase Aggressive addict Aggressive Paranoid addict Addict Anaffective To be detained for weeks To To be detained for months To be detained for years To Scheduled discharged Non-scheduled discharge Addicted detainees with children Appendix 1. Guidelines for imprisoned methadone-treated addicts by addiction phase at incarceration Appendix 1. Guidelines for imprisoned methadone-treated 210 · CHAPTER 3.5 - Side measures Psychoeducation Antidepressants and/or mood stabi lizers Malpractice Let the patient choose Antagonists, Chronic Antagonists, Chronic Bdz administration drugs neuroleptic - Rationale Effectiveness of agonist Effectiveness of sponta regardless - for treat neous request ment Antidysphoric and of effects antiaggressive opioids Anti e.v. injection effects injection effects Anti e.v. of opioid Advisable conduct Propose therapeutic parole Propose Agonist Maintenance Maintenance programme Addiction phase Non-compliant addict Suicidal addict Somatically impaired Somatically impaired addict Appendix 1. Guidelines for imprisoned methadone-treated addicts by addiction phase at incarceration Appendix 1. Guidelines for imprisoned methadone-treated 3.6

Clinical Foundation for the Use of Methadone in Therapeutic Communities

M. Pacini, G. Giuntoli and I. Maremmani

1. Premise: addiction as a social disease for that attitude of conflict. Problems between the addicted person and the environment worsen as the core addictive symptoms wors- Addiction is born as a disease of the in- en, and may also fluctuate in response to the dividual. As with any individual condition, person’s current socio-economic status. Com- whether physiological or pathological, the en- paring equal levels of craving, poorer addicts vironment is affected as a result of the hijack- will enter into conflict with society and engage ing action of the disorder upon the individu- in criminal activities earlier than their richer al’s behaviours and attitudes. peers. Over time, however, the disorganizing Personal and family resources, affective influence of craving is bound to exert an equal- bonds and social skills are gradually exploited izing effect on rich and poor addicts, driving by addictive drives and become ways to ob- both categories towards the same kinds of so- tain supplies of the substance. Eventually, ad- ciopathic behaviours. dicts will tend to handle their skills and points All in all, even if drug addiction can be of strength primarily from a substance-related described in terms of a disease with social perspective, and will set aside original purpos- symptoms, it basically remains a disorder of es and dynamics. When substance supplies are an individual’s brain, upon which commu- enough, or faster channels are accessible, ad- nity- or individually-oriented feedbacks lose dicts leave their social life and productive com- their power to exercise any positive influence. mitments behind them, and any request com- On the other hand, society can play a crucial ing from the environment becomes a source role in favouring, and acting as a guide to, of stress and conflict. Both for the addicted treatment-seeking addicts. Far from stating person and their significant ones, engagement that social factors may be curative of the dis- with the substance stands as the main reason ease itself, what can be said is that potentially

211 212 · CHAPTER 3.6 Clinical Foundation for the Use of Methadone in Therapeutic Community · 213 effective therapeutic instruments, and chan- complish detoxification procedures, as a pre- nels leading to treatment options, are always liminary to initiation of the actual ‘therapeutic’ in society’s hands. From the moment a drug programme. This practice can be defined as a addict asks for generic help, society’s answer rehabilitative paradox. By limiting access to can make a difference, as long as it is based on psychosocial treatment to methadone-free pa- scientific evidence and provides strong sup- tients, the rehabilitative potential of patients port on cultural and interpersonal grounds is sharply reduced, so paving the way to the (laying the foundations for the ‘therapeutic al- failure of rehabilitation as a whole, no matter liance’). For any treatment-seeking addict, the if early results are encouraging, since no pro- first answer to society should be the chance to tection against predictable relapse is allowed enroll in an agonist maintenance programme. for. Methadone-treated addicts are more likely For patients who are absolutely resolute in re- to be willing to engage in psychosocial reha- sisting such a setting, harm reduction may be bilitation, which actually means a better treat- a temporary solution, mainly because of the ment outcome. hope that resistance to actual treatment may Especially if addiction treatment is con- be overcome as time passes. Therefore, any ceived, as it was originally, as rehabilitation low-threshold intervention should include of the individual’s free will and social func- dynamics which tend to promote the patient’s tions, methadone itself may be enough for transition to a higher threshold programme, in patients to achieve that objective, without any order to provide him/her with a higher grade additional psychosocial interventions. Beyond of achievable results. that, methadone has proved that it can func- ‘Community’ or ‘residential’ programmes, tion as a gateway for addicts to proceed along usually referred to as ‘therapeutic communi- rehabilitative programmes: in its presence, the ties’, need to be reclassified as psychosocial programme continues to be accessible, where- interventions, in order to clarify their ancillary as, without it, rehabilitation becomes awk- and complementary role to a disease (i.e. as ward or is reversed by re-emerging addictive providers of brain-centred intervention). symptoms. Authors already talk about “phar- From this standpoint, some residential pro- macologically assisted rehabilitation” [4, 6, 9, grammes are unacceptable on medical grounds, 10], but it would be even more correct to resort while others can be included in integrated treatment to the expressions “pharmacological access to programmes for categories of subjects displaying rehabilitation” or “pharmacological enabling basic critical features (e.g. the homeless, the men- of psychosocial treatment”. De Leon and col- tally ill). In other words, a residential setting may leagues state that residential treatment may represent the missing link between the disease and be useful in [1] providing relief from a state of treatment for those who also need social support drug-abuse and [2] allowing the implementa- outside their own setting and massive rehabilitative tion of a productive and socially constructive resources. A residential setting may also be a chance lifestyle, “for those who follow a methadone main- for the very severely ill to start treatment and build tenance program”. The same authors indicate up some motivation to continue along that path, as the effectiveness of methadone maintenance long as it detaches the patient from anti-therapeu- integrated with community treatment (“TC tic environmental factors (such as street life, family methods”), which is compared with metha- conflicts, poverty or geographic isolation). done treatment alone [2]. Otherwise, treatment modality 1 or 2 alone can be expected to have an impact on addic- 2. No-Methadone Residential treatment: tion that will vary according to baseline dis- A rehabilitative paradox ease severity. Mildly ill individuals, with no dual diagnosis, may show initial improvement by either treatment modality, and are regarded So far, methadone has been available with- as those who display the most satisfactory out- in therapeutic communities in order to ac- come. 212 · CHAPTER 3.6 Clinical Foundation for the Use of Methadone in Therapeutic Community · 213

The issue of an intention-to-treat perspec- least in their minds, under better control. In tive, that is, what retention rate can be expect- such a setting, preliminary detoxification is no ed with a subject whose illness is of average more than a gateway procedure to a relapse- severity when these modalities are applied, is prone condition, and is literally ‘craved for’ often neglected. by addicts, since it enables them to reverse Moreover, when improvement is achieved tolerance and intoxication, and start back on without the employment of pharmacological substance use at a lower initial expense. Nor is means, these results are regarded as “more a therapeutic community able to achieve any promising”, in line with a cultural bias. Any- therapeutic impact other than through inter- way, severely ill addicts, some of them possi- ventions that remain external to a core condi- bly with a dual diagnosis, may be retained in tion, such as detoxification in response to ad- therapeutic communities, but their outcome diction. tends to worsen over time, contrary to expec- When combining psychosocial interven- tations. This course it just the opposite of what tions with detoxification, the higher rate of happens to methadone-maintained subjects, detoxification achieved is the only result [1], whose outcome tends to improve over time while there is no impact in terms of relapse [8]. prevention. Thus, the detoxification of addicts with the help of psychosocial intervention is a choice 3. Therapeutic Communities as a chance that is not only without any relapse-prevent- for treatment ing value, but actually favours the relapsing course of addiction, as long as it goes along with the patients’ addictive way of thinking. In general, addiction treatment should al- The fact the addicts require some protect- ways be available within any residential set- ed environment to undergo successful with- ting claiming to be “therapeutic”. Further- drawal from therapeutic opiates (methadone, more, therapeutic communities may offer a buprenorphine) is likely to reflect average- bridge towards treatment to particular catego- to-high levels of craving. In a study on 215 ries of patients, by prompting them with basic methadone-maintained patients showing no psychosocial interventions (e.g. homing) right satisfactory response, only 44% managed to from the beginning. The benefit for patients is go through with withdrawal from methadone, the focus of this integrated approach: resourc- even though they were in a protected environ- es are organized in a hierarchical order such ment; in addition, as many as 21% applied for that the first one to become available is that methadone treatment again after reaching a which enables the patient to benefit from the methadone-free condition, and some dropout next one, too. The provision of psychosocial from treatment took place soon afterwards. A facilities to addicts with overwhelming crav- second look at these data indicates that some ings but no protection against relapse would patients simply feel pushed towards relapse, leave a gap between therapeutic premises and others end up achieving “no result” and go rehabilitative goals. back to their original treatment, and some Therapeutic communities should provide others become less likely to stay in treatment addicts with a safe and protected environment, after going through this unproductive detoxi- human support and isolation from stressful fication cycle [5, 7]. Certainly, dose-adjustment social challenges, in order to favour the onset and retention support would be more reason- of methadone treatment. able objectives of integrated psychosocial in- Otherwise, the only function of some thera- terventions than the withdrawal of medication peutic communities is to provide protected en- can ever be. vironments where addicts just search for tem- A variety of artificial environments may set porary relief and a break, in order to prepare up a possible venue for treatment: therapeutic for a new wave of substance use, this time, at programmes may take place in jail, residential 214 · CHAPTER 3.6 Clinical Foundation for the Use of Methadone in Therapeutic Community · 215 settings, specialized inpatient clinics or hospi- of non-therapeutic communities is that they tal wards. may delay complications and lethal events, Each environment matches the specific without having any fundamental impact on needs of some categories of addicted persons, the likelihood of relapse. At most, non-thera- so enhancing their motivation, minimizing at- peutic communities can be viewed as harm trition and favouring longer-term compliance. reduction, as long as no cultural bias against A unique treatment network should take specific treatment is inculcated in the patient’s on the task of directing different categories minds. Nevertheless, possible harm reduction of patients to specific treatment programmes, is usually counterbalanced by unrealistic ex- targeting the shared core symptoms of their pectations and the support given to blindness disorder, which is the common formal basis of over the dangers of relapse; these factors ham- their condition. per the self-help potential of relapsing patients and their significant ones’ reactions on such occasions. 4. A classification of therapeutic communities for drug addicts with respect to therapeutic instruments 4.3 Anti-therapeutic communities.

Some residential centres have explicit crite- 4.1 Therapeutic communities. ria which sound like a paradox not only with respect to addiction treatment, but even to harm reduction. Those centres actually admit Any community offers a specific treatment low-craving individuals, who have reached facility for drug addiction; an obvious instance a drug-free state spontaneously, and have ac- is agonist maintenance for opiate addiction. complished rapid detoxification procedures All phases of treatment should be viable in while queuing up to be admitted, and showing the residential setting (induction, stabiliza- respect for community rules. In other words, tion, maintenance). The only treatment phase severely ill addicts are excluded from treat- which should, preferably, be performed out- ment by the same criteria which should func- side is that of medication withdrawal. Besides tion as therapeutic. The adoption of evaluation treatment, various psychosocial interventions systems which only measure improvement in may be provided in order to improve produc- retained individuals, or do so at predetermined tive and social skills [3]. observation terms, are just a way of avoiding an intention-to-treat perspective. One could say that anti-therapeutic communities work 4.2 Non-therapeutic Communities. best for substance abusers who are not addicted. In fact, it is not uncommon for diagnosis to be based exclusively on the generic reason of Any community which offers some basic a request for admission based on ‘problematic facilities (e.g. a home, food, hygienic surveil- drug use’ rather than on a diagnosis that dif- lance, general health care, human support) but ferentiates between use, abuse and addiction. fails to provide specific treatments for addic- Addicts going through anti-therapeutic com- tion, inevitably fails to offer protection against munities run the risk of relapsing into more withdrawal. Communities which provide hazardous conditions, dying before admission psychopharmacological treatment to opiate or after discharge. Some prisons, considering addicts as a compromise between pharmaco- the trend towards withdrawing medication logical treatment and a methadone-free con- before scheduled discharge and the subse- dition are a recent example of a community quent trend towards lethal overdosing after that is non-therapeutic. The only advantage discharge, are one example of what an anti- 214 · CHAPTER 3.6 Clinical Foundation for the Use of Methadone in Therapeutic Community · 215

Table 1. Differential Characteristics between Therapeutic Communities

Therapeutic Non-therapeutic Anti-therapeutic Community Community Community Use of methadone during the programme Available Available Unavailable Opportunity to start methadone treatment inside the community Yes No No No reason for No reason for Reason for refu- Use heroin at entry into community refusal refusal sal Use of medications to detoxify patients inside the community Available Available Unavailable Use of methadone to detoxify patients inside the community Available Available Unavailable Opportunity to continue methadone maintenance Yes Yes No Dosage of methadone at programme Generally not termination modified Slow reduction No Methadone Overdose prevention at programme blocking dosa- None: None termination ges naltrexone Control over alcohol and CNS depressants Yes Yes No Enrolment of families, mothers with children, pregnant women Yes Yes No Enrolment of methadone-maintained pregnant women Yes Yes No Concomitant use of other substances No reason for No reason for Reason for refu- of abuse refusal refusal sal Mortality reduc- Aims of the treatment Treatment of tion, harm reduc- To cure patients the illness tion Programme ter- Outcome evaluation Follow-up Follow-up mination Not medically Philosophy Evidence-based Harm Reduction oriented, drug- medicine free

pharmacological treatments versus pharmacological therapeutic setting means. treatments for opioid detoxification.Cochrane Database Differential features of these three types of Syst Rev. 18:(4) CD005031. 2. DE LEON G., STAINES G., PERLIS T. E., SACKS S., therapeutic communities are reported in table MC KENDRICK K., HILTON R., BRADY R. (1995): 1. Therapeutic community methods in methadone maintenance (Passages); an open clinical trial. Drug Alcohol Depend. 37:(1) 45-47. 3. DEL REY A. J., KIRBY J., LANGROD J., LOWINSON J. References H., ALKSNE L. S. (1978): The therapeutic community as adjunct to methadone maintenance. In: SCHECTER 1. AMATO L., MINOZZI S., DAVOLI M., VECCHI A., ALKSNE H., KAUFMAN E. (Eds.): Drug Abuse: S., FERRI M., MAYET S. (2004): Psychosocial and Modern Trends, Issues, And Perspectives. Marcel Dekker, 216 · CHAPTER 3.6

New York. pp. 191-199. 8. MCLELLAN A. T., CHILDRESS A. R., GRIFFITH J., 4. GRÖNBLADH L., GUNNE L. M. (1989): Methadone- WOODY G. E. (1984): The psychiatrically severe drug assisted rehabilitation of Swedish heroin addicts. abuse patient: methadone maintenance or therapeutic Drug Alcohol Depend. 24 31-37. community? Am J Drug Alcohol Abuse. 10:(1) 77-95. 5. KAUFMAN E. (1979): The therapeutic community 9. RAVNDAL E., LAURITZEN G. (2004): Opiate users in and methadone: a way of achieving abstinence. Int J methadone-assisted rehabilitation one year and two Addict. 14:(1) 83-97. years after admission. Tidsskr Nor Laegeforen. 124:(3) 6. KORNOR H., WAAL H. (2004): Methadone dose, 329-331. treatment duration and heroin use in drug-assisted 10. WAAL H., KROOK A. L., WELLE-STRAND G., rehabilitation. Tidsskr Nor Laegeforen. 124:(3) 332-334. ESPEGREN O., HOLE R., LAZARIDIS K. B., 7. MAGURA S., ROSENBLUM A. (2001): Leaving SANDVOLD M., MOEN S., HOISETH T. (2001): A methadone treatment: lessons learned, lessons national model for drug-supported rehabilitation of forgotten, lessons ignored. Mt Sinai J Med. 68:(1) 62- opiate addicts. Tidsskr Nor Laegeforen. 121:(19) 2301- 74. 2305. 3.7

Clinical Foundation for the Use of Methadone in General Practitioner’s Office. Italy as Case Study A. Michelazzi, F. Vecchiet and I. Maremmani

1. Introduction cial complexity of heroin addiction is clearly fundamental here, and must be adequately addressed, without ever overestimating that Prescribing methadone as a replacement complexity to the point of demanding a level treatment became possible for the general of specialized knowledge beyond what is re- practitioner (GP) in Italy after a national ref- quired in providing a satisfactory response erendum in 1993 which modified the existing to the needs of the patient/addict. Opiate ad- legislation on drug use – law No. 309 – by al- diction affects individuals from all socio-eco- lowing GPs to make use of a therapeutic tool, nomic backgrounds, and may be further com- methadone, which had previously been pro- plicated by the co-presence of other addictions hibited to them. In Trieste and other Italian cit- such as polydrug dependence, as well as vari- ies, such as Cagliari and Arezzo, some pioneer- ous kinds of primary or secondary psychiatric ing experiments took place in this field during disorders. that period, and made a new treatment option Having said this, it is undeniable that of- available to heroin addicts [4, 8, 9]. It should be fering inadequate care to the patient or ex- stressed from the outset that this therapeutic cessively penalizing him/her, makes it more approach sees methadone as an effective tool likely that a ‘simple’ heroin addiction will for treating heroin addiction, and considers become polydrug abuse or a psychiatric dis- heroin addiction to be a chronic relapsing ill- order caused by the additional stress placed ness, which, as such, can be treated pharmaco- on the patient’s original condition. Hence the logically using the instruments made available importance of making sure this does not occur by accredited scientific research. through preventive measures of a pre-primary, The question of the medical and psychoso- primary or secondary nature. The safety and

217 218 · CHAPTER 3.7 effectiveness of replacement treatment at the 3) the concentration of a large number of maintenance doses that are used to detoxify addicts in one place can lead to bad feel- opiate addicts, and/or taper where possible, ings and protests from local residents; are now widely accepted by the international 4) there are often too few staff members em- scientific community [2, 3]. The general practi- ployed in the CDTS for them to be able to tioner is a professional who, after appropriate cope properly with the demand; training, is able to intervene rapidly, but also 5) the criteria for recruiting, monitoring and in a context that is unique for its therapeutic managing the treatments are often ex- potential [1, 5-7, 10-12]. cessively standardized and regimented, In the next section, alongside an account with rules that make it difficult for pa- of how the treatment protocol developed, we tients to become re-integrated in the so- shall describe in greater detail the advantages cial framework (rigid time schedules for of this model of care, which can be summa- methadone administration, difficulty of rized briefly as follows: obtaining take-home doses, suspension 1) The ‘large containers’ for drug addicts are of treatment after following repeated re- gradually emptied; lapses). 2) A doctor-patient relationship develops The disservice that follows often leads ad- which shows certain similarities to the dicts to accentuate certain aspects of a person- kind of relationship that develops in situ- ality already ravaged by drug dependence or ations involving other chronic relapsing the mental illness that is complicating diag- illnesses; nosis, while staff members end up playing a 3) A new level is established that functions role uncomfortably similar to that of a public as an interface with other levels of care, warden co-responsible for coping with a form so as to optimize responses. of deviance not manageable within the ‘clas- sic’ institutional circuits – psychiatric services, prisons, and drug rehabilitation communities. 2. The impetus for change The network of institutions becomes a trap, and the patient all too often falls victim to it. Their recognition of the severity, in medical The institutional arrangements for treat- terms, of the biological trauma inflicted as a re- ing addiction were laid down in what became sult of repeated self-administration of a toxic known as the Jervolino-Vassalli Law of 1990, substance, causing neurochemical changes in which decreed that the Central Drug Treat- the brain and eventually a neuro-psycho-en- ment Services (CDTSs) would be the only docrinal disorder – opiate dependence – led places where the addict could receive replace- a number of general practitioners in Italy to ment medication. The only replacement drug take advantage of the legislative modifications allowed at that time was methadone, and the to the existing Law on Narcotics – the Jervo- dosages and methods of administration varied lino-Vassalli Law (no. 309) – introduced by the – as they still do – from one treatment centre national referendum of 1993. These doctors to another. The result was, and still is in many began to treat patients suffering from heroin cases, that a large number of patients were addiction pharmacologically, using metha- herded together into a few institutional ‘con- done as their replacement medication. This is tainers’ where the service available to them a method of treatment which relies on a tool often becomes more like a disservice, for the endorsed by the international scientific com- following reasons: munity to treat an illness caused by the action 1) keeping a large number of addicts in the of a substance which has damaged the brain same place encourages an exchange of – damage which may prove to be irreversible abnormal ‘identities’; – and brought about related psycho-physical 2) the CDTSs themselves can end up becom- alterations. These are the alterations which ing a place for illegal drug dealing; are characteristic of the set of symptoms that 218 · CHAPTER 3.7 clinical foundation for the use of methadone in general practitioner’s office · 219

are peculiar to opiate addiction. Of course, as 3.1 How is the methadone prescribed? a form of medical treatment it had to have its own set of criteria and take on a form compatible with the institution that was already op- In Trieste, we chose to adopt the method of erative at the local level, the Central Drug Ad- prescribing referred to in Article 43 of Law 309 diction Service. (CTU 309/90), which does not entail keeping a register of supplies or a safe in which to store the drug. The reason for this decision was to 3. The general practitioner and treatment avoid keeping methadone in doctors’ sur- in the doctor’s surgery geries, which could have made it a target for burglaries. The patient collects the drug from the pharmacist with a prescription made out Opiate dependence is considered by the in the special prescriptions book for narcot- general practitioner to be a chronic relapsing ics, and then comes to the doctor’s surgery to illness, a chronic illness which, just like any drink the dose under GP supervision, as often other, can be treated but not necessarily cured. as is deemed necessary, depending on the pa- Like any relapsing chronic illness, there can, tient’s reliability and the level of stabilization of course, be relapses, and there may be inad- reached in the treatment. Prescriptions cannot equate patient compliance with treatment; it be made for more than eight days’ supply; may present complications of a psycho-social in any case, the patient has to drink the dose nature requiring an approach that is integrat- in front of the doctor at least once or twice a ed with other health services (such as the Drug week to allow assessment of tolerance levels. Addiction Service, the psychiatric services, Actually the law has changed, infact there is and social workers). It can be complicated by a modification of CTU 309/90 which requires other illnesses which either need preventive a therapeutic plan which must be done inside treatment or call for a prompt response from a pubblic service. This should assure a better a multispecialist perspective (e.g. that might collaboration between general practictioner involve liver disorders or infectious diseases). and public service. For optimum treatment, it is an illness which entails the close monitoring of certain biological parameters. 3.2 How are the urine tests organized? As we noted above, in Trieste, immediately after the 1993 Referendum, a few doctors, including the authors of this chapter, began to The frequency with which patients’ urine is prescribe methadone to heroin addicts, and tested is determined by the patient’s degree of set up an Association of General Practitioners reliability and the level of stabilization reached for a Local Response to Drug Addictions (the in the treatment. The urine samples must be Italian acronym was COMBATT), which soon produced in such a way as to allow staff to be became part of the Italian Association for Drug sure of the identity of the individual who pro- Addictions (SITD), an association which of- duces them. The patient can go to the Central fered scientific advice and support, and helped Drug Addiction Service, to a local health clinic to make the practice of prescribing methadone where GPs are on duty (see next paragraph), more widespread in Italy. or to the surgery of his/her own doctor, who The main questions that arose were the fol- will make sure that the sample is delivered to lowing: the laboratory. Some private laboratories offer this service, too. Actually we are reorganizing the presence inside the local primary health care clinics functionally to the new law. 220 · CHAPTER 3.7

3.3 Which patients can be entrusted to the Undoubtedly, it was, and still is, received care of a GP, and how many? opinion that the patient/addict is unreliable, and by nature inclined to take personal advantage of every situation he/she may come Initially, drug addicts came to be entrusted across. What the patient wants is a substance to the care of GPs almost by chance, as patients that will make him/her feel well, and not ill, happened to hear about the new opportunity without worrying whether this feeling of be- of being able to obtain methadone from GPs, ing well or ill coincides with what we mean by the only limit being the small number of GPs in a healthy state or a sick one. It is also received Trieste willing to carry out the treatment, and opinion that these patients are capable of ag- the condition that the patient was not allowed gressive behaviour if their requirements are to receive other treatments (from the Drug Ad- not met, and of illegal actions whenever they diction Services or another GP) at the same get the chance. time. Thanks to an increasingly effective level Our daily experience in our surgeries has of communication with the Central Drug Ad- led us to conclude, however, that as long as diction Service, and the experience gradually the number of patients on methadone in each gained by GPs, it became possible to establish surgery is kept small, it is possible to build a some basic guidelines in deciding whether a relationship based on trust, obviously as long patient could be taken into a GP’s care: as the patient’s needs’ are taken into account a) A maximum of 5 patients per doctor’s without preconceived ideas about the use surgery. of the replacement medication. By ’precon- b) Only patients with proven reliability in ceived ideas’ we mean the types of opinion terms of certain parameters (family more that often make health professionals insist on present than not, employment, no crimi- tapering methadone doses when the condi- nal charges pending, no serious mental tions are, or insist on low doses of methadone illness, no polydrug abuse). These are the when these are clearly not effective, or again, same parameters as those set out in the insist on the supervised administration of the Italian Ministry of Health guidelines (Cir- drug when the patient has a job and his/her cular No. 20, Gazzetta Ufficiale, Septem- working hours make it impossible to come ber 1994). to the doctor’s surgery every day. This does c) A consensus of opinion with the Drug not mean that the patient can have as much Addiction Service as well as with the methadone as he/she ‘wants’ or can be al- patient, about the treatment protocol: lowed to do what he/she ‘wants’. It means ap- dosage, type of treatment, method of plying the codes of good practice which have consignment, type of psychotherapeutic emerged from successful procedures that have and social support, method of biological been applied within the scientific community, monitoring, and so on. while respecting the needs and rights that are This collaborative approach led to our sign- respected as a matter of course when patients ing a Common Protocol with the Depart- have other disorders. Once the patient is being ment of Addictions, which made it possi- treated properly, many of the possible reasons ble to provide financial incentives for GPs he/she might have for behaving aggressively who were willing to treat patients with or engaging in illegal activity disappear, and opiate addiction in their own surgeries. he/she becomes a patient like all the others, with an increasing awareness of a patient’s rights. 3.4. How reliable is the patient/addict? What Clearly, there exists a sub-population of are the contro-indications to caring for drug addicts with severe psychiatric disor- them in the setting of a GP’s surgery? ders, or with histories of polydrug depen- What are the prejudices surrounding this dence which cannot easily be treated in a GP’s idea? surgery, and this is one of the reasons why a 220 · CHAPTER 3.7 clinical foundation for the use of methadone in general practitioner’s office · 221

multi-specialist approach is so important, al- ment with the heroin addicts who were suit- lowing collaboration with those departments able for this kind of treatment – fairly well-bal- that are able to give a more targeted response anced subjects with the occasional relapse into whenever this is necessary. With this in mind, heroin use, but with the backing of a reason- in Trieste we decided to set up an intermediate ably good social and welfare network. treatment level in the local primary health care The setting we chose to offer treatment clinics. in was that of a ‘normal’ surgery in a district health facility. The city of Trieste is divided into four health districts, each with its own 4. General practitioners and daily health clinic. We insist on the importance of practice in local primary health care the idea of normality, because we believe drug clinics addicts are normal patients who happen to need long-term treatment, just because they are suffering from a chronic illness. Patients of This chapter concern the situation before every kind can be found in a district surgery 2006. As already said, actually, the practice in- waiting-room, and so far there have been no side the local primary health care clinics is a unpleasant incidents, so the clinic’s daily rou- work in progress tine has never been disrupted. In 1993, as we mentioned above, there was The surgery for drug addictions is open a fundamental change in the approach to the for one hour a day from Mondays to Fridays, treatment of heroin addiction. At first, this with take-away doses given to patients for new approach to treatment – caring for heroin weekends or longer periods around public addicts as patients in GPs’ surgeries – seemed holidays. Whenever possible, we prefer to to be the solution to the problem, but, with give weekend doses of methadone to a family the passing of time, new and seemingly insur- member (whether a parent or grandparent, a mountable obstacles emerged to the idea of husband or wife) because, by doing so, a fur- basing a treatment programme for heroin ad- ther opportunity is opened up for the patient’s dicts solely on care in a surgery setting. resocialization. The opening time for surgery One of the obstacles GPs had to face – and tends to be from 12.30 to 13.30, to help patients it was all too frequent – was responding to who work, although a fixed time is obviously pressing demands from their most difficult a limit in itself for people with a job. The fact patients for help with problems unrelated to that a different doctor is on duty each day, the replacement drug regimen, such as issues and each of the doctors involved covers only related to psychiatric and psychological top- one hour a week, means that the nurse, who ics, and a need for counselling and advice over is present every working day, is absolutely vi- family matters, unemployment, and housing. tal for the continuity of care, as he/she is able Perhaps thanks to these more demanding to keep doctors informed about any problems patients, it was decided to try to deal with that arise with their patients on days when no some of these problems by setting up a surgery doctors were present (each doctor has a maxi- at the district level, as a kind of ‘intermediate’ mum of four patients in care). At this district structure situated between the surgery of a GP surgery level, the Common Protocol drafted as an individualized care setting appropriate together with the Central Drug Addiction Ser- to ‘stabilized’ patients, and the Central Drug vice involves very close collaboration in decid- Addiction Service, which was able to rely on ing treatment regimens. As soon as the district the expertise of specialists, and to dedicate level treatment programme was set up, how- special attention to the most problematic pa- ever, a number of problems arose. tients. Once a suitable place had been found For GPs: (a surgery located in one of the district health 1) An ever-increasing number of drug users clinics) and staff had been recruited (GPs and asked to be taken on by a GP for metha- nurses), we started to use methadone treat- done maintenance and medical care. 222 · CHAPTER 3.7

2) After an initial phase in which a large relationships, and rehabilitation in terms of number of GPs joined the treatment pro- education and training, which are useful for gramme (about fifty, which was a fifth reintegration into the workplace. of all the GPs practising in Trieste), the The opening in the winter of 1997-1998 of number levelled off, making it impossible four district surgeries for methadone mainte- to take on any more patients. nance did indeed solve the Central Addiction 3) We had thought that, after an initial treat- Service’s problem with the antisocial behav- ment phase of being stabilized in the dis- iour of its drug users; it also marked the be- trict surgery, the drug user would then be ginning of a long series of discussions between able to go back to the surgery of his/her GPs and the staff from the Central Service as GP, who would then continue to care for the best place for organizing supervision of the a patient who by then was already stabi- state of abstinence from illegal opioids on the lized by applying an effective treatment part of our patients. regimen. As laid out in the legal regulations (which, 4) The role of the health district would incidentally, require the individual’s identity therefore be to attract the drug users who to be determined without specifying how this were reluctant to talk about their problem should be done), the Central Service expected with their GP, since the district obviously strict monitoring of the urine tests, with sam- provides a more anonymous setting both ples produced under supervision. compared to the surgery of a GP, where By violating the trust which should exist the patient and his/her family may be between health professional and patient, this known, and to the Central Drug Addic- inflexible interpretation of the rules on toxi- tion Service, which, even if it is a special- cological testing led the patient to seek vari- ized service, may make the drug user feel ous ways of faking the urine sample, thereby marginalized. spoiling a relationship which had often been For the Central Drug Addiction Service: difficult to establish, and turning the urine test The high number of drug users coming to into a police-like inspection, with prompt pun- take their methadone every day in the Service’s ishment at the first sign of a positive result for two structures (one situated in the grounds of the presence of heroin. The punishment took the old psychiatric hospital, the other in a con- the form of prescribing rapidly tapering doses dominium on the outskirts of town) caused of methadone until toxicological tests for opi- two different kinds of problem: oids became negative again, and the tempo- a. the gradual depersonalization of the doc- rary impossibility of resuming replacement tor-patient relationship: the addict be- treatment. In practice, what happened was came a number, or a dose by which he/ the opposite of what is supposed to happen in she was identified; cases of relapse into substance abuse. b. the increasing exasperation of local resi- Instead of pondering over a relapse and, if dents with the uncivilized behaviour of possible, finding its cause, perhaps with the patients in the street outside the condo- help of improved psychological support, the minium, with brawling and drunkenness drug user is left alone in the worst state of in- causing disturbances. terior conflict, exposing him more than ever to By opening the district level surgeries, it the risks connected with heroin use (buying was hoped that the Central Drug Addiction methadone on the ‘grey’ market, if not actu- Service would be relieved of a lot of its work, ally giving up everything, and going back to so allowing it to improve its collaboration drug abuse). with GPs, and provide specialist support and In our opinion, the experience gained in the backup with respect to the various forms of re- district surgeries has given us an excellent op- habilitation necessary. These include psycho- portunity to provide the best possible care for social services, offering help in resocializing our addicted patients, not just from the medi- the drug user as regards family and personal cal point of view, but above all as regards the 222 · CHAPTER 3.7 clinical foundation for the use of methadone in general practitioner’s office · 223

patient’s family and social situation, and em- tient takes it for granted that he/she should tell ployment status. With the addition of this new us everything that has to do with a possible re- intermediate level, there are now three health lapse of his/her illness, ranging from a wish to structures providing care for this kind of pa- take the illegal drug again to the explanation, tient: if there is one, of why he/she actually did use 1) The Central Addiction Service; it again. The trust our drug-dependent patient 2) The district surgery; has in us is that we will always use the best 3) The GP’s surgery. treatment available in our therapeutic model, The path that a drug user might follow without making moral judgements about past (though not necessarily in this same order) be- behaviour in deciding whether to begin treat- gins with the Central Addiction Service, whose ment or continue it. staff members know the patient personally, are Is this model of care applicable at the Dis- familiar with the individual’s specific prob- trict surgery level? lems and set up the treatment plan (not limit- It might be pointed out that many of the ed merely to prescribing methadone). He/she functions currently performed by the dis- then moves on to the district surgery structure, trict surgery could be carried out in the GP’s where, as we have said, a fairly well stabilized surgery, if a more ‘constructive’ relationship patient can get away from the large numbers could be established with the specialists of the of users who congregate at the Central Service; Central Service. the final step is the GP’s surgery, where this At present, the aim of the District surger- kind of patient is taken on just like any other ies should be to facilitate this relationship and patient who has a chronic illness, and is cared provide training opportunities for the GPs who for with prevention measures, treatment, pe- are interested in treating drug users, while si- riodic check-ups and everything else that can multaneously promoting access to the District help him/her to keep well. Surgery for patients from the Central Service After five years’ experience with district who, once stabilized, can be discharged into surgeries, it is now time to draw some conclu- primary care and be looked after by their own sions. If drug addiction is an illness, and we GP. These aims are difficult to attain, howev- think it is, it must be treated as such. As with er. any illness, there is a professional, the doctor, One possible solution might be to formalize who has a job to do: this job consists of know- the GPs’ surgery-based treatment of addicts, ing all about that illness and finding out about by including it in the General Practitioner’s the best ways to treat it (we cannot talk about Contract. In this way, the function of the Dis- curing it, since we are well aware that we are trict Surgery would be transformed; indeed, dealing with a chronic illness which is subject it would no longer need to exist, since opiate to relapses). So it is unclear why this oppor- addiction would be considered simply as an tunity should be given to someone with heart illness, even if with its own specific character- disease, in the knowledge that we can improve istics, to be treated with adequate support pro- his quality of life without having to reproach vided by specialist services. him for eating too much or threatening not to prescribe any more drugs the first time he dares to smoke a cigarette (that is, if we have 5. Relations with the central drug succeeded in persuading him to give up smok- addiction services ing, and, anyway, how can we check whether he starts again?). Then there is a patient who has to be made aware of his condition. When In Trieste, the Central Drug Addiction Ser- we have become convinced of these starting vice was willing right from the outset to work points, then we have set up a doctor-patient re- together with new institutional agents, namely lationship that can be built on and reinforced. those GPs who had started treating heroin ad- The trust we place in our drug-dependent pa- dicts with methadone in their surgeries. In fact, 224 · CHAPTER 3.7 a dedicated team was soon in place within the 6. Conclusions Department for Addictions, with the specific task of collaborating with GPs. Then working groups were set up (consisting of GPs and The decision by primary care physicians in DAS staff) in which treatment protocols were Trieste to treat patients who are heroin-depen- designed both for the general practice setting dent in a general practice setting has undoubt- and district health clinics. edly been fruitful, both from the point of view The Central Service also offered to play the of the enhanced autonomy and ‘freedom’ of role of ‘institutional representative’ within our patients, and of the specialist institutions, who Local Health Agency, so as to deal with the have seen their caseload diminish consider- various problems as they arose, such as get- ably and have made valuable new allies in ting approval for the Agency Proposal on fi- their struggle to deal with opiate dependence nancial incentives for GPs working in the Dis- and so save lives. trict surgeries, mediating at the regional level In Trieste, it has been proved that this ap- to get methadone defined as a Class A drug (so proach is feasible, valid, and cost-effective. making it free of charge on prescription) and, Obviously, the forms that this kind of care may lastly, putting forward for approval by the Na- take can vary, depending on where it is being tional Drug Fund a project involving GPs’ sur- implemented. In any case, primary health gery-based activity with drug users. care providers in Europe, Australia and North At the moment, this kind of collaborative America are being utilized successfully as relationship still exists, with the various insti- methadone prescribers, while, in some coun- tutions having different roles and responsi- tries, buprenorphine has come to be preferred bilities in a shared care approach arrangement because of its greater ease of use. which seems to work. The crucial step forward is to recognize the The financial incentive is now an official fact that most heroin addicts have a chronic voice of the GP’s pay packet, specific for opi- illness, and overcome the prejudices that may ate addiction care. derive from a limited acquaintance with the Obviously, the Central Service is able to problem, prejudices that lead to attitudes of provide a variety of institutional responses blame and social exclusion towards addicts, depending on the patient’s needs, from pre- whether young or old, based on value judge- vention and low-level intervention, to reha- ments of a moral nature which have nothing to bilitation, support for incarcerated drug users, do with sound medical practice. social assistance (protected jobs, income support, and so on), and also organizing stays in residential therapeutic communities. References General practitioners are able to provide 1. COPPEL A., BLOCH-LAINE J. F., CHARPAK Y., SPIRA R. (2001): Evaluation survey of a Methadone a satisfactory, innovative response to patients Treatment share care programme between a without a lot of complications; with appropri- specialized clinic and a network of GPs. Heroin Addict Relat Clin Probl. 3:(2) 21-28. ate backup from specialist services, they are 2. DOLE V. P. (1994): What have we learned from three also able to care for more complex cases. In decades of methadone maintenance treatment. Drug Alcohol Rev. 13:(3) 330-338. district surgeries, for example, it is easier to 3. DOLE V. P. (1995): Methadone Maintenance. Comes manage a more complex case through a collec- of Age. In: TAGLIAMONTE A., MAREMMANI I. (Eds.): Drug Addiction and Related Clinical Problems. tive approach. Figure 1 and Table 1 show the Springer-Verlag, Wien New York. pp. 45-49. roles and functions of the various agents who 4. MAREMMANI I., MAZZESI S. (1999): Progetto Aliante: due anni di attività. Risultati e prospettive future. In: contribute to the institutional network in Tri- MAREMMANI I., MAZZESI S. (Eds.): Progetto Aliante este. e Giornate Aretine di Farmacotossicodipendenze 1997. Pacini Editore Medicina, Pisa. pp. 9-33. 5. MARTIN E., CANAVAN A., BUTLER R. (1998): A decade of caring for drug users entirely within general practice. Br J Gen Pract. 48:(435) 1679-1682. 6. MATHESON C., BOND C. M., FINDLY H. (1999): Prescribing and dispensensing for drug misusers 224 · CHAPTER 3.7 clinical foundation for the use of methadone in general practitioner’s office · 225

in primary care: current practice in Scotland. Family 10. ORTNER R., JAGSCH R., SCHINDLER S. D., Practice. 16 375-379. PRIMORAC A., FISCHER G. (2004): Buprenorphine 7. MC KEOWN A., MATHESON C., BONO B. (2003): A maintenance: office-based treatment with addiction qualitative study of GP’s attitudes to drug misusers clinic support. Eur Addict Res. 10:(3) 105-111. and drug misuse services in primary care. Family 11. VIGNAU J., BRUNELLE E. (1998): Differences Practice. 20:(2) 120-125. between general practitioner- and addiction centre- 8. MICHELAZZI A., LEPRINI R., CIMOLINO T., prescribed buprenorphine substitution therapy in MAREMMANI I. (2000): Cronistoria di una pratica France. Preliminary results. Eur Addict Res. 4 Suppl 1 medica. Alcologia. 12:(Suppl 2) 95-98. 24-28. 9. MICHELAZZI A., VECCHIET F., CIMOLINO T. 12. WEINRICH M., STUART M. (2000): Provision of (1999): General Practitioners and Heroin Addiction. methadone treatment in primary care medical Chronicle of a Medical Practice. Heroin Addict Relat practices: review of the Scottish experience and Clin Probl . 1:(2) 39-42. implications for US policy. Jama. 283:(10) 1343-1348. 226 · CHAPTER 3.7 4.1

Psychoeducation and Counseling for Methadone-Treated Patients I. Maremmani, G. Giuntoli and M. Pacini

The term ‘psychoeducation’ refers to a Psychoeducation can be implemented dur- form of communication that acknowledges a ing any phase of treatment and at any stage of patient’s role in understanding the nature and the disease, except for emergency conditions. coping with the dynamics of his/her disease. Although we have defined psychoeduca- The basis of this exchange is the patient’s trust tion as a form of acknowledgement, it is not to in the physician’s skill, which is the general be understood as an oral, interactive version basis of any patient-physician relationship in of an informative brochure about drug-related a treatment-request setting. The purpose of pathology. Rather, it is a strategy of interaction psychoeducation is to get the patient to stick which aims to guide a patient’s way of think- to treatment rules, while avoiding or actually ing away from a relapse-favouring setting to countering the power of misleading convic- a treatment-compliance context. Its true re- tions and drives. sult is not a series of elements of knowledge Psychoeducation may be applied to many about addiction, but a psychological exit route situations characterized by psychic disorders, from the conditioning effect of addiction on and is useful when the request for treatment is a patient’s cognitive orientation. Obviously, not expected to be consistent with the patient’s psychoeducation is unable to produce any insight, so that poor compliance and ambiva- substantial improvement in the absence of ef- lent behaviour can, as a rule, be expected soon fective treatment, so that it should not be con- after treatment initiation, whether stably or in fused with some sort of abstinence-oriented a fluctuating manner. No psychoeducation is psychotherapy or the encouragement of absti- feasible when no insight at all is present, nor nence on rational grounds [3]. can any be recuperated by means of treatment. Addicts are usually experts on the risks That is the situation in delusional disorders and effects of substances of abuse, and they and psychotic states in general. are often able to focus on the core dynam-

227 228 · CHAPTER 4.1 Psychoeducation and Counseling for Methadone-Treated Patients · 229 ics of their addictive disease when reporting taneous abstinence is mistaken for remission, their problem spontaneously (the instinctual and subsequent relapse is seen as a distinct drive to repeat a certain behaviour, the self- episode in their addictive history. Moreover, it perpetuating course of craving, the repercus- is just when patients achieve relief from acute sions on their life and goals, and the parasitic discomfort that their insight takes a step back, action upon the general level of pleasures and in the sense that they will probably claim they drives). On the other hand, addicts cannot pre- are able to handle their cravings and substance vent their relapsing behaviour, because that is use. Nor will they accept any relapse-preven- the main result of the strong instinctual drive tion perspective, as they will be blind to the towards substance use. It follows that the cog- concept of addiction as a chronic relapsing nitive setting of a typical addict will be that of disorder. Psychoeducation is a technique that ‘defending’ his/her freedom to use drugs, al- aims to promote a different view of the prob- though they have just agreed on the fact they lem and a higher level of insight. are slaves to their addiction. A typical addict Patients are quite likely to report un- will automatically reset in order to favour on- founded and misleading convictions about going use, rather than treatment maintenance their therapeutic needs and the characteristics according to standard rules, which are per- of therapeutic techniques [1, 2, 4]. This is the ceived as a form of control. In other words, typical situation that can be approached by they can be expected to react as if they were psychoeducation, as long as the acute phases avoiding becoming enslaved to treatment, and have been treated. No judgmental attitude were struggling to get back to free substance is allowed, since this kind of intervention is use again. based on a therapeutic alliance, and when pa- The automatic drive towards substance use tients perceive some moral orientation in the does induce a cognitive style, which can be the physician’s attitude, their trust is hampered, sole and crucial obstacle to allowing effective and hostility is favoured. treatment to continue long enough to produce A second important basis of knowledge in results. Besides, baseless opinions about ad- delivering psychoeducation is the question of diction are widely rooted in the cultural main- addictive ambivalence. Patients are torn apart stream, so that addicts are led to think that by two conflicting drives, a hypertrophic one their ideas are obvious, reasonable and scien- towards substance use, and a weaker one to- tifically founded. wards treatment compliance. Patients often Cultural prejudice is particularly harmful ask for some sort of permission or approval by because it runs parallel to the patient’s sponta- the doctor when making their decisions about neous ambivalence and disturbed insight. Psy- treatment, although it may be clear that they chiatric patients, in fact, are victims of cultural are doing the opposite of what has been pre- prejudice to a greater extent than other catego- scribed. This kind of attitude should not be ries of patients, who have enough psychic read as distrust or hostility, but simply as the balance to overcome it and defend them- combination of the two unequal drives. Physi- selves against their disease by complying with cians should count on their professional role treatments. to prevent the patient from feeling approval of Treatment-seeking patients are usually led their anti-therapeutic decisions and opinions. by current critical conditions (general impair- The negotiation of treatment and dropping out ment, withdrawal), but have partial insight; should not be a reason for heated confrontation in other words, they are aware that craving with the patient: conversely, physicians should is the main reason for relapse. On the other coolly maintain their therapeutic standpoint hand, they have no disease awareness, which and reject any compromise between correct means they deny any chronic risk of relapse treatment and addictive ambivalence [5, 6]. or lack of control: relapse and control are seen Psychoeducation is usually awkward at the as dependent on their current involvement in beginning, because of the patient’s resistance, drug use (in quantitative terms), so that spon- but it is an effective means for making the 228 · CHAPTER 4.1 Psychoeducation and Counseling for Methadone-Treated Patients · 229

Table 1. Treatment specificity

Disease-favouring thought Treatment-favouring feedback I must get off drugs: the solution is to stop and stay clean. This time I must find the way to do Stopping may be more or less awkward, but it the trick. I have tried so many times already only produces an interval between relapses, since – this time I mustn’t fail! that is the nature of the disease. I should move to another town, abroad maybe, As long as one craves for the substance, the change the whole environment. I will not be able environment can only make just a temporary to stop as long as I stay here. difference. Staying in a community is more of a challenge than entering it. On the other hand, isolation I must join some therapeutic community gives no guarantee of relapse prevention once back in the outside world, no matter how long one has been inside. I should get back to the old times, using it only Getting back to pleasant and controlled use is over the week-ends; that works as long as I don’t just what addiction makes impossible, once it go too far and put a limit on it. has developed. Starting with lower doses, or less frequently, is This time I may try using it from time to time as just a prelude to dose increases and regular use, the solution, I just have to be careful not to start which will actually happen more quickly than using it regularly… expected. Maintenance of control is just impossible once someone has become addicted. I want no substance at all in my body; therapies Medical drugs and drugs of abuse are radically are all the same; I do not want to get hooked on different, so that their being chemical in nature medical drugs! is not the key issue. Addiction will not allow you to. It is not reasonable to condemn oneself to certain failure when treatment can make improvement possible. Ill I must work it out by myself. people are not required to prove anything; so it is pointless for a patient to struggle in complete isolation. ‘Hitting the bottom’ may actually mean dying or losing any chance to move up again. When Maybe hitting the bottom is what I need to get the disease becomes more severe, it allows no the motivation to stop. higher insight or capacity to reverse its course; in fact, the real situation is usually the opposite, but combined with a higher chance of a tragic end. There is no chance that a medicine will change Certain behaviours can be controlled through my mind! pharmacological treatment. I am really motivated to stop using it. Medical Motivations have nothing to do with one’s capa- treatment is not necessary if you really try hard city. Addiction does not allow people to go ahead enough… with their projects for staying clean.

doctor’s leading role sounder. If the ‘human channelled towards effective treatment, in their touch’ can be crucial in persuading the patient own interest [1]. If these premises are fulfilled, to decide to ask for treatment after the resolu- the therapeutic response is bound to convince tion of acute symptoms, cognitive conditioning patients that they have been well advised. Psy- by psychoeducation is crucial to getting them choeducation may not be successful at the first 230 · CHAPTER 4.1 Psychoeducation and Counseling for Methadone-Treated Patients · 231

Table 2 . The concept of loss of control and the irreversible nature of relapsing behaviour in addictive diseases

Disease-favouring thought Treatment-favouring feedback Addiction may be impossible to heal, but metha- As long as I take methadone I am addicted. done treatment can keep it under control and allow you to lead a normal life. We do not actually know whether life-long I cannot continue treatment my whole life treatment is needed for every patient. In any long! case, treatment is the only reasonable way of improving the chances of healing. Addiction is itself a life-long problem. Methadone If I start taking methadone, I will become a allows it to be kept under control, throughout chronic addict. one’s life if necessary. It is pointless to take methadone, If I want to use Methadone treatment can influence one’s will heroin, I can do it all the same. and put a stop to craving. Addicts want to quit by definition, and the reason When you are really motivated, you don’t need why the want to is that they cannot do it in an any methadone. automatic way, because of addiction. Addicts usually stop from time to time. Metha- I once stopped using drugs for long, and I needed done treatment aims to prevent relapses, rather no methadone at the time ! than allowing drug use to be interrupted. Addiction means being incapable of carrying I am not an addict, I have been clean for many out an intention to stay clean. Stopping is ea- days. sier than it seems, whereas avoiding relapses is impossible. To regain self-control while on treatment is the I managed to stop, so I cannot be considered prime goal of treatment, and success depends an addict. on that. Methadone treatment is the only factor that dif- ferentiates between being with or without stable Do you think I am not using heroin just because control (even if abstention is not complete); all I am taking methadone? the rest follows, and derives from the acquired freedom to choose. Tolerance to methadone and susceptibility to What if I stop taking methadone? I would be withdrawal is a feature of treatment and not of sick ! addiction. Getting off methadone is common among addicts, who hate going through methadone Once you start taking methadone, it becomes withdrawal because it takes longer. The reason impossible to stop. is that methadone is not craved for. The urgency to get off methadone is usually a symptom of disease severity. I don’t want to depend on methadone for the whole of my life ! The alternative is to depend on the disease. Treatment duration is a key factor to reducing the It has been a long time since I started taking likelihood of relapse after treatment termination. methadone, so now there is no way I could have A good response to treatment is not predictive a relapse …hasn’t the time come for me to get of successful abstinence after treatment termi- off treatment ? nation. Craving is a characteristic of heroin, and not of If I stop using heroin and start taking methadone, methadone. The chronic use of methadone does that’s just another drug problem ! not induce any methadone addiction, while it allows the remission of heroin addiction. 230 · CHAPTER 4.1 Psychoeducation and Counseling for Methadone-Treated Patients · 231

There must be a way to get rid of addiction without any maintenance treatment ! To date, no such method has been discovered. Gradual tapering makes no difference, the result My intention is to taper gradually and eventually of treatment termination is a higher likelihood get off methadone. of relapse. The only known factor allowing disease control Methadone helped me, but I managed to quit is methadone treatment. One’s own resources can because I decided to do so. develop in the room left free by craving.

attempt. However, when dropouts come back very beginning of treatment, will lead ambiva- to ask for treatment, they have implicitly ac- lent patients to ineffective treatment attempts, cepted the doctor’s role, as long as they had far from any actual healing perspective. perceived it as sound and specific in the past. The issues of psychoeducation correspond Patients may adhere to treatment on the basis to what the doctor knows about the biology of their healthy mental functions, while their of the disease. A golden formal rule is that of unhealthy functions will be restored later by adapting the patient’s resources to the rules of ongoing treatment. Treatment negotiation, as effective treatment, rather than adapting the well as a patient-specific approach from the latter to the patients’ requests or behavioural

Table 3. Mechanism of treatment functioning and the course of response

Disease-favouring thought Treatment-favouring feedback Pleasure is obviously the key to substance use, but treatment does not deal with the pleasure I do like the effect of drugs, so I will never be that derives from using substances, and is not able to stop. hampered by itspositive relationship with the effects of the substance. Addicts relate to certain environments because I have had a relapse because the environment is of their addiction; addiction pollutes social rela- hostile towards me. tionships in a predictable way. The environment is not the key at all. ‘Reasons’ do not apply to addiction, which is a self-perpetuating phenomenon. Reasons may The reason why I started was... come into play before addiction develops, but The reason why I got hooked on it was… afterwards they don’t influence its course, positively or negatively. This kind of problem is centred on the head – in The problem is with my mind concrete terms, the brain – and that is where therapy counts. The real problem is that I can’t always find as much of the drug as I need; even when I succeed, Effort is a consequence of addiction. If any balan- it takes me a huge effort to get hold of it. ce were possible, the effort would be far less. A choice implies the capability not to perform It is my choice to stop or continue… a behaviour, which excluded in cases of addiction. 232 · CHAPTER 4.1 inclinations. The patients should develop the ance of Methadone Advocates, for instance). idea that the doctor has some specific, sound The following issues may be discussed in and independent know-how about treatment. psychoeducational terms: a) what is treatment Patients should give up the idea that their specificity (table 1); b) the concept of loss of opinions are as important as the doctor’s, in a control and the irreversible nature of relaps- peer-to-peer exchange of views. Later on, pa- ing behaviour in addictive diseases (table 2); c) tients feel relieved when they can count on a mechanisms of treatment functioning and the physician who will not be influenced by their course of therapeutic response (table 3). Mis- own inappropriate suggestions or anti-thera- conceptions are listed in the left-hand column, peutic insistence. Arguments may be common whereas the psychoeducational feedback to be in the early phases, but when patients choose given to the patient appears in the right-hand to comply with treatment, this transition marks column. a radical reversal of their cognitive setting. The doctor should reject any view according to which ‘believing’ in some treatment will References make it effective, which mirrors the patient’s misconception that control over addiction is 1. HAGMAN G. (1994): Methadone maintenance made possible by one’s own will. Patients usu- counseling. Definition, principles, components. J ally think of standard treatment as consisting Subst Abuse Treat. 11:(5) 405-413. 2. KAHAN M., SUTTON N. (1996): Opiate-dependent of foolish and superficial ways of approaching patients receiving methadone. How physicians their problem, and will claim that their view- should manage therapy. Can Fam Physician. 42 1769- 1778. point on the disease is the best, because they 3. STARK M. J. (1989): A psychoeducational approach are the ones who are addicted. to methadone maintenance treatment. J Subst Abuse Treat. 6:(3) 169-181. With respect to counselling, psychoeduca- 4. WESTMAN W. C. (1974): A solid front: unity, timing, tion can be seen as a theoretical model targeting goal oriented counseling break drug addiction cycle. J Rehabil. 40:(3) 15-17. the cognitive distortions of addiction, which 5. WOODY G. E. (2003): Research findings on can also be addressed directly through coun- psychotherapy of addictive disorders. Am J Addict. 12:(2 suppl) 519-526. selling sessions. Moreover, psychoeducation 6. WOODY G. E., BLAINE J. D., ONKEN S. L., may be used as the formal basis of counselling MCLELLAN A. T., LUBORSKY L., O’BRIEN C. P., KLEINMAN P. H., TODD T. C., MILLMAN R. [3]. The sites that spread correct knowledge B., KANG S. Y., KEMP J., LIPTON D. S., CRITS- about addiction treatment techniques can be CHRISTOPH P., BEEBE K. L., CONNOLLY M. B. (1990): Psicotherapy and counseling in treatment of viewed as a virtual means of psychoeducation drug abuse. NIDA, Rockville,MD. (Addiction Treatment Forum or National Alli- 4.2

Motivational Interventions for Methadone-Treated Patients

A. Kantchelov

1. Introduction

fective method for helping clients to achieve Since the late 1980s the development of behavioural change. It presents an outline of Motivational Interviewing and its adaptations the theoretical background, outcome research, has been acknowledged as the most important rationale for use and state-of-the-art practical recent advance in the field of addiction treat- methods for implementing motivational inter- ment. Effective strategies, brief interventions ventions that can be integrated into the MMTP and structured approaches have been devel- context and daily work. oped to enhance client motivation, while cli- This paper is closely based on a thorough nicians’ interest in motivational interventions view of the research literature and on well- has substantially increased. Surprisingly, it grounded empirical findings; it is organized seems that theseinterventions have still not within the Transtheoretical Model, which of- been given an adequate role in MMT pro- fers an integrative framework for conceptu- grammes. alizing and implementing behaviour change This paper aims to provide the best prac- among people who have a problem of sub- tical guidelines to methadone maintenance stance abuse. programme managers, programme planners, It presents a motivational communication counsellors and clinical staff, to make them style for working with clients, based on the aware of the power of motivational enhance- most advanced technologies, which have been ment strategies, to provide them with a taste developed in the field of psychosocial addic- for, and understanding of. the spirit of the mo- tion treatment and the enhancement of moti- tivational style of interacting with clients, and vation and behaviour changes, and it is spe- to enrich their clinical view with a highly ef- cifically designed to match the clinical needs

233 234 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 235 of an MMTP. alone may only be effective for a minority of There are many ways in which motivational patients, and argued that the addition of coun- concepts, principles and interventions can be selling, and of medical and psychosocial ser- applied in an MMT setting. The main aspects vices brought dramatic improvements over and practical implications of the motivational the effect of methadone alone. approach in an MMT are discussed with em- phasis on style, spirit, strategies and ways of incorporating it into MMTP clinical work and 3. Theoretical framework: the into the treatment model. The principles, strat- transtheorethical model egies, methods and interventions described here are explicitly intended to help clinicians facilitate change in MMT clients. They can be In recent times, the treatment of addictions used as a stand-alone treatment, can be inte- has been dominated by the so-called Transthe- grated with a broad range of other treatments oretical Model (TTM), proposed by Prochaska and strategies, and can also be used to prepare and DiClemente [20, 21, 22, 23] and revised by a motivational foundation for other therapeu- Prochaska et al. [24, 25] and DiClemente and tic approaches within MMT. Prochaska [6]. The model is ‘transtheoretical’ in that it is not based on any school of therapy, but offers an integrative framework for under- 2. The role of counselling and standing and intervening with human inten- psychosocial services in MMT tional behaviour change and practical guidelines, irrespective of the therapist’s favoured approach. The model proposes three organiz- A number of studies have stressed that ing constructs: the stages, the processes and although methadone maintenance treatment the levels of change. has powerful effects in terms of stabilizing clients, keeping them in treatment and making them available for psychosocial interven- 3.1 The stages of change tions, a purely pharmacological approach will not be sufficient for most patients, and better outcomes are associated with higher levels of The stages represent the dynamic and mo- psychosocial treatments [4]. tivational aspects of the process of change over The best treatment retention percentages time. Five sequential stages have been identi- and the best outcomes, evaluated in terms fied; people pass through each of these in the of improved social functioning, were seen in course of changing a problem. These stages the initial methadone clinical trials [7] in pro- seem to apply equally well to self-change and grammes characterized by the careful screen- to therapy-assisted change. In or out of thera- ing of clients, adequate dosing policies and ex- py, people seem to pass through similar stages tensive adjunctive services. The extent to which and employ similar processes of change: counselling is an important part of MMT was 1. Precontemplation: During this stage, indi- also addressed by Ball and Ross [1] in their cor- viduals are unaware of the nature and ex- relational study. They noted that both staff and tent of a problem needing to be changed, patients viewed counselling as the most im- or are unwilling to change problematic portant component of the rehabilitative aspect behaviour. of methadone treatment. Their results strongly 2. Contemplation: In this stage people are suggest that MMTPs which delivered more aware that a problem exists and have got counselling tended to have better outcomes. to the point of seriously thinking about The highly positive effect of psychosocial ser- overcoming it, but have not yet made a vices was clearly confirmed by McLellan et al. commitment to take action. [13].These authors concluded that methadone 3. Preparation: This stage constitutes a reso- 234 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 235

lution of the decision-making task; in this [6]. Generally speaking, cognitive strategies stage, individuals intend to take action, should be more appropriate to clients in the and there is a commitment to a plan for early stages of change, and behavioural strate- change to be implemented in the near fu- gies should be more appropriate at the action ture. stage of change [2]. 4. Action: This is the stage when the plan for change is implemented, active coping is initiated, and the actual change in 3.3 The levels of change behaviour occurs. This is when individuals modify their behaviour, experiences and/or environment so as to overcome Individuals have multiple problems that their problems. interact with the process of changing any sin- 5. Maintenance: In this stage, already gle addictive behaviour. The concept of levels achieved behaviour change is sustained, of change incorporates the realization that and people work to integrate it into their individuals are at different stages of change lifestyle, to stabilize behaviour, to prevent with respect to different problem areas, and any relapse and consolidate the gains at- that addictive behaviour always occurs within tained during the action stage. various interrelated levels of human function- Once change has become completely inte- ing. These levels are organized hierarchically grated into his/her lifestyle, an individual can as follows: symptom/situational, maladap- exit from or terminate this process of change. tive cognitions, current interpersonal conflicts, family/system problems, intrapersonal con- It is normal to go through this whole process flicts. several times before a stable form of change is The Transtheoretical Model provides a achieved. Relapse is viewed not necessarily as foundation for the development of practical a failure, but as a normal, predictable part of the strategies and interventions in countering ad- process, and as a stage of growth with its own dictive behaviours. opportunities. Working with patients during the period when a relapse is likely is essential to ensure continued change [8]. 3.4 The concept of motivation

3.2 The processes of change Motivation plays an important role in people’s decisions to change their behaviour and substance use. It has been defined as “the prob- The processes have been derived from ability that a person will enter into, continue, many diverse theories of behaviour change and adhere to a specific change strategy” [5]. and are at the heart of the Transtheoretical A key dimension of motivation is adherence to Model. Ten processes have been reliably iden- or compliance with a change programme, so tified: raising of consciousness, self-re-evalu- motivation may be thought of as the probabil- ation, environmental re-evaluation, dramatic ity of a certain behaviour. relief, social liberation, self-liberation, counter- Miller and Rollnick [17] suggest that moti- conditioning, stimulus control, reinforcement vation should not be thought of as a person- management and helping relationships. ality problem, or as a trait that a person car- The processes are intended to clarify the ries through the counsellor’s doorway. Rather, type of activity that is initiated or experienced motivation is a person’s present state or stage by individuals in modifying their behaviour. of readiness for change, which may fluctuate According to the model, particular processes from one time or situation to another. Most im- employed at particular stages are responsible portantly, a person’s motivation can be influ- for movement through the stages of change enced by attuned clinical interventions and is 236 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 237 affected by how he or she is treated by clinical change is possible. staff. Thus, increasing motivation becomes an * Preparation stage — getting started: The inherent and central part of the professional’s main task here is to help the client de- task. It is the counsellor’s responsibility to velop plan for change that is acceptable, motivate — to increase the likelihood that the accessible, appropriate and effective, and client will follow a recommended course of ac- determine the best course of action to tion directed towards change. take in seeking change. There is no doubt that for patients in MMT * Action stage — reaching change: The the intake of an adequate dose of methadone goal here is to help the client implement is of dominant importance, but it is also clear the action plan by achieving change. that the success of methadone programmes is * Maintenance stage — stabilizing closely related to strictly following a therapeu- change: Helping the client maintain the tic regimen and programme rules, while ap- achieved change, integrate it into his/her plying a range of psychosocial interventions. lifestyle, prevent relapse and keep the cli- The participation of patients in these activities ent in treatment are the main goals for the is based on their level of motivation to do so therapist at this stage. [28]. * Relapse — stop and start again: The counsellor’s tasks here are to help the person avoid discouragement and demoraliza- 3.5 Stage-specific interventions tion, reframe the relapse crisis and help him/her see the crisis as an opportunity to learn rather than a failure, and to initi- What motivates people to engage in treat- ate another change attempt to change by ment, progress in therapy and continue to renewing the processes of contemplation, progress after therapy is receiving interven- preparation, action and maintenance. tions and treatments that match their current stage of change. Motivational interventions are a powerful tool in assisting clients to move 3.6 Assessment of stage status through the stages of change. They are invalu- able and most appropriate for the early stages of precontemplation, contemplation and prep- Several different methods of measuring a aration, and again in the relapse stage. Indi- client’s stage of change are now avialble. Of viduals in the action and maintenance stages these, the most commonly reported in the cur- may need skills, training in addition to moti- rent literature are the Staging Algorithm [24] vational strategies (Table 1). and the University of Rhode Island Change * Precontemplation stage — building Assessment (URICA) Scale [12, 11], along with readiness: A person in the precontempla- the Stages of Change Readiness and Treat- tion stage needs information and feed- ment Eagerness Scale (SOCRATES) [16] and back to raise his/her awareness of the the Readiness to Change Questionnaire [27]. problem and of opportunities for change. Given that the client’s readiness for change The major strategy here is to raise doubts tends to fluctuate, the therapist’s judgment of in clients about the harmlessness of their the client’s current stage of change based on substance use patterns, and increase the material presented during the counselling ses- clients’ perceptions of risks and problems sion is of indispensable value. with their current behaviour. * Contemplation stage — increasing commitment: The key here is to help the con- 4. The Method templator think through the risks of the problem behaviour and the potential benefits of change, and to instil hope that The motivational approach begins with the 236 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 237

Table 1: Appropriate Motivational Strategies for Each Stage of Change

Client’s Stage of Change Appropriate Motivational Strategies for the Clinician Precontemplation Establish rapport, ask permission, and build trust. Raise doubts or concerns in the client about substance- The client is not yet considering change using patterns by or is unwilling or unable to change. Exploring the meaning of events that brought the client to treatment or the results of previous treatments Eliciting the client’s perceptions of the problem Offering factual information about the risks of substance use Providing personalized feedback about assessment findings Exploring the pros and cons of substance use Helping a significant other intervene Examining discrepancies between the client’s and others’ perceptions of the problem behaviour Express concern and keep the door open. Contemplation Normalize ambivalence. Help the client “tip the decisional balance scales” toward The client acknowledges concerns and change by is considering the possibility of change Eliciting and weighing pros and cons of substance use but is ambivalent and uncertain. and change Changing extrinsic to intrinsic motivation Examining the client’s personal values in relation to change Emphasizing the client’s free choice, responsibility, and self-efficacy for change Elicit self-motivational statements of intent and commitment from the client. Elicit ideas regarding the client’s perceived self-efficacy and expectations regarding treatment. Summarize self-motivational statements. Preparation Clarify the client’s own goals and strategies for change. Offer a menu of options for change or treatment. The client is committed to and planning With permission, offer expertise and advice. to make a change in the near future but Negotiate a change--or treatment--plan and behaviour is still considering what to do. contract. Consider and lower barriers to change. Help the client enlist social support. Explore treatment expectancies and the client’s role. Elicit from the client what has worked in the past either for him or others whom he knows. Assist the client to negotiate finances, child care, work, transportation, or other potential barriers. Have the client publicly announce plans to change. 238 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 239

Table 1: Appropriate Motivational Strategies for Each Stage of Change

Client’s Stage of Change Appropriate Motivational Strategies for the Clinician Action Engage the client in treatment and reinforce the importance of remaining in recovery. The client is actively taking steps Support a realistic view of change through small steps. to change but has not yet reached a Acknowledge difficulties for the client in early stages of stable state. change. Help the client identify high-risk situations through a functional analysis and develop appropriate coping strategies to overcome these. Assist the client in finding new reinforcers of positive change. Help the client assess whether she has strong family and social support. Maintenance Help the client identify and sample drug-free sources of pleasure (i.e., new reinforcers). The client has achieved initial goals Support lifestyle changes. such as abstinence and is now working Affirm the client’s resolve and self-efficacy. to maintain gains. Help the client practice and use new coping strategies to avoid a return to use. Maintain supportive contact (e.g., explain to the client that you are available to talk between sessions). Develop a “fire escape” plan if the client resumes substance use. Review long-term goals with the client. Recurrence Help the client reenter the change cycle and commend any willingness to reconsider positive change. The client has experienced a recurrence Explore the meaning and reality of the recurrence as a of symptoms and must now cope learning opportunity. with consequences and decide what Assist the client in finding alternative coping strategies. to do next. Maintain supportive contact.

assumption that the responsibility and capac- and employing motivational strategies to mo- ity for change lies with the client. The style and bilize the client’s own resources in achieving strategies of the interventions are based on the change. use of empathy and warmth, not authority or power, and developing non-judgmental and collaborative therapeutic interactions. Increas- 4.1 Motivational interventions ing client motivation is seen as a central part of the clinician’s task. The counsellor works to elicit the client’s own concerns. When the cli- A motivational intervention can be defined ent (rather than the counsellor) formulates the as any clinical strategy or method designed to reasons for change, the client’s internal moti- enhance client motivation for change. Motiva- vation is harnessed, and he/she is more ready tional interventions can involve a variety of for change. Most of the work to be done in- approaches, ranging from brief interventions, volves exploring a client’s ambivalence about client assessment and feedback, counselling, change, matching interventions to the client’s single or multiple sessions, to formal struc- current stage and level of readiness for change, tured therapy, which may be thought of as ele- 238 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 239

ments of a continuum of care. The focus here is rather than a division of roles between expert on interventions designed to enhance intrinsic and recipient. In MI the counsellor does not as- motivation and readiness for change. sume an authoritarian role, and avoids teaching and telling clients how to change or what 4.1.1. The FRAMES approach they should do; rather, he/she works actively towards building a commitment to change. Miller and Sanchez [15] analyzed the con- Responsibility for change is left to the client. tent of brief motivational strategies and de- It is the client’s task, not the counsellor’s, to scribed six counselling elements that appeared articulate and resolve his/her ambivalence. to be the commonly used ‘active ingredients’ The counsellor seeks to create a positive at- in effective brief interventions. These are sum- mosphere that is conducive to change and is marized in the acronym “FRAMES”: directed to helping the client examine and re- * Feedback regarding personal risk or im- solve ambivalence. pairment is given to the individual fol- Readiness for change, as well as resistance lowing an assessment of substance abuse and denial, are not viewed as a trait in the cli- patterns and associated problems. ent, but as a fluctuating product of the interper- * Responsibility for change is attributed sonal interaction between client and therapist, squarely and explicitly to the individual. and feedback regarding therapist consulting * Advice about changing (reducing or stop- behaviour. The overall goal is to increase the ping) substance use is clearly given to the client’s intrinsic motivation, so that change client by the clinician in a non-judgmen- arises from within, rather than being imposed tal manner. from without. When this approach is enacted * Menu of self-directed change options and properly, it is the client who presents and voic- treatment alternatives is offered to the cli- es the arguments for change, rather than the ent. therapist. The appearance of a motivational * Empathetic counselling, showing interviewing session is quite client-centred, warmth, respect, and understanding, is yet the counsellor maintains a strong sense of emphasized. Empathy entails reflective focus, purpose and direction, along with clear listening. strategies and skills for pursuing that purpose, * Self-efficacy or optimistic empowerment and actively chooses the right moment to in- is engendered in the person to encourage tervene in particular ways at crucial moments them to change. [17]. There are five broad clinical principles in MI that give the context regarding the‘why’ of 4.2 Structured motivational intervention practice. These are: express empathy, develop models discrepancy, avoid argumentation, roll with resistance, support self-efficacy. They underlie the specific practical strategies (‘how-to’ 4.2.1 Motivational interviewing elements): ask open-ended questions, listen reflectively, affirm, summarize, and elicit self- Motivational Interviewing (MI) is an ap- motivational statements (Change Talk) (Table proach designed to help clients reach a deci- 2). A fundamental goal in MI is to have clients sion and build commitment to change. It is a present and voice arguments for change. One client-centred, directive method for enhancing major task of a counsellor is that of leading the intrinsic motivation to change by exploring therapeutic process in a way that facilitates cli- and resolving ambivalence [18]. ents to express self-motivational statements. The spirit and style of MI are central to Hearing oneself state the reasons for change is the approach. The counselling style is a quiet a powerful way of increasing personal motiva- and eliciting one. The therapeutic relationship tion. is more like a partnership or companionship MI incorporates two major phases of the 240 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 241

Table 2. Sample Questions to Evoke Self-Motivational Statements

Problem Recognition What things make you think that this is a problem? What difficulties have you had in relation to your drug use? In what ways do you think you or other people have been harmed by your drinking? In what ways has this been a problem for you? How has your use of tranquillizers stopped you from doing what you want to do? Concern What is there about your drinking that you or other people might see as reasons for concern? What worries you about your drug use? What can you imagine happening to you? How much does this concern you? In what ways does this concern you? What do you think will happen if you don’t make a change? Intention to Change The fact that you’re here indicates that at least part of you thinks it’s time to do something. What are the reasons you see for making a change? What makes you think that you may need to make a change? If you were 100 percent successful and things worked out exactly as you would like, what would be different? What things make you think that you should keep on drinking the way you have been? And what about the other side? What makes you think it’s time for a change? I can see that you’re feeling stuck at the moment. What’s going to have to change? Optimism What makes you think that if you decide to make a change, you could do it? What encourages you that you can change if you want to? What do you think would work for you, if you needed to change?

therapeutic process, building motivation for only statistically significant, but also clinically change and strengthening commitment to significant; most of the studies deal with alco- change. hol-related problems and addictions, and most of them are quite strong in external validity 4.2.2 Brief motivational interventions (i.e. results can be generalized to other settings, problems and populations); brief AMIs The research literature shows brief adapta- perform as well as long AMIs and as more ex- tions of motivational interviewing (AMI) ef- tensive alternative treatments. fective for a variety of problems, common in MMTP, which are not affected by methadone 4.2.3 Motivational enhancement therapy (MET) alone (like problem behaviour, problem drinking and non-opiate substance abuse). Also, MET is a brief adaptation of MI that incor- brief AMIs have turned out to be as effective porates a ‘check-up’ form of assessment feed- as much longer treatments. back. It is a systematic intervention approach In their review on the effectiveness of AMIs designed to produce rapid, internally moti- Burke, Arkowitz and Dunn [3] drew the fol- vated change through mobilizing the client’s lowing conclusions: AMIs are more effective own change resources. The integrated MET than no treatment and are as effective as cred- approach was delineated in a detailed thera- ible alternative treatments; AMIs are effective pist manual for work with problem drinkers both as stand-alone treatments and as preludes [19], developed for Project MATCH, and was to other treatments; outcomes of AMIs are not later adapted for clinical work with drug abus- 240 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 241

ers by W.R. Miller [14]. vention is the Simple Reflection, performed In MET, treatment is preceded by a battery by the nurse at methadone delivery. It is very of assessment instruments. The initial two ses- brief and may take the form of an open-ended sions provide the client with objective feed- question, to be followed by a simple reflection, back regarding his drug use and related prob- an amplified reflection, or a double-sided re- lems and focus on building motivation and flection, and concluding with a brief reframing strengthening commitment for change. The or summary. subsequent sessions serve as periodic rein- The 2nd level intervention is the Brief Mo- forcement and check-ups of progress towards tivational Intervention, delivered for 3-5 min- change and make specific use of the follow- utes by the case-manager; it is based on the through strategies - reviewing process, renew- FRAMES strategies. These two interventions ing motivation, redoing commitment. are routinely practised in everyday contacts MET consists of four to twelve sessions to be with clients and form the dominating style of completed within a period of three months. staff communication with clients. Project MATCH [26], the largest psycho- The 3rd level is the Brief Motivational Ses- therapy outcome study conducted to date, sion, which is highly structured, and delivered found that 4 sessions of Motivational Enhance- by the case-manager in Motivational Inter- ment Therapy proved to be as effective as two viewing style for 10-20 minutes. longer treatments (12 sessions of cognitive-be- The 4th level intervention is the Full Moti- haviour therapy, and 12 sessions of AA-based vational Session; this takes 30-60 minutes and treatment) in the case of problem drinkers. is delivered by a counsellor who is qualified and experienced in motivational interven- 4.2.4 The structured stepped model for motivational tions. It implies the principles and strategies interventions in MMT of Motivational Interviewing, and has a strong focus on a particular problem or problem be- Examining the work carried out by clinical haviour. staff in MMTPs, Ball and Ross [1] concluded The last, 5th level, is the Motivational En- that most of it can be more properly described counter with the Team. It is applied with the as casework, rather than counselling, which most difficult clients — those that break pro- deals with day-to-day issues, mostly of a prac- gramme rules in a harsh way, that are aggres- tical nature. How these interactions are con- sive and impulsive, and capable of creating ducted, and particularly the attitude of staff serious problems — the people that are most members, is probably the next most important difficult to deal with. This encounter is struc- determinant of treatment effectiveness after an tured in a non-judgmental, supportive, caring adequate dose of methadone [10]. and empathetic way, and is concise, focused Based on these findings, a structured set and directive. of motivational interventions was developed The main principles of implementing the as a stepped model, specifically tailored for model imply routine implementation of less dealing with everyday contacts with clients, intensive interventions, while the more dif- routine problems, tough and conflicting situ- ficult clients and the more complex problems ations, and difficult clients in methadone are assigned to more experienced counsellors, maintenance programmes [9]. It creates the who are responsible for structuring more in- programme’s spirit and therapeutic context, tensive and specific interventions. Interven- which turn every contact with clients into part tions are matched up with specific problems, of the overall flow of interventions, which aim situations and the individual characteristics of to achieve better psychosocial adjustment and clients. positive behaviour change. The Model is designed as a stepped scheme, 4.2.5 Group work models with 5 levels of stepped interventions: The first, most brief and most simple inter- Many motivational activities and strategies 242 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 243 can take place in increasing the effectiveness model counselling, and methadone mainte- of group work. In recent years there has been nance [18]. a raising interest in developing structured motivational approaches for group work based on the Transtheoretical Model and on Moti- 5.1 Engagement and retention in treatment vational Interviewing principles (see the Re- source List ). It should be borne in mind that conducting motivational interviewing-based Motivational interventions can be a useful therapy in a group setting is considerably adjunct to increasing client engagement, reten- more complicated than individual treatment, tion and participation in treatment. A single and requires a high level of training and coun- session (or a couple of sessions) of motivation- selling skills. al interviewing added to the routine protocol at the beginning of treatment, prior to entering treatment, or as part of the assessment or treat- 5. Addressing specific problems in ment entry procedure, may result in better MMTP forms of involvement in later treatment, better retention and more favourable outcomes.

Incorporating motivational interventions and approaches into MMTP services may 5.2 Compliance and non-compliance greatly enhance the likelihood of client change, treatment effectiveness and the overall quality of services. Some of the ways in which moti- Here non-compliance is viewed as a largely vational interventions can be used involve motivational issue, and is discussed from the addressing specific problems and treatment is- perspective of the Stages of Change Model. sues; they can be applied as a means for: rapid Client non-compliance may arise when the cli- engagement to facilitate treatment referral and ent is in the precontemplation or contempla- treatment entry, an empowering brief consul- tion stage, and is not yet ready for action-ori- tation for clients already placed on waiting ented interventions, but may feel prematurely lists, a preparation for treatment to increase pushed to action. Such clients need specific engagement, retention, participation and com- interventions to resolve their ambivalence and pliance, overcoming client defensiveness and enter the stages of preparation and action. resistance, working with difficult and coerced Another possibility is that the non-compli- clients, dealing with conflicting situations ant behaviour arises as a result of underly- in a positive way, providing an introductory ing client resistance due to an inappropriate motivational boost for the inclusion of other interaction with a counsellor, with staff or a therapeutic components, or else a prelude to prescribing physician. This is where the MI further treatments, stand-alone interventions strategies for rolling with resistance should be or a counselling style to be used throughout applied. the course of treatment. Research testifies to these effects: clients who receive MI at the beginning of treatment 5.3 Difficult clients, coerced clients, and are likely to stay in treatment longer, work conflicting situations harder, adhere more closely to treatment recommendations, and experience substantially better treatment outcomes than those who re- The motivational approach provides alter- ceived the same treatment programme with- native ways for dealing with problem situa- out MI. Additional MI was found to facilitate tions and clients in a positive way by imple- treatments as different as cognitive-behav- menting interventions that are directive, yet ioural skill training, twelve-step and disease non-judgmental, empathetic and caring, while 242 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 243

providing a basis for reframing the conflict functional analysis of substance use in the into an opportunity for positive behavioural person’s life. All this is then drawn together in change, and for communicating with clients a treatment plan, drawing on a menu of CBT through therapeutic negotiation, instead of skill-training modules to address specific goals confrontation and conflict. for change. These modules are then delivered Difficult and coerced clients are at least as within an MI style, and the counsellor can fall amenable to a motivational counselling style back on MI whenever particular motivational as any others. Research now demonstrates issues or obstacles arise. Personal choice and that positive treatment outcomes are associ- autonomy are emphasized throughout treat- ated with a high level of empathy in clinicians, ment [18]. as reflected in their warm, supportive listening. If clients receive interventions appropriate to their motivational stage, they may become 5.5 Use of motivational interventions in low- invested in the treatment process and benefit threshold MMT programmes from oportunities for positive change.

Motivational interventions can be particu- 5.4 Use of motivational interventions in larly useful in treatment programmes with comprehensive MMT programs limited staff, resources, time, numbers of adjunctive services and treatment components, numbers of individual sessions and consulta- Motivational interventions can be effec- tions per client, and particularly in cases where tively integrated into more comprehensive only one intervention can be offered. Brief treatment plans for clients in MMTPs. These motivational interventions may be applied in approaches can be particularly useful in MMT dealing with specific problems in helping to when they are used to address specific client maintain a user-friendly atmosphere and good target behaviours, problems and issues in client-staff relations and communication. the treatment process that may be difficult to change by standard action-oriented approaches. Motivational interventions can be used 6. Training issues with clients before, during and after substance abuse treatment. The most obvious integration is to offer a Although brief interventions can be ad- motivational intervention as a first consulta- ministered by a wide range of professionals, tion and prelude to other services. Another op- practicing therapy requires training in specific tion for integration is to use motivational inter- therapeutic modalities. Therapists should be ventions as a counselling and communication sufficiently well-trained in the motivational style that can be used in parallel with other approach and should not rely solely on read- methods throughout treatment. A third possi- ing texts to learn this approach. This chapter bility is to keep motivational interventions in is not designed to teach clinical skills. To train the background, to be returned to when mo- clinical personnel, there is a need for special- tivational issues emerge in the further course ized training courses. These are provided by of treatment. qualified trainers from the Motivational Inter- These three applications can be integrated viewing Network of Trainers. A key to acquir- into a comprehensive intervention method, ing the necessary skills for MI is practice with where the first session is strictly motivational feedback and under supervision. interviewing, eliciting and listening to the person’s concerns and reasons for change. Feed- back of assessment results in an MI style begins in the second session, followed by a thorough 244 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 245

Replacement Therapies. Amsterdam B.V.: Harwood 7. Conclusion Academic Publishers. 11. McConnaughy, E.A., DiClemente, C., Prochaska, J., Velicer, W.F. (1989). Stages of change in psychotherapy: A follow-up report. Implementing a motivational approach in Psychotherapy, 26, 494-503. 12. McConnaughy, E.A., Prochaska, J., Velicer, MMT acts as a powerful resource in positively W.F. (1983). Stages of change in psychotherapy: influencing in a positive way the dominant Measurement and sample profiles. Psychotherapy: Theory, Research and Practice, 20, 368-375. programme atmosphere, staff-client interac- 13. McLellan, A.T., Arndt, I.O., Metzger, D.S., tions, quality of services and programme func- Woody, G.E., & O’Brien, C.P. (1993). The effects of psychosocial services in substance abuse treatment, tioning as a whole. There are various ways in Journal of the American Medical Association, 269, which motivational interventions can be suc- 1953-1959. 14. Miller, W.R. (1995). Motivational Enhancement cessfully applied in MMT. The evidence to date Therapy with Drug Abusers. NIDA, (R01-DA08896). is very encouraging in suggesting that even 15. Miller, W.R., Sanchez, V.C. (1994). Motivating young adults for treatment and lifestyle change. In: brief interventions can enhance client motiva- Howard, G., and Nathan, P.E., eds. Alcohol Use and tion and trigger significant improvement and Misuse by Young Adults. Notre Dame, University of Notre Dame Press. change. The use of these promising methods 16. Miller, W.R., Tonigan, J.S. (1996). Assessing in the future will depend on the creativity of drinkers’ motivations for change: The Stages of Change Readiness and Treatment Eagerness Scale clinicians and researchers in adopting, adapt- (SOCRATES). Psychology of Addictive Behaviors, 10, ing and evaluating motivational interventions 81-89. 17. Miller, W.R.,, Rollnick, S. (1991). Motivational to make them more widely and effectively Interviewing: Preparing people to change addictive implemented in MMT clinical practice for the behaviour. New York: Guilford Press. 18. Miller, W.R.,, Rollnick, S. (2002). Motivational good of our clients. Interviewing: Preparing people for change. New York: Guilford Press. 19. Miller, W.R., Zweben, A., DiClemente, C.C., Rychtarik, R.G. (1992). Motivational Enhancement References Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse 1. Ball, J.C., Ross, A. (1991). The effectiveness and Dependence. Project MATCH Monograph Series, of methadone maintenance treatment: Patients, Vol. 2. NIH Pub. No. 94-3723. Rockville, MD: National programs, services, and outcome. Vienna: Springer- Institute on Alcohol Abuse and Alcoholism. Verlag. 20. Prochaska, J., DiClemente, C. (1982) 2. Barber, J. (2002). Social work with addictions, Transtheoretical therapy: toward a more integrative Second edition, British Association of Social Workers, model of change, Psychotherapy: Theory, Research New York: Palgrave Macmillan. and Practice, vol. 19, 276-8. 3. Burke, Arkowitz, Dunn (2002). The Efficacy 21. Prochaska, J., DiClemente, C. (1983). Stages of Motivational Interviewing and its Adaptations: and processes of self-change of smoking: toward an What we know so far. In W.R. Miller and S. Rollnick, integrative model of change, Journal of Consulting Motivational interviewing: Preparing people for and Clinical Psychology, vol.51, 390-5. change. New York: Guilford Press. 22. Prochaska, J., DiClemente, C. (1984). The 4. Carroll, K.M. (1998).Treating Drug Dependence: Transtheoretical Approach: Crossing the Traditional recent advances and old truths. In W.R. Miller and N. Boundaries of Therapy, Homewood, III., Dow Jones/ Heather (eds.), Treating Addictive Behaviors, Second Irwin. edition, New York: Plenum Press. 23. Prochaska, J., DiClemente, C. (1988). Towards 5. Council for Philosophical Studies. (1981). a comprehensive model of change. In W.R. Miller and Psychology and the philosophy of mind in the N. Heather (eds.), Treating Addictive Behaviors, New philosophy curriculum. San Francisco: San Francisco York: Plenum Press. State University. 24. Prochaska, J., DiClemente, C. (1992). Stages 6. DiClemente, C., Prochaska, J. (1998). Towards of change in the modification of problem behaviors. a comprehensive, transtheoretical model of change: In M. Hersen, R.M. Eisler and P.M. Miller (Eds.). stages of change and addictive behaviors. In W.R. Progress in behavior modification, Vol. 28, pp.183- Miller and N. Heather (eds.), Treating Addictive 218. Sycamore, IL: Sycamore Publishing Co. Behaviors, Second edition, New York: Plenum Press. 25. Prochaska, J., Velicer, W.F. (1997). The 7. Dole, V.P., & Nyswander, M. (1967). Heroin transtheoretical model of health behavior change, addiction: A metabolic disease. Archives of Internal American Journal of Health Promotion, vol.12, pp.38- Medicine, 120, 19-24. 48. 8. Hagman, G. (1997). Stages of Change in Methadone 26. Project MATCH Research Group. (1997). Maintenance, Journal of Maintenance in the Project MATCH secondary a priori hypotheses. Addictions, 1 (1), 75-91. Addiction, 92, 1671-1698. 9. Kantchelov A., Vassilev G. (2003). Structured 27. Rollnick, S., Heather, N., Gold, R., Hall, Motivational Interventions for Methadone W. (1992). Development of a short, “readiness to Maintenance Treatment, Heroin Addiction and change” questionnaire for use in brief, opportunistic Related Clinical Problems, 5 (3), 13-22. interventions among excessive drinkers. British 10. Mattick R.P., Ward J., Hall W. (1998). The Journal on Addictions, 87, 743-754. role of counselling and psychological therapy. In: 28. Vassilev G., Kantchelov A. (2001). The use Ward J., Mattick R.P., and Hall W. (eds.), Methadone of brief motivational interventions in methadone Maintenance Treatment and Other Opioid maintenance programme, Bulgarian Psychiatric 244 · CHAPTER 4.2 MOTIVATIONAL INTERVENTIONS FOR METHADONE-TREATED PATIENTS · 245

Association, Annual Conference 2001. Institute on Alcohol Abuse and Alcoholism. - Velasquez, M.M., Maurer, G.G., Crouch, C., DiClemente, C. (2001). Group Therapy for Resource List Substance Abuse: A Stages-of-Change Therapy Manual, Guilford Press. The following texts are highly recommended as key - www.motivationalinterview.org resources for detailed information on theory and practice - Stages of Change Readiness and of motivational interventions: Treatment Eagerness Scale (SOCRATES) - Miller, W.R.,, Rollnick, S. (1991). Motivational This instrument is in the public domain and may be Interviewing: Preparing people to change addictive obtained by contacting its author: behaviour. New York: Guilford Press. William R. Miller, Ph.D. - Miller, W.R.,, Rollnick, S. (2002). Motivational Director Center on Alcoholism, Substance Abuse, and Interviewing: Preparing people for change. New Addictions 2350 Alamo SE University of New Mexico York: Guilford Press. Albuquerque, NM 87106 Phone: (505) 768-0100 Fax: - TIP 35: Enhancing Motivation for Change in (505) 768-0113, E-mail: [email protected] Substance Abuse Treatment, SAMHSA, CSAT, DHHS - University of Rhode Island Change Publication No. (SMA) 99-3354. Assessment Scale (URICA) - Miller, W.R. (1995). Motivational Enhancement This instrument is in the public domain and may be Therapy with Drug Abusers, NIDA, (R01- DA08896). obtained by contacting its author: - Miller, W.R., Zweben, A., DiClemente, C.C., Carlo C. DiClemente, Ph.D., Professor and Chair, Rychtarik, R.G. (1992). Motivational Enhancement University of Maryland Baltimore County, Department Therapy Manual: A Clinical Research Guide for of Psychology, 1000 Hilltop Circle, Baltimore, MD Therapists Treating Individuals With Alcohol Abuse 21250, Phone: (410) 455-2415, Fax: (410) 455-1055, E- and Dependence. Project MATCH Monograph Series, mail: [email protected] Vol. 2. NIH Pub. No. 94-3723. Rockville, MD: National 246 · CHAPTER 4.2 4.3

Psychotherapy for Patients in Methadone Treatment

E. Bignamini and S. Zazza

1. The management of Methadone that the management of methadone treatment treatment requires the doctor to have a good range of relational and psychopathological competences and be attentive in assessing the non-pharma- Patients in therapy with methadone obvi- cological factors involved that are viewed as ously do not originate from a homogeneous “confusing” in scientific research on the effi- series of clinical situations. Morever, treatment cacy of a drug (and which researchers attempt with methadone assumes particular character- to eliminate through suitable methodologies, istics, revealing the therapeutic route within such as double-blind, randomized and con- the entire care system (not in the medico-phar- trolled studies), factors that have proved to macological system alone), and in the specific be precious, powerful tools in implementing physician-patient-drug interaction. the action of the drug as part of an integrated In clinical practice, therefore, there are pa- strategy. tients who take high and constant doses of a Successful pharmacological treatment nec- drug while showing satisfactory results and a essarily implies an effective but also partly good level of compliance with prescriptions, instinctive and intuitive management of the patients trapped in a pattern of increases in relationship with the patient through which dosage, or in a series of repeated, inconclu- the authority of the doctor, the patient’s faith sive attempts to scale down, “phobics” who in improvement together with the motivation never accept adequate doses of the drug, and to achieve it, adequate expectations of the val- “anxious” patients who, at the end of their ue of the drug, confidence in the service being scaling down, cannot let go of the last few mil- provided and reassurance of anxieties, can all ligrams. be transmitted. From these few examples it will be clear Apart from the basic relational aspects

247 248 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 249 guaranteed by the professional qualifications This change becomes the subject’s key experi- of the doctor, specific psychotherapeutic in- ence and is unforgettable; all other experiences tervention may be necessary. Drug addiction will be compared with it and, without an ad- is a “pathological condition correlated with equate personal response, those other experi- an alteration of the system of gratification ences will remain secondary to it. What else and with a coercion of the modality and the could provide similar gratification, pleasure, ways in which the subject achieves pleasure, or oblivion? And why should the patient give characterized by cravings and by a relation- it up? The prize is so great that obtaining it is ship with the object (substance, situation or worth more than his own life. Even when ev- behaviour) distinguished by reiteration and erything seems ruined by drugs, the habit is so marked difficulty in giving it up” [4, 5]. This deeply rooted that it cannot be exchanged with conceptualization stresses all the biological, anything else. Morever, the life-style imposed psychological and behavioural aspects that on the drug addict is very stressful and excit- sustain the pathology in question in an insepa- ing, and its attraction is a worthwhile com- rable way. The “pleasure disorder”, as drug pensation for impending depression, which addiction may be defined, is the result of an will make the addict adopt maniacal defence imbalance which involves, and is determined mechanisms. by, all the dimensions of the individual. One It is not possible to go any further into the therefore faces specific psychopathological as- psychopathological aspects in this paper. I pects which should be treated on the psycho- need only say that, even if in different forms therapeutic plane in order to achieve a positive and dimensions, drug addicts share the fol- overall result from the treatment. lowing features: In addition to what has already been said, a) Greed: a voracious oral drive to get “ev- psychotherapeutic intervention may be neces- erything immediately”, and a maniacal sary for other psychopathological disorders triumph in the destruction of every ob- which often accompany and are tangled up stacle (a mechanism that can be made with drug addiction, and which are currently to work in the care programme – which conceptualized as “double disorders” or “dou- should itself be fast and painless). ble diagnoses”. b) Compulsion: the onset of desire, sly and tu- multuous; this puts every other object out of focus, changes the value of things and 2. Specific treatment nuclei in the one’s way of thinking, and is followed by psychotherapy of drug addiction the motor release of acting out the addictive event, and then by the down phase, so determining a traumatic, destabilizing Independently of the aetiology (which is emotive and cognitive discontinuity. much discussed: it can now be recognized that c) Mourning for the lost object: the drug-ob- a multiplicity of the factors involved – genetic, ject leaves a deep emptiness which is dif- environmental, pharmacological, psychologi- ficult to fill up with other less totalizing cal and cultural, are modulated differently in and gratifying objects. The patient experi- each subject, so determining the pathology) ences existential disorientation in which and of the socio-economic-cultural conditions, the prevalent feeling is nostalgia for what the drug-addicted subject, once the condition has been left behind and cannot be sub- of drug addiction has been ascertained, finds stituted. Furthermore, as the mourning himself facing several psychopathological is metaphorical and depends on a choice problems typical of his condition. made by the subject, a choice which can The encounter with the substance leads to never be reversed, the thoughts and a radical transformation: the subject’s experi- mood of the patient swing between a de- ence changes him deeply, as it affects the deep- sire to give in and a desire to abstain. est biological and psychological dimensions. d) Regrets for the fusional-heroic dimension: the 248 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 249

high emotional level connected with the The subject may think: “By taking action, I life-style of the drug addict sustains great, will obtain a chemical substance ‘outside me’ heroic experiences (even if these may be that will magically solve my problems”. That tragic) which offer a sense of gratifying, is a misleading approach; the trouble brought though illusory, fullness. The involve- by addiction is bound to deep emotional needs ment of the profound, archaic structures that have not been worked out at the level of connected with pleasure strengthens the the Ego, or to a situation of evolutional impair- sensation of living a totalizing experience ment that stops the individual feeling whole which will alter the boundaries and forms or self-confident. of external objects and of the components The addicted character then transforms of the self, so offering an exalting per- the process of elaboration into an “immedi- ception of fusion. Giving up drugs does ate gratification” relational model, involving not cancel the memory of the experience an acting-out — the well-known “everything which, in time, undergoes a transforma- now” greedy attitude. tion that removes the negative aspects In a regular structure, a dynamic balance (which motivate change) and retains the between three registers develops the individ- positive ones (which increase the risk of ual personality: relapses). Life without drugs often offers • Intellectual register (thought) dull, grey and depressing panoramas that • Somatic register (body) comprise no trace of greatness; the pro- • Behavioural register (action) cess of adaptation to a “normal” life does In an addicted structure, the behavioural not proceed spontaneously or coherently. scheme is bound to prevail. A recollection, or These features, which become fixed in a the meaning of an experience, means getting pattern constituting the specificity of the drug through an event, which must be re-represent- addiction experience, require psychotherapeu- ed verbally through language. tic treatment whose objective is the resetting The recollection process can take place if of the strategies of gratification and of one’s the newborn’s “empty mouth” is filled by the plans for life. These general concepts are ap- words of the person who enacts the mother plied through specific techniques in different function, by words spoken to the newborn and psychotherapeutic schools and are often car- over the newborn, and by thinking about him ried out in a variety of distinctive organiza- as a complete being. As a result, emptiness, tional care settings. instead of being frightening, is a way of opening oneself to others through the mediation of language. 3. Psychotherapeutic methodologies This does not occur with addicted individuals, who convert the process into an act of taking in. (That act involves the utilization of an external object that is able to magically 3.1. Psychodynamically oriented therapy heal an emptiness that can never be accepted, because it is primarily experienced as a source of anguish and persecution). According to psychodynamic theory, ad- Olivenstein [18], in discussing addicted in- diction is the result of a failure to succeed in dividuals, depicts a “broken mirror evolution dealing with ambiguous and/or anguish-gen- stage”. erating deeds. This evolution stage occurs between the There is the attempt to solve and subdue newborn’s 6th and 18th months, at the time an inner conflict between clashing requests de- when a newborn should structure a differ- riving from different needs, or to replenish the ent Ego detached from the mother’s Ego: in shortfall in psychic structures that have been pathological individuals, their relationship missing or inadequate. with the mother is the obstacle in attempting 250 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 251 this evolution stage; the mother experiences tient-therapist relationship, inclusive of: “all the newborn as her vanished desire and not in the phenomena establishing the patient-psy- itself. (“We find ourselves looking at a mirror choanalyst relationship”[15]. Transference and carrying a fragmented image that is capable of counter-transference have to be conceived as bringing the baby to a later stage, where there interactive concepts, so allowing “transfer- is a unifying identity between the mother and ence” to be defined as everything contributed its own Self”). by the patient to the therapeutic relationship In talking about the narcissistic personality at the present moment or as a habit belonging organization of his subjects, Green [13] identi- to their past relationship, and “counter-trans- fies a “dead mother affliction”. In this afflic- ference” as the therapist’s emotional reaction tion, the mother is physically near, but gives towards a given patient in their specific rela- her son an objectively devitalized relationship, tionship. In the opinion of some authors, the within which the son’s real needs are not per- patients that should react best to this kind of ceived or satisfied. therapy are those with a strong motivation, The result is a double impact on the to-be- possessing reflective and introspective skills, addicted baby’s psychic development: which drug addiction has mainly developed “Unconscious identification with the dead through intrapsychic conflict (e.g. Cancrini mother“: between mother and son an inverse [6, 7]: “reactive drug addiction”); according relationship is structured, with the assisted be- to other authors, the therapy is functional for coming the assistant. It is now the baby who motivated patients who are affected by drug feeds the dead mother in an exclusive, totali- addiction and a strong psychopathology, but tarian relationship. not by antisocial personality distress. “The collapse of making sense”: the baby hasn’t got the skills needed to make sense of the accidents that happen to him, so that his 3.2. Systemic relationship psychotherapy experience loses its meaning. Physical and psychical experience is absent, and so is the opportunity to be sustained; According to this therapy, drug addiction the body is unable to experience the agreeable is a symptom of major distress in the patient’s integration dimension essential to an adequate parental relationship system, and a failure in narcissistic development [20]. “A well-struc- the management of distance in important re- tured narcissistic process lies in the main- lationships, whose opposites are union and tenance of the unity and solidity of the Ego, identification. which continues to stand whole and solid at The family, as a unit made up of different every moment of life, without being corrupted but related individual parts, is described as a or lacerated by a variety of psychophysical “system”. adjustments to the external world and to the Relationship-forming family members internal world of emotions and drives”). identify, from different points of view, what According to authors whose work is based happens in the system to develop a circuit of on psychoanalysis, heroin addiction is the mutual influences. symptom of a breakdown located in the “oral The family system accomplishes two main phase” of the evolutionary path. This phase functions. The first isstability ; in time it allows accounts for the whole range of psychopa- the subjects to recognize that specific group of thologies comprising the key elements of oral- people as “his family” (family identity). The ity, separation and the differentiation between second is flexibility; it allows the family to rec- Self and non-Self. ollect and reorganize in an unending process The peculiarity of this psychotherapy tech- of adjustment of the distances within emotion- nique is its transference and counter-transfer- al links when critical events or potential causes ence analysis. The object of that transference of unsteadiness occur. and counter-transference analysis is the pa- Cirillo and co-workers [8] suggest an aetio- 250 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 251

pathogenetic, trigenerational model for heroin The restructuring makes it possible to addiction. They have collected the emotional bring new sense and value to the verbal re- history of three family generations (the third alities expressed during the therapy. In this is the one that includes the addicted child), way, therapist and patient are able to build up which is useful in understanding the process a new reality: “Restructuring is a therapeutic that brought about the current pathogenic technique bringing into play the concept that structure. all the rules, all the secondary realities, are mi- The observed generations are connected nor and life is what it is said to be” [22]. by a shared factor: some of the parents had, The patients that should react best to this on their own account, been “needy” sons or treatment are those that have a primary net- daughters in some respects, without receiving work of helpers willing to cooperate; their recognition or understanding of that “needi- symptoms should be recollected and main- ness”. tained by a dysfunctional relational process. Generation by generation, this condition of (E.g. – Cancrini (1984): Addiction associated deprivation is passed on; three main parent- with personality disorders and neurotic addic- child relational exchange forms have been lo- tion) [6, 7]. cated within this model: a) Mimic caring: Whoever takes care of the baby proposes a form of nursing founded 3.3. Cognitive-behavioural psychotherapy on a non-real emotional baby’s needs, so that the relational exchange become illusory. (It is as if the carer were to say, “I These psychotherapeutic models offer no am taking care of you to satisfy my pa- aetiological definition of addiction and the rental needs, as I myself am an unfulfilled borders between the different approaches are child”.) usually blurred, so fusing the models into b) Advantageous caring aimed against the an integrated whole called cognitive-behav- spouse: A mother or father, more likely the ioural. mother, is over-committed to the child; The aim of the behavioural model is to teach this over-commitment is turned to ad- the patient self-control by applying techniques vantage in stepping up the war against able to modify his mistaken behaviour. the other parent. (This intense but false Throughout an analysis of inputs, the ther- relationship leaves the child confused apist drives non-adaptive reactions on the be- and unable to discover the trick.) havioural level by exactly defining the kind of c) Dumping: According to these parents, problem to be solved. their children seem not to exist; they jus- Among currently practised techniques, we tify dumping them as an objective neces- should recall systematic withdrawal and op- sity, but the problem is that there is no ev- erational conditioning. idence that the parents have any plan for The purpose of systematic withdrawal is the family. In this kind of psychotherapy, to teach patients how to transform an unac- the most commonly used techniques are ceptable behavioural reaction into an adaptive those of prescription and restructuring. one by acknowledging a hierarchy of stimuli The prescription, which is given to the fam- which have prompted a mistaken reaction up ily by the therapist, may vary in its contents, till the present. covering the structural rules within the family, Patients are increasingly provided with its specific communication patterns and/or the hierarchies, in accordance with the increasing symptoms themselves. Prescriptions are used difficulty of facing a stimulus. to strengthen the evolving process between The structure of operational conditioning is therapeutic meetings or to reveal within the based on the assumption that a subject’s reac- family the difficulty of enacting the prescrip- tive answer will be repeated if it is followed by tions. a “pleasant” (as defined by the subject) conse- 252 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 253 quence (positive reinforcement) but will not be techniques are questionnaires or “self-evaluat- repeated if it is followed by an “unpleasant” ing” schemes, together with a diary consisting one (negative reinforcement). of daily entries written by patients to express When a therapist applies this model, he or their thoughts and emotions. she will study and analyse the behaviours to Before being admitted to this therapy, pa- be retained and learned, and those that are to tients are asked to comply with the therapist’s be discouraged. requests (this includes homework) and to ac- The purpose of the cognitive model is to cept the status of the therapist as the one in explain the process that causes the patient’s re- charge of what is to be done [10]. turn to an addicted state and the continued use of toxic substances, so as to teach the patient some cognitive analytic skills and emotional 3.4. Group psychotherapy control pertinent to the use of substances. Cognitive therapy evaluates the automatic thoughts, the convictions, and the “make- The group treatment of addicted patients believe” that set up interference between an has developed both from clinical-psychoana- event and its emotional and behavioural con- lytic theory and cognitive-behavioural theory. sequences. The psycho-educational group, as the set- The modification of deeply held beliefs ting for cognitive-behavioural group therapy, leads to a change in convictions and, therefore, has the aim of developing an awareness about in automatic thoughts, so generating a trans- the practical, medical and psychological conformation in behaviour and emotion. This sequences of drug addiction through discus- therapeutic model considers psychological sions, the provision of informative materials problems to be the result of how individuals and teaching sessions. This kind of group is consider themselves, the world and the fu- often used as a starting step in a therapeutic ture. programme. There are probably some mistaken adap- The monosymptomatic group of analytic tive beliefs or cognitive distortions capable of therapy [9], a kind of group psychoanalytic generating psychological problems if they are therapy, has the goal of transforming the Self used as primary mental organization schemes by allowing psychic structure maturation, ad- to evaluate and elaborate externals inputs. equate communicational and social abilities Three areas are considered to generate (pointing to socially oriented interpersonal changes in drug addiction: aspects linked with drug addiction) and an in- a) Beliefs about the use of drugs and addic- tegration of the mind-body relationship. These tion-induced behaviours (the aim being goals comprise the healing of symptoms and abstention from the use of drugs); the restoration of psychic functionality. b) Thoughts on life, the self and the future The recollecting function group, RFG [24], (the aim being growing confidence in is a short group experience for those shown to one’s self and in others); be suffering from a fragile Self by a psycho- c) The learning of social skills, self-evalua- structural analysis diagnosis. The RFG goal is tion and techniques for self-help (the aim to strengthen the primary psychic functions being growing levels of self-esteem and –– recognizing your own Self and taking care gratification). of it. The heroin-addicted patient has a frag- Marlatt and Gordon’s cognitive models of ile Self that is insufficiently structured to me- substance abuse consider a circularly linked, diate between instinctual needs and external seven-step process, with the last step linked reality. Group treatment permits a lowering of to the first by a feedback method, while a “re- the stressful tension that may occur in an in- lapse” may occur at any moment in the pro- dividual patient-therapist relationship that is cess [16]. invasive for the addicted patient: the group of According to this model the most useful equals makes acceptable and feasible a prox- 252 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 253

imity, while the equals are perceived as less they ask them for help, they apply relational exciting objects with a lower transference pos- models and methods they are accustomed to sibility. and know well. Public health services become an institutional environment for developing the help 4. Psychotherapy in public services relationship, the Third, and structuring a triangular patient-operator-service relationship, within which each participant brings his or “Men live upon statements whose authen- her own different culture, in terms of values ticity is related to the trust they give to the and images. statements themselves” [2]. These three hubs constitute a mutually in- The psychotherapeutic treatment models teractive, triangular relationship; an analysis discussed above have a specific setting, which of what happens within it needs a self-reflec- should be functional to the work of “relational tive capability [1]. Every professional should organization” to be carried out within the ther- use self-reflection about what happens in the apist-patient relationship. relationship, real or imaginary, with the pa- The setting is the device that regulates the tient, but the institutional working group frequency of meetings, their mode (face to face, should itself have a self-reflective capability, with or without a desk, a bed, an armchair or which should be stimulated through the orga- unidirectional mirror), duration of meetings, nization the group has given itself. payment, and so on. The form taken by the organization con- When an individual approaches a psycho- veys and transmits the values embodied in the therapist, he accepts the setting the therapist treatment typology offered to those requesting suggests; this setting then becomes the back- help [17]. drop to the therapeutic process. Some addiction pathology service opera- “When we translate setting as aspect or tors should have a specific psychotherapeutic situation, we do not have to think about the training, to be able to evaluate this complex situation seen by an observer, indeed we have correlation of variables and levels in meeting to think to the situation produced by the act of patients, so benefiting the whole work group. observing itself involving a border, a limit. The This professional training strengthens the setting is the establishment of requirements to context for the therapeutic act itself within a observe and to study [3]. clinical planning system. The therapeutic act Organizing a setting in space and time is acquires a different significance, but it also al- itself a therapeutic action; the creation of limits lows an easier pathway for “what is happen- brings with it a therapeutic function of direc- ing” interpretative hypotheses, so giving sense tion and control that is capable of structuring to what seemed without sense at first glance. mental assets. According to addicted patients, pharmaco- Whoever works in a public facility faces a logical methadone therapy acquires the value more complex task related to the setting con- of a “transactional object” in a doctor-patient cept, so it may be helpful to consider the differ- relationship, so driving the acted-out com- ent acting levels playing a role when a patient municative levels and also the representations arrives at a facility centre against drug addic- given to the Self and to the Other in that spe- tion. cific relationship. The bio-psycho-social characteristics of From this viewpoint, medicine is an object drug addiction call for a service able to provide viewed “in transit” from doctor to patient, and integrated treatments, whether clinical or psy- is recognized by both as being a real “third” cho-social-educational. Patients applying for endowed with symbolic value. help to a service attached to a National Health Both actors in a doctor-patient relation- System clash with a group of professionals ship can use medicine to re-balance emotional possessing a variety of different skills; when distances, and re-define power positions, as 254 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 255 an offensive or a seductive instrument, or to procedures based on clinical and therapeutic implement a triangulation between operators knowledge at every step in treatment, opens capable of distinguishing “good” from “bad” up the opportunity of thinking of the thera- operators. peutic process as a co-construction between The helper and the individual asking for the health service and the patient. help share the idea of a relationship they think This way of imagining the therapeutic they should have in their respective role-mo- process links, and defines as co-dependent, ments. thought and action, organization and clinic; Parsons [19] presents the ill individual’s re- to reinforce the process by subsequent steps is quests within a patient-therapist relationship the right way to approach patients. as: A public service for drug addicts offering • A lowering of everyday social, work, and a “step by step” integrated multimode treat- family role responsibilities; ment should divide those steps into: • The idea of healing as not being the out- Therapeutic contract: come of a deliberate act; a) Definitions of timing and goals; • A wish for improvement from the current b) Verification of a patient’s achieved goals. state of illness; Every step should be considered as an • A clear request for help or collaboration opening to further steps or on its own. Step- from the health system. specific actions generate two-way information On the other hand, a drug-addicted pa- and knowledge both for patient and operator: tient who asks for help in an imperative mode the horizontal way refers to the growing rela- (“everything now”), focusing all his needs on tionship in a specific space and time (here and his physical condition as an evident and clear now) and the vertical way refers to a hypoth- expression of suffering, undermines Parson’s esis on projects and future procedures (there system of expectations. and then). With this kind of request as starting-point, Request for help in healing step: the patient it becomes essential for the health organiza- is unwell and confused; he needs to be listened tion to decide on a therapeutic way of acting to. This is the first contact step. The service right from the patient’s earliest contact with should be organized so as to be adequately re- the health service. straining but reassuring, and it should be able If the physical problem was, for example, to direct the request for help from the outset. considered a minor one, in a theoretical di- This step’s main objective is to make a pa- mension, a pharmacological therapy of regu- tient able to be aware that he is being listened lar dosage substitution would be considered to. It should be possible to give information on “no good”, and any patient unable to accept the functions of the service and the requests treatments other than clinical ones would be the patient will be subjected to. considered as “lost”. Or if the health care in- At the end of this step the patient is al- stitution was socially concerned and it con- lowed to choose whether he would like to start sidered collaboration as its standpoint, any diagnostic treatment by signing a therapeutic addicted patient would be considered “hard” contract agreement. and “manipulative”. Diagnostic treatment step: the service has a If a health organization was structured on commitment with the patient to produce a di- a pedagogical command philosophy, the heal- agnosis able to help define the best treatment, ing and treatment of patients would be based and address individual problems. Every time on a double and/or contradictory communi- a patient’s requests or problematic aspects –– cative system, resembling the “double bond” physical, social and emotional — emerge, the mirror messages between parents and addict- Service must respond with suitable treatments. ed child. The objective is not to “solve” problems, but The idea of taking action in an organized to bring awareness, by means of treatment ac- way, comprising plans for structures and tion, about the kind of relationship the patient 254 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 255

can build with the service, and about what he 5. Psychotherapy and methadone is asking for and what he is willing to do and treatment: possible integration to act on. Targeted treatment step: this puts forward a therapeutic project based on the appropri- Psychotherapy and pharmacotherapy alone ate problem discussed with the patient in the are not able to provide a cure for the majority previous step. Patients can access this step if a of drug addicts. There are, however, still many suitable problem has been identified. If a psy- theoretical and operative difficulties impeding chotherapist is required, the proposed setting the achievement of truly integrated therapies. could vary. From the psychological standpoint, there It is possible to reach agreement with a are still many doubts about the possibility of patient on a contract involving supportive carrying out psychotherapy with a patient psychotherapy, over a definite time-span, fo- being treated with methadone. It is true that cused on limiting symptomatic behaviour, or resistance towards psychopharmacological a change-focused psychotherapy, or both at drugs by psychotherapists has been reduced, later or at different times. but methadone is still considered to be a spe- The Guidelines to the psychotherapy of cial case, and is liable to be considered a con- drug addiction [14] point to three steps in dition of exclusion from psychotherapy. The treating drug addiction: objections that are still made regard the capac- a) Sobriety attainment step ity of the drug to modify the defences of the b) To evaluate the degrees and consequenc- ego, along with the quantity of psychic energy es of using substances available, to alter the expression of the person- c) To adopt methods for detoxification and ality by influencing the emotional and cogni- abstinence tive aspects of the patient, and to strengthen d) To adopt methods to safeguard abstinence the subject’s dependence and passivity. The as a precondition for psychotherapy patient in therapy with methadone is consid- e) To diagnose and treat every associated ered unstable, still sensitive to cravings for psychiatric disorder drugs and thus exposed to the possibility of f) To involve each patient’s family altering his psychic state, by taking, if not her- g) Early restoring step (6-24 month absti- oin, cocaine or benzodiazepines, or drinking nence) alcohol. When such patients are accepted into h) Goal: abstinence psychotherapeutic treatment (in groups, dur- i) Supportive and directive psychotherapy ing intensive treatment), special attention is j) To act against addiction as a disease paid to the best way of managing patients who k) Re-orienting of defences go to sittings under the effect of substances. l) To use psychodynamic techniques to From the pharmacological viewpoint, a strengthen the “12 step” principles reductive attitude often prevails. There is a m) Advanced restoring step (1-5 years of ab- tendency to correct undesired behaviour in a stinence) “technical” way, negating the further (often vi- n) Goal: awareness and psychological tal) significance of the symptoms and, follow- change ing the cult of the omnipotent drug, reintro- o) Traditional re-constructive psychothera- ducing the risk of biochemical moralism (“if py the patient took the therapy correctly, every- p) Consolidation of a patient’s identity, with thing would be resolved”), as if the problem a continued focus on the centrality of the were that of correcting imbalances between substance problem neuromediators, rather than that of managing q) Exploration of defences and deeper a subject a vitally important issue when facing themes a poor level of compliance in the patient. r) Recollection of cognitive-behavioural On the other hand, psychotherapeutic in- controls terventions are not applicable to patients who 256 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 257 are strongly destabilized and transformed by terconnections between mind and brain: substances, just as pharmacological therapy data are being collected through the tech- constitutes a base on which other therapeutic niques of neuro-imaging on the capacity and rehabilitative tools should intervene in of psychotherapy to modify brain activity. order to complete care. The psychotherapist, This strengthens the hope that intensive together with the pharmacologist, should ask psychotherapy may have a significant himself how much of the suffering expressed impact on biological, as well as psycho- by the patient is tolerable, and whether it can logical vulnerability to psychic disorders be worked on to favour any opportunity to in- [11]. tegrate psychic needs and aggressive compo- • Other data testify to the advantages of nents more effectively, or how far a drug can psychotherapy in the treatment of pa- function as a sedative and an external integra- tients with severe disorders. The associa- tor which momentarily reinforces weakened tion of psychotherapy with programmes psychic functions that are probably incapable of partial hospitalization seems to reduce of sustaining an evolutive process. Conversely, the risk of suicide, self-offending acts, the from a psychic point of view, suffering may need for later hospitalization and the in- strengthen regressive phenomena which are cidence of depression and anxiety. then translated into resistance to treatment • Furthermore, some studies seem to dem- and into crystallization. onstrate that patients treated with inten- The question of integrated therapies is still sive psychotherapy continue to improve open today. There are many problems in this after treatment [21], and that the im- area: indications about the different psycho- provement acquired with psychotherapy therapeutic techniques; a typology of subjects associated with methadone treatment and integrated diagnosis; different “weight- persists over a longer period than that ob- ings” of the two therapeutic components; tained with the methadone-counselling what is sometimes a separation between the association [23]. The methodology used management of pharmacological and psycho- in studies is changing; it now takes into logical therapies and, overall, a theory of the consideration not only patients selected psyche able to keep mind and brain together. in academic contexts, but those in natural Prospects of progress in this field come from a settings, complicated and unselected pa- methodology which is becoming more widely tients, so reflecting the “real world” to a used, originating from American universities, greater extent. of constituting interdisciplinary work groups, • The other sector of evaluation has to do where different researchers are committed to with the cost-benefit relationship: interest- the same problem, independently of the disci- ing data are being collected on the capac- pline to which they belong. ity of psychotherapy to reduce the cost of managing seriously ill patients, above all those with personality disorders (reduc- 6. The efficacy of psychotherapy ing hospitalization, the intensive use of health and emergency structures, and the frequency of suicide attempts and self-of- Psychology has to defend itself from the fence). aggression of mere techniques and from em- • Lastly, the psychotherapeutic formation pirical evidence which has increasingly come of the doctor allows a better manage- to question its effectiveness. ment of the relationship with the patient, It is not feasible to examine such a compli- which, as a result, seems to bring about cated theme in this context; the key points in greater patient compliance with pharma- this discussion have been recalled and sum- cological treatment. marized in a masterly way by Gabbard [12]. In reality, it also seems that psychotherapy • The first area of research regards the in- is preparing itself to respond adequately to the 256 · CHAPTER 4.3 PSYCHOTHERAPY FOR PATIENTS IN METHADONE TREATMENT · 257

requests of current culture, committing itself A more precise focusing upon the psycho- to serious research which removes it from the pathological aspects activated by drug ad- esoteric dimension, in order to evaluate what diction may allow a better evaluation of the may be useful to introduce into daily clinical efficacy of the psychotherapeutic approach, practice and the universe of real patients. even beyond the exclusive evaluation of be- So far, the psychotherapeutic approaches havioural changes. which seem to satisfy the need to check up on the results obtained have mostly been those of the behavioural type, focused on changes References in features directly observable even outside 1. Aron L. (1999): Clinical choices and relational matrix. Psycho-Analytic-Dialogues. 9:(1) 1-29. the psychotherapeutic setting and on the 2. Bateson G. (1972): Steps to an Ecology of Mind, achievement of results expected from the con- Ballantine Books, New York 3. Berlincioni V., Petrella F. (1993): Quadro e text (family, society) in which the patient is cornice: il setting clinico. Gli Argonauti. 56 27-42. inserted. Nevertheless, as regards the radical 4. Bignamini E. (1996): Dall’accoglienza al trattamento diagnostico. Animazione Sociale. 6-7 53-60. changes induced by the drug addiction of the 5. Bignamini E., Cortese M., Garau S., subject and described previously, an approach Sansebastiano S. (2002): Dipendenza da sostanze e patologia psichiatrica, Editeam, Bologna. capable of making him work out deep aspects 6. Cancrini L. (1984): Quei Temerari sulle macchine of his psychic functioning seems fundamental, volanti, NIS, Roma. 7. Cancrini L. (1997): Lezioni di psicopatologia, Bollati above all if one reflects on the direct linkage Boringhieri, Torino. that the pathology of pleasure has with the 8. Cirillo S., Berrini R., Cambiaso G., Mazza R. (1996): La famiglia del tossicodipendente, Cortina, fundamental existential dissatisfactions of the Milano. human being. 9. Di Maria F., Lo Verso G. (2002): Gruppi, Raffaello Cortina, Milano. 10. Dowd E. T., Rugle L. (1999): Comparative treatments of substance abuse, Springer-Verlag, New York. 11. Fonagy P. (2003): Psychoanalysis today. World 7. Conclusions Psychiatry. 2:(2) 73-80. 12. Gabbard G. O. (2001): Empirical evidence and psychotherapy: a growing scientific base. Am J Psychiatry. 158 1-3. Drug addiction is a pathology which in- 13. Green A. (1983): Narcisime de vie, narcisisme de mort, Editions de Minuit, Paris. volves and modifies the functioning of the 14. Kaufaman E., Reoux J. (1988): Guidelines for the connections between the biological and the successful psychotherapy of substance abusers. Am J Drug Alcohol Abuse. 14 199-209. psychological, forcing us to face the unity and 15. Laplanche J., Pontalis J. B. (1967): Vocabulaire the complexity of the human being. The dis- de la psychanalyse PUF, Paris. 16. Marlatt G. A., Gordon J. R. (1985): Relapse tinction between psychotherapeutic and phar- prevention, Guilford, New York. macological interventions highlights the need 17. Morgan G. (1997): Images of organization Sage Publications, Thousand Oaks, CA for scientists to simplify reality in order to 18. Olivenstein C. (1984): Destin du Toxicomane, manage it, rather than being a real distinction Librairie Arthème, Fayard, Paris. 19. Parsons T. (1951): The Socia Systeml, Free Press, between different existential dimensions. Glencoe. The clinical dimension, which should take 20. Ruggieri V. (1997): L’esperienza estetica, Armando, Roma. account of the ideographic dimensions and 21. Sandell R. (1999): Long term findings of Stockholm: which aims to treat the person cannot function outcome of psychotherapy and psychoanalysis project, Paper presented at the Meeting “Psychoanalytic effectively if it does not reconstitute the psy- long term treatment”, Hamburg. chobiological unity of the subject. 22. Watzlawick P., Nardone G. (1997): Terapia breve strategica, Raffaello Cortina, Milano. Paradoxically, more effective pharmacolog- 23. Woody G. E., McLellan A. T., Luborsky L., ical therapies highlight the need for their inte- O’Brien C. P. (1995): Psychotherapy in community methadone programs: a validation study. Am J gration with a correct psychological approach, Psychiatry. 152 1302-1308. so as to implement all the transformational 24. Zucca Alessandrelli C. (1998): Come per magia: la ripresa delle funzioni. Gli Argonauti. 79 and evolutionary potentials of the treatment 265-280. as a whole. 258 · CHAPTER 4.3 5.1

Methadone and Treatment Quality. The EFQM Excellence Model

A. Flego

1. Introduction 2. Quality in the treatment of the addictions: search for a method.

In the technologically advanced world, providers of products and services have been What do we mean when we speak about dealing with the problem of quality, of how to ‘quality’? The word suggests the concept of assess its level, and of how to improve it con- ‘doing something better’ or more precisely ‘at tinuously and systematically for many years. the best’. It also suggests the concept of ‘doing Therefore, this aspect cannot be eluded when something better than before’ or ‘better than scientifically planning and practically organiz- other people’. ing a methadone treatment program. There is a term more and more used that The treatment with methadone, although it calls to mind this concept. It is the word is safe and relatively easier than others, is still ‘benchmarking’. The word means to evaluate at the centre, at least in Italy, of a great con- by comparison with a point of reference. Thus, troversy. This is mainly due to the fact that we can compare different things to know the controversy lies in the basic reasons of the which is the best or which performs better, but treatment with methadone rather than in the we can also see which is the lowest point – and effectiveness of this treatment. this is very important when we speak about For this reason, in a quality manual, this quality - under which a product or service is of second aspect cannot be analysed without ful- unacceptable quality. ly understanding the first. To decide whether the quality of a product or a service is acceptable or not means to ‘plunge’, as Cicourel says [1], in the ‘study of the obvious’. It means to analyse what is taken

259 260 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 261 for granted in the common sense, ‘the whys’ sustained by the media. of an action. This concept calls to mind that of For this reason, in our work, as well as in a ‘rationale’ in pharmacology, which does not quality manual, it is necessary to explicit some only mean how to prescribe a drug but also unbreakable assumptions on which to found a why the drug is prescribed and why with such method to interpret events and interventions modalities. that can support quality assessment. A product or a service is of good quality if The assumptions are as follows: it corresponds to the purposes for which it has 1. Illicit drug addiction is a chronic and re- been realized and if it meets the user‘s require- curring disease, as pointed out by Man- ments. naioni [2]. Nowadays, a car going at a maximum speed 2. It produces physical and psychological of 30 km/h and consuming 1 litre/km would suffering, in addition to social suffering, be considered of unacceptable quality. One of and part of it has a strictly biologic patho- the reasons is that it would not meet the driv- genesis. er’s expectations with regard to medium speed 3. As in other medical fields, this suffering and fuel costs. Moreover, it could not compete has to be treated on the basis of scientific in a market where competition is based on dif- evidence. ferent cost-performance ratios. However, the Thus, the scientific method becomes the most important reason is that our daily liv- model for clinical practice, as well as for ing has elected as common ‘value’ – and has benchmarking, which means that the concep- founded an epistemology on it – the choice of tual model of choice is evidence-based medi- going at a speed between 100 and 130 km/h cine (EBM). consuming 8 to 12 l/km. Finally, this habit is possible because the roads and highways can support such performances (although car ac- 2.1. Continuous quality improvement (CQI). cidents occur) and because a road code exists that regulates the matter and possible contro- versies. The benchmarking for the production The first operative concept regarding the of cars is based on these parameters and not on quality assessment of a product was the ‘qual- other ones. However, this epistemology – at- ity control’ concept. Initially, a product was tribution of meanings – with regard to cars did checked at the end of the productive cycle and not exist or was different in other times and the defective items were eliminated before nowadays it is different in other places. putting them into the market. Obviously, their Similarly, when considering illicit drug costs were charged on the good items. How- addiction, it is not possible to speak about ever, this first attempt to evaluate quality was quality without analysing the ‘obvious’ of the ineffective and expensive in the results and purposes of drug addiction treatments, that is, was soon replaced by a more rational action before founding a common epistemology. And aiming at checking the ‘process’. In this case, in Italy, there is an epistemology chaos with re- the causes of the defects were analysed and the gard to drug addiction. intervention was on them in order to reduce For example, a treatment for heroin addicts or eliminate the defects. Thus, it was possible that does not use methadone or uses it only at to save money and to sell at more competitive low doses and for short periods is still consid- prices. This intervention mainly improved the ered of good quality. The objection that this use of the resources, thus reducing the number does not correspond to any scientific-based of reject items. evidence does not weaken this position, be- Soon it was clear that this process was nei- cause it relies on an epistemology other than ther punctual nor linear but circular, as shown that commonly defined as ‘scientific’. Not only in the following diagram (figure 1). this epistemology is allowed but it is also part This model is based on the concepts by of the common feeling of the society and is Deming [3] that define the cycle “plan-do- 260 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 261

invalidate the improvement brought by the others. The fourth dimension (outcome) deserves a particular attention because it implies the translation or not of efficient performances into efficacious interventions. The efficacy of an intervention is also guaranteed by factors external to the organization and related to environmental and social conditions on which health care workers cannot always act. From the methodological point of view, the assessment of outcome implies research models, such as Randomized Clinical Trials (RCT), which are not always feasible in normal health care organizations. Therefore, while all health care organiza- Figure 1. Circular process of CQI tions should implement a CQI process that takes into consideration the dimensions of input, process and output, the assessment of check-act” (plan the actions, implement the ac- outcome is reserved only to some of them. tions, assess the effects, correct the actions) as However, all of the organizations can refer to a continuous cycle that constitutes the process the literature, in particular to that conducted of “Continuous Quality Improvement” (CQI). according to Evidence-Based Medicine (EBM), This model can be successfully adopted also of which the Cochrane Centres are an example in the sector of services production, including in Italy. health care services. CQI has progressively re- A further development called “Total Qual- placed the previous, and perhaps more known, ity”, introduced by Deming and by Japanese expression of “Quality Assurance”, which was researchers, has paid attention to the human introduced in Italy by Perraro and Gardini [4] factor as the main productive factor. The fun- many years ago under the denomination of damental principle of this approach is that the “VRQ – Verifica e Revisione della Qualità”, in best quality (or excellence) is achieved when Italian language . all people participating in the production pro- An important contribution to the theory of cess are involved and motivated to pursue it. quality in health care services was made by Thus, excellence is achieved when every em- Avedis Donabedian [5]. He defined the four ployee of an organization does his/her work basic dimensions on which quality analysis in a creative manner. This concept, as well as was to be performed: input (human, instru- that of CQI, has merged into the more recent mental and financial resources), process (mo- European Foundation for Quality Manage- dalities to produce services), output (provided ment (EFQM) model 1. services) and outcome (results of services in terms of health improvement of the end users - individuals or, as in the case of prevention, 2.2. The EFQM excellence model. population). Because of their different nature, these four dimensions need different approaches during The EFQM model represents a novelty in assessment and different means to assess them. the panorama of approaches to quality. The However, a process of continuous quality im- novelty is not only temporal, the model is a provement implies a continuous intervention recent one, but also of content because it intro- on and monitoring of all the four dimensions duces new concepts compared to the previous because each can influence the final result or models. This innovative model perhaps can 262 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 263 be better implemented in the sector of health care and social security than more traditional an organization, even those not usually stan- models. dardizable. Moreover, it emphasizes ‘quality At present, it has been adopted by some management’ at all levels as an integral and important European businesses such as British necessary part of the overall organization Telecom, Volkswagen, Rank Xerox and Philips, management. Finally, it favors the processes of and by some Dutch health care organizations, ‘organizational development’ and CQI. among which the Jellinek Zentrum (Amster- The EFQM Excellence Model is a model for dam) for pathological addiction. quality management that has been formulated Some years ago, the European Commission by the European Foundation for Quality Man- started a research project called “ExPeRT Proj- agement and was revised in 1999 in Geneva. ect" [6] to make a critical review of the most EFQM is a non-profit, membership-based used models to guarantee quality in health organization created in 1988 by the presidents care organizations in Western Europe. of 14 leading European businesses such Bosch, From the study, it emerged that four mod- BT, Bull, Ciba-Geigy, Dassault, Electrolux, Fiat, els were widely used in Europe: KLM, Nestlé, Olivetti, Philips, Renault, Sulzer, 1. ISO approach Volkswagen, with the support of the European 2. Accreditation of health care services Commission. By January 2000, it included 800 3. Peer Review members from most European countries [38 4. EFQM countries) and most sectors of activity, includ- The ISO model defines the characteristics ing public administrations and health care or- or standards to which an organization and its ganizations. functional procedures should conform to be EFQM helps European businesses to im- considered of ‘good quality’. Such standards prove their products and to provide better ser- represent a sort of norms, which sometimes are vices by means of efficacious and state-of-the- very detailed and mandatory. Based on these art management techniques. norms, a number of certification agencies will From the very beginning, the ‘vision’ of be able to grant a certification of quality. EFQM was to contribute to the creation of Similarly, in the Accreditation model, a strong European organizations that applied public actor (or a private one acting on behalf the principles of Total Quality Management of the Government) assesses and checks the in their economical activities and in their re- features and functioning of an organization. lationships with the employees, stakeholders, Then it issues an Authorization to Operate fol- customers, and communities in which they lowed by and Accreditation, to be verified at operated. fixed deadlines, that recognizes the organiza- The mission of EFQM is: tion and allows it to obtain public or insurance 1. To stimulate and help European organi- funding. This is the case of the American Joint zations to participate in improvement ac- Commission for Accreditation of Health-Care tions aiming at excellence in terms of cli- Organizations (JCAHO) which, on behalf of ents and employees‘ satisfaction, impact the Federal Government, recognizes hospitals on society and economical results; and other health care organizations. 2. To provide support to the managers of Peer Review means that an organization is European organizations to accelerate the assessed by experts from another organization process that sees total quality as a deter- who have the same professional competences minant factor to reach a global competi- and experience in the specific field. This model tive advantage. is more dynamic, more concerned with ‘pro- The introduction of Total Quality Manage- fessional competence’, and it is lesser bound to ment programs can result in important bene- specifications or regulations. fits for the organizations, such as growing effi- The EFQM model has a more ‘general’ ap- ciency, reduced costs, and greater satisfaction, proach in that it deals with all the aspects of which means better economic results. 262 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 263

The EFQM model is based on the concepts ent trend in management. The last revision by Deming with regard to the continuous was initiated in January 2003. quality improvement through the cycle “plan- The approach with which an organiza- do-check-act”, which constitutes the process tion pursues and achieves its goals may vary of continuous quality improvement. As for and the assessment of the procedures and ap- the description of the organization, the EFQM proaches is not based on conformity to stan- model is similar to the model of Donabedian, dards but on the efficacy in achieving the re- which distinguishes structure, process, and sults. outcome. In fact, the EFQM model recognizes that The EFQM Excellence Model was intro- there are many approaches to achieve sustain- duced in 1992 as a reference model to award able excellence. Within these non prescrip- the European Quality Award. It is the most tive approaches, there are some Fundamental used model in Europe to evaluate organiza- Concepts. They are non exhaustive and can be tions. While the Quality Awards are limited changed or integrated based on the improve- to few users, the real measure of the efficacy ments of the organizations that have reached of the EFQM model is its wide use as a man- excellence. At present, the fundamental con- agement system and the associated growth of cepts are: managerial capacities in organizational self- 1. Results orientation. Excellence is achiev- assessment. ing results that delight all the organiza- Independently of the sector, dimensions, tion’s stakeholders (consigners, suppli- and structure or maturity, to be successful an ers, employees, and final customers). organization has to define an appropriate man- 2. Customer focus. Excellence is creating agement system. The EFQM model is a good sustainable customer value. tool to do this because it allows an organiza- 3. Leadership and Constancy of Purpose. tion to evaluate at what point it is in its way to Excellence is visionary and inspirational excellence, it helps to understand the causes of leadership, associated with constancy of failure, and it stimulates adequate solutions. purpose. The innovations of this model are many 4. Management by processes and facts. Ex- compared to the previous models. Some of cellence is managing the organization them are of particular interest for the health through a set of interdependent and inter- care and drug addiction therapy in Italy. related systems, processes and actions. First, the EFQM model is European, which 5. People development and involvement. is not only a geographical connotation. One Excellence is maximizing the contribu- of the aim of EFQM is “to stimulate European tions of employees through their devel- organizations to achieve global competitive opment and involvement. advantage, aiming at the satisfaction of the cli- 6. Continuous learning, innovation and im- ents and employees, and at a positive impact provement. Excellence is challenging the on the society”. status quo and effecting changes by us- Secondly, the EFQM model is not ‘norma- ing learning to create innovation and im- tive’. The attention is not focused on confor- provement opportunities. mity to specifications that are continually 7. Partnership development. Excellence is redefined. In fact, this model recognizes that developing and maintaining value-add- there are many efficacious approaches and it ed partnership. fixes only few Fundamental Concepts, which 8. Corporate social responsibility. Excellence can be implemented in different manners. is exceeding the minimum acceptable Moreover, EFQM updates the model taking level of functioning of the organizations into consideration the outcome of ‘good prac- and striving to understand and respond tices’ assessed in thousands of European and to the stakeholders’ expectations. non European organizations. By this way, the Thirdly, the model has fully adopted the model remains dynamic and reflects the pres- principles of Total Quality, i.e. it tends to em- 264 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 265 phasize the quality of people rather than pro- The arrows indicate the dynamic nature of cedures. If the goal of every single person of the model. They show how Innovation and the organization is to provide a product or Learning support the improvement of En- service of quality and if everyone can develop ablers, which in turn improve Results. his/her creativity in pursuing quality, this will The nine boxes represent the Criteria with become a necessary value. which to assess the progression toward excel- The EFQM excellence model is based on lence. For each of the nine criteria, a definition nine Criteria. Five of these - leadership, per- explains what it means to achieve a high level sonnel management, policy and strategy of in that Criterion. the organization, partnership and processes Among Enablers Criteria, Processes and – are Enablers, and they enable an organiza- Leadership are considered the most important; tion to implement its ‘mission’ and pursue its among Result Criteria, Customer Results and objectives. The other four criteria – customer Key Performance Results are the leading. results, people results, society results, key Each of these criteria can be investigated performance results – are Results, and they taking into account the 32 sub-criteria, 24 are the real object of quality assessment. The for the Enablers and 8 for the Results. These Result criteria cover what an organization has sub-criteria are used as areas of ‘assessment’, achieved. Results criteria are caused by En- which are tools to assess, through clear and ablers and feedback from the Results help to comprehensible examples, the ‘status’ of an improve the Enablers criteria. organization. The model, which recognizes different ap- Unlike others models, the EFQM model proaches to achieve sustainable excellence in is not based on a definition of quality. In con- all aspects of services, is based on the follow- trast, it considers quality management as an ing assumption: integral part of the management function, as “Excellent results with respect to Perfor- well as of the professional functions present in mance, Customers, People and Society are an organization. achieved through Leadership which leads Pol- However, the real novelty of the EFQM icy and Strategy, that is delivered through Peo- model is that it allows and legitimate self-as- ple, Partnership, Resources and Processes". sessment, whereas one of the principles of the The diagram of the EFQM model is as fol- previous models was external assessment (cer- lows: (Figure 2) tificate of conformity by external agencies in

Figure 2. Diagram of the EFQM 264 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 265

the ISO model, review by public organizations Dutch variant of the EFQM model is that five in Accreditation, review by external profes- different phases of organizational develop- sionals in Peer Review). ment have been defined: Product Orienta- Self-assessment can be applied to small and tion, Process Orientation, System Orientation, big organizations, in the public and private Chain Orientation, and Total Quality. sectors. An increasing number of organiza- Product Orientation is when the attention tions is using data from self-assessment in the of the organization is on providing correct planning of their activities and use the EFQM performances. For example, to define what is model to review them. a good medical and toxicological assessment The EFQM model can also be used as a di- and a good pharmacological protocol. agnostic tool to assess the present ‘status’ of However, the most important processes an organization. By this process, an organiza- are Process Orientation, System Orientation, tion is able to better balance its priorities, allo- Chain Orientation, and Total Quality, which cate its resources and define a realistic activity could be defined as ‘meta-processes’ because plan. In doing this, the process of self assess- they integrate the interventions of different ment is important. EFQM gives the following knowledges and disciplines. definition: At one meta-level, the management (e.g. “Self-assessment is a comprehensive, sys- the director of an Addiction Department) can tematic and regular review of an organiza- maximize the probability that the services pro- tions’ activities and results referenced against vided are correct without caring for them per- the EFQM Excellence Model. This process al- sonally if the people are in the right place and lows the organization to discern clearly its if there are rules of collaboration and respon- strengths and areas in which improvement sibility that are scientifically validated and ac- can be made. Through this process of evalua- cepted. The actors of these performances will tion, an organization improves the balance of guarantee the quality, especially if they are its priorities, the allocation of its resources and gratified with what they do. This is an exam- produces a realistic plan of its activities”. ple of process-oriented organization. It is clear that this model which allows self- Considering the next meta-level, the orga- assessment of all nine dimensions (Criteria) nization can focus on the interactions between and throughout all the organization at almost different areas of activity. In other words, it can no cost is preferable to external assessment, study how different segments of intervention, when the results are the same. Moreover, with which follow different logics and scientific an internal review there are fewer controver- knowledges, can integrate to meet the user’s sies between professional workers and man- needs. Addiction departments offer a good ex- agement. ample of system-oriented management in that different professionals interact, each with his/ her own competence, to develop a multidis- 2.3. Implementation of the EFQM model at ciplinary therapeutic and rehabilitative pro- Jellinek Zentrum - Amsterdam. gram. A system-oriented organization tries to govern these complex interactions on the basis of the context in which it works and monitors The Jellinek Zentrum - Amsterdam is an their effects on the end user. organization with 500 health care workers that In a chain-oriented organization, the atten- cure and care for 5,000 patients with addiction tion of the management is on the problem of problems, distributed in 24 different programs “therapy and assistance continuity”. In other of medical, psychosocial and rehabilitative words, the attention is on the chain or sequence treatment. The quality model adopted by this of events, some of them within the organiza- centre is based on the EFQM model and its re- tion, which can produce a good therapeutic sults have been recently published [7-9]. result if governed or can introduce bias and The most interesting characteristic of the distortions if not. Some examples? The family 266 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 267 doctor who prescribes buprenorphine while to refer in order to work better and to present methadone is administered; the therapeutic his/her own results (maybe also to obtain a community that accept addicts without agree- reward). ing a therapeutic program with Addiction The Jellinek Zentrum has been subjected to Facilities; a hospitalization which has failed various assessments based on the EFQM mod- because it was decided by the family without el and different changes has been introduced an agreement between health care workers of in its organization in these years. Addiction Facility and the hospital; a sudden release from prison without a program. Because it implies non-hierarchical – i.e. 3. Methadone and quality partnership - relations, the chain-oriented management has to use new tools, ranging from external credibility for its workers to Until now I briefly exposed a new interest- budget management in a therapeutic sense, for ing quality assurance model. But how can it be example negotiating funding to the communi- applied to Methadone Maintenance Therapy ties in exchange of quality assessment of the Programs (MMTP)? services provided, formulation and assessment First, the planning of a treatment with of operative protocols which, to function, have methadone too can be divided in different to consider the convergence of motivations components: mission, vision, enablers cri- and interests among all the organizations in- teria, result criteria and self-assessment. All volved. In some ways, this action is diplomatic these components are essential but should be and can be synthesized as follows "to make a analysed and defined separately. In fact, every constant effort to orient all resources towards process to improve quality implies a clarifica- the health of the end user”. tion of its components, a sort of ‘declaration’ The last process is Total Quality. Every of how they should be, followed by a circular worker can work well if he/she is in the con- evaluation of how they are in reality in order dition to do it. Many of these conditions do to introduce changes leading to excellence. not depend on external factors or on top management. There are some organizational conditions that depend directly on the operative 3.1. The “mission” and “vision” of a metha- management. done treatment program. The motivation of the workers distribute in a Gaussian curve; this means that, considering the good and the very good workers, there Because of the existence of more than one are high probabilities to comprise more than epistemological model on methadone treat- 80% of workers from the start. Moreover, it is ment and of the confusion between them, as known that money does not motivate people, previously mentioned, is necessary to make a and this applies also to people working in Ad- choice. Thus, starting from the three assump- diction Departments. tions of the second paragraph, which are arbi- They are much more motivated when they trary for some people but which we consider feel their work as “their own”. Leadership fundamental to implement a scientifically evi- also consists in having a direct or indirect re- dence-based MMTP, it is possible to formulate lationship with all workers. In this relation- a precise definition of the ‘mission’ of MMTP: ship some messages should be clear: what is 1. To reduce and eliminate heroin use, mini- expected from the worker and why (i.e., the mizing the risks of relapse and promot- benefits for the end user), which are the mar- ing such a state for a long period (months gins of autonomy and creativity of each per- or years). son (each person must benefit of such margins 2. To stabilize as far as possible the psychic and they must be proportional to what he/she state of the patients without severe psy- can give), and finally to whom, when and how chic diseases, eliminating craving and 266 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 267

preventing hypophoria. diction treatment services to properly ad- 3. To promote and favour, eventually in as- minister methadone in a hostile environment sociation with other therapeutic interven- demonstrate how an intervention, although tions, a change in the life of drug addicts, conducted following the state of the art, can sometimes resulting in a long drug-free have a greater or a minor impact on the target condition. population according to the context. Moreover, Such a general “mission” can be personal- hostile environmental conditions may lead to ized according to the physical conditions, the an inappropriate use of the drug. In Italy, for whole diagnostic picture and the response to example, methadone have been used inappro- treatment of the patients. In fact, not all pa- priately for many years on the basis of ideo- tients can achieve the above-mentioned goals logical motivations. to the level, but methadone should not be It follows that the “mission” is associated used systematically to pursue goals other than with scientific knowledges that are recognized those, or else the intervention will be ineffica- and codified in the literature, whereas the “vicious and non scientific. sion” is associated with the context in which The “vision” of MMTP is a component that one acts. Thus, the “vision” is the interface deals with the context in which one acts. In between acquired scientific evidence and its other words it forecasts the scenarios within transferability to a real context. It consists in which the treatment interacts and studies the an analysis of the situation and actions aiming impact of treatment on the health of the pa- at improving the feasibility of the mission in tient, in order to maximize it. accordance with the above-mentioned circular To define the “vision” adequately it is nec- process. essary to ask oneself some questions. These Some years ago, the Strategic Plan 2000- can be summarized as follows: 2005 of NIDA, the federal organization in USA 1. Questions concerning the epidemiology dealing with drug addiction, started Clinical of the phenomenon investigated. For ex- Trial Network aiming at increasing the use of ample, which is the prevalence of heroin scientific knowledge in the clinical practice by addiction among our patients? Which services for drug addiction. This because the is the rate of psychiatric comorbidity? transferring of acquired knowledge into clini- Which is the rate of patients with com- cal practice was contradictory and poor. Prob- plex organic disease? ably, this also occurs in Italy, although the is- 2. Questions concerning the attitude of the sue has not been raised yet. health care workers. For example, which This can be due to an inadequate defini- is the degree of acceptance of MMTP epis- tion of the “mission”, but also to a “vision” temology? How much are the health care which is insufficient to efficaciously transform workers convinced of its efficacy? Which knowledge into adequate services. interactions exist between operators with As previously mentioned, methadone has different professionalities with regard to proven inefficacious in contexts where people methadone treatment? think that a heroin addict should not be treat- 3. Questions concerning the opinion of the ed with drugs and think that methadone is not society on methadone treatment, especial- therapeutic. Thus, a different epistemology of ly of the community in which one works. the context makes scientific evidence less ef- A greater social acceptance favors the ficacious in the practice. treatment, also because it has a positive From this, it is clear that the definition of influence on the users and their families. “mission” is essential to plan an efficacious If there is a scarce acceptance, some infor- MMTP, and that the attention to “vision” and to mative-formative interventions should the actions necessary to modify the resistance be planned that modify the culture in a of the context is a necessary complement. more favourable sense. The great difficulties encountered by ad- 268 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 269

3.2. Enablers criteria tional protocols and should be trained to manage aggressiveness, violence and in- congruous behaviours. These aspects are As previously mentioned, the Enablers often left to the common sense and to the Criteria of the EFQM model are Leadership, sensibility and abilities of the health care People, Policy and Strategy, Partnership, and workers. A good quality manual for ad- Processes. What do they mean with respect to diction services should contain protocols MMTP? Here are some examples. or procedures for these situations too. 1. The Leadership defines the “mission” 3. Policies and strategies are the modalities and “vision” for all health care workers with which the “mission” is oriented to (see previous section). Moreover, it sup- the interests of the stakeholders. There are ports the principle that “there is always two types of stakeholders: the users and something which can be improved” in the consigners. In methadone treatment, MMTP by introducing a periodic process the main interest of the users is to take the of comparison and evaluation. It also maximum advantage in terms of health, makes sure that clear and univocal mes- in the present and future time. Thus, the sages are received by the user as to the effect of methadone on users should be finalities and modalities of the service. monitored at short, medium and long Finally, the leadership identifies and pro- term in order to select those clinical and motes the changes that may be necessary organizational behaviours that better while continuing pursuing the finalities pursue the goals of the “mission”. The described in the “mission”. consigner is in this case the public admin- 2. People are crucial in the management of istration because methadone is also used MMTP. Because the MMTP is a very wear- for the public health. Thus, strategies ing out component of our work, the staff will be defined in order to reduce social must be in a sufficient number. Consider- problems (petty crime, hanging about the ing that a good service has to administer out-patient room) but also to reduce the methadone every day, including Sun- spreading of transmissible diseases. days and holidays, the minimum num- Policies and strategies should be ex- ber of health care workers should be of plained to the health care workers through one doctor and two nurses. The presence a “key processes scheme”. In this way, of other professionals is recommended. those processes that are determinant for However, this is not always possible be- the success or the failure of a strategy are cause the resources are few, but a good emphasized. For example, the manage- program for quality improvement should ment of the external space of the out-pa- consider that the lower is the number of tient room (when the resources exist) can workers, the greater is the risk of work- influence the correct use of methadone ers’ “burn-out”. The problem is not only and in the outcome of the therapy. The ethical (people working in unacceptable modalities to implement such a strategy conditions) but also arithmetical. Fewer should be made clear through a scheme workers means an increasing “burn-out”, of behaviour or protocol to be used by the which results in greater turn-over, which health care workers. results in difficulty in finding new work- 4. External partnership and internal re- ers, which finally results in even fewer sources should be planned and managed. workers. A sufficient number of workers In the case of methadone treatment, pos- for the administration of methadone pre- sible partnerships are those with volun- vents this vicious circle and at the end it is tary workers, and private or voluntary a good investment. Moreover, the workers groups . These relationships should be administering methadone should have codified in the framework of the so-called access to accurate clinical and organiza- Enlarged Department. Such partnerships 268 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 269

can strengthen the efficacy of MMTP, es- munications regarding the adopted pro- pecially in the rehabilitative sector. An- cedures should be clear for the users. other strategic partnership is with the po- So far, much has been said about quality, lice. The management of an out-patient but anything is fixed and immutable. Indeed, room for MMTP implies security risks for in the search for quality- especially total qual- the workers and the public order. For a ity – all the interested parts are involved in a correct collaboration with police, the pri- continuous re-definition and elucidation of the vacy of the patients should be respected above-mentioned contents. and the patients should be warned that no disturbances to the services are allowed, to defend both the workers and the rights 3.3. Result criteria of those users who behave adequately. This should be defined and advertised within the out-patient room activities. A good elaboration and definition of the With regard to the internal resources, Enablers Criteria allows a correct planning of there is the problem of the continuous re- the Result Criteria: customer results, people definition of the adequacy of the rooms results, society results and key performance and the furniture of the out-patient room, results. which must follow health care norms The continuous monitoring of the results is for security. A periodic review of these the most important aspect of the EFQM mod- specifications by the health care workers el. For all result criteria, two features are moni- should be a component of a good quality tored: performance and subjective perception. plan. In the case of customers, the measurement 5. The processes are the heart of the added of performance can be conducted through value of the service. The clinic of MMTP, the identification of a set of clinical indicators according to the criteria of evidence- which should continually monitored, such as based medicine, is probably the most im- the negativity rate of urine analysis, the degree portant process to manage systematically. of reliability of the patient (in this regard, the The supply and custody of methadone judgment should not be only a subjective one and the thematic of giving the methadone of the worker but objective and shared criteria to take home, the so called “entrusting”, should be defined), and the rate of “retaining are other important processes to codify, in treatment”. to manage daily, and to review systemati- In the case of people, each worker should be cally. ‘Entrusting’ (how much methadone given precise objectives and the achievement can be taken away, for how many days, of these is assessed according to the policy of and according to what criteria) risks to be the organization. However, the assessment is the weak point of every service deliver- efficacious if two indications are respected: 1) ing MMTP. In relation to this matter, the it should be clear what is expected from the differences between health care profes- worker; 2) the evaluation modality should not sionals should be minimized through a be inquisitional or inspectorial, but colloquial process of consensus conference, so as to and aiming at finding actions to improve per- offer to the other workers, starting from formance. the nurses, and to the users themselves, In the case of society, the social perception a point of reference which is certain and of the activity of the service should be moni- rigorous. “Entrusting” practice can also tored. Sometimes, the society only sees the lead to aggressive behaviour. In these cas- negative aspects of drug addiction (the pres- es, a change in the rules and behaviour ence of drug addicts in the streets near the out- should be planned and implemented in a patient service is often the object of animated progressive manner, informing the work- discussions in population’s meetings). In some ers and the police, if necessary. The com- way, this is physiological in that the existence 270 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 271 itself of drug addicts is not appreciated. How- 3.4. Self-assessment ever, this aspect should not hide other aspects such as improvements or worsening of the disturbance caused by drug addicts, which can be As previously said, the EFQM model, un- associated with precise and identifiable causes. like others, is not based on a definition of qual- In the case of worsening, corrective actions can ity; thus, it does not assess the conformity to be identified to be effected inside and outside precise norms, but it assess the efficacy in the the health care structures. achievement of the goals. Moreover, unlike Finally, to monitor key performances, these other models, it makes use of a process of self- should be first identified. In a service provid- assessment of the organization. Self-assessing MMTP, key performances are few. For ex- ment is carried out on all nine dimensions – or ample, the identification of indicators for each criteria - through a tool called RADAR (acro- of the three processes identified in the previ- nym for Results – results with respect to the ous section: evidence-based medicine of meth- mission -, Approach – approach to the prob- adone, supply and custody of methadone and lems -, Deploy – use of resources -, Assess – as- the thematic of ‘entrusting’ with associated list sessment of the effects of the action -, Review of reliability criteria and flow-chart of assign- – periodic review). ment to the different phases and modality of The RADAR system is the heart of the treatment. EFQM model. The above-mentioned elements The dimension of subjective perception is represent five moments of a process of self-as- more complex to monitor. However, it allows sessment that is built according to the follow- the identification of tools that can be adequate ing logic: to: 1) give voice and visibility to the percep- 1. To determine the Results to be achieved tion that users have of the given service; 2) as part of a process of definition of its pol- give voice and visibility to the perception of icies and strategies. These results include the workers; and 3) monitor social perception. organization performance, from the fi- Because the EFQM model is not prescrip- nancial and operative point of view, and tive, the ways to implement these actions are the perception of it that the stakeholders various. Each person should identify the prob- have. lems considered so far and should find solu- 2. To plan and develop an integrated set of tions adapt for his/her context, placing them Approaches to highlight the results. at others’ disposal in a forum on quality. 3. To make these approaches explicit and In the EFQM model, each criteria is associ- available (Deploy) in a systematic way to ated with sub-criteria. These consist of ques- guarantee their implementation in the or- tions that must be considered. Finally, for each ganization. sub-criterion, there are guidance points. They 4. To Review the approaches used through are neither mandatory nor exhaustive, but analysis and monitoring of the results they exemplify the meaning of the sub-crite- achieved and through activities of contin- rion. The guidance points can be found in the uous learning. Based on this, identify the publication of the EFQM Excellence Model. necessary improvements and decide their The Jellinek Zentrum has elaborated a specific priorities, planning and introduction. Excellence Model, unfortunately not trans- When the model is used within an orga- lated from the Dutch, which can be adopted nization, the elements of Approach, Deploy- for programs for addiction treatment, among ment, Assessment and Review have to be used which MMTP. for all Enablers sub-criteria, and those of Re- sult for all Result sub-criteria. The RADAR is used as follows: Results This aspect is concerned with the results achieved by an organization. In an excellent 270 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 271

organization, the results show a positive trend the set of indicators described in the previous and a good performance, the goals are appro- section. However, the model has to be adapted priate and in line with or superior to what is for drug addiction and obviously this can be necessary, the performance can be compared done only by professionals working in that with that of others and depends on a good ap- field. So far, the Jellinek Zentrum is the only proach to the problems. organization that has developed a model spe- Approach cifically for addictions, which unfortunately is This aspect is concerned with the plans of not yet available. In the future, the directions an organizations and the reasons for them. In to follow are two: 1) to adopt the Dutch model; an excellent organization, the approach has and/or 2) to elaborate an original model based a clear rationale and well defined and devel- on the specific context. oped processes, it focuses on the necessity of the stakeholders, it is consistent with the policies and strategies, and it is appropriately con- 4. Quality in clinical practice: excellence nected with the other approaches used. Deployment This is concerned with how much an orga- The EFQM model, and in some way also the nization is able to make the approaches visible other models, tends to trigger a virtuous circle to and usable by the workers. In a good orga- in which every detail is considered. Excellence nization, the approaches are used in a system- means to have achieved, by continuous adjust- atic way and in areas which are strategic for ments following periodical assessments, ‘the the organization. best possible’ or ‘sustainable quality’. Assessment & Review However, the change from a situation in These aspects are concerned with what an which quality is not considered (or of pre- organization assesses and reviews both in the contemplation as Prohaska [10] would say) to approaches and in the deployment. In an ex- one strongly quality-oriented is only the start. cellent organization, the approaches and their All organizations tend to entropy and all open deployment are periodically reviewed, actions systems (an organization is an open system) are activated based on the review results, and has to continuously work on homeostasis to these are used to identify possible changes, to maintain their identity in the interchange with establish their priority and to plan their intro- the environment. Thus, Excellence also means duction. 1) to maintain and progressively improve the Self-assessment of an organization can also level of all the dimensions and 2) to continu- be carried out through a tool called “Path- ously change to adapt to new realities and new finder Card”, which helps identify the op- scientific evidence. portunities of improvement and plan the action of improvement. There is no score but a list of questions which can be answered in a 4.1. Quality of the pharmacological and short time. The logic is the same as that of RA- non-pharmacological aspects and their DAR, but it is simpler and less rigid. One or integration. more Criteria, or any sub-criteria associated with them, and the corresponding questions of the card are selected. The questions are not The use of methadone in the treatment of mandatory prescriptions, but an occasion to drug addicts has been considered for a long reflect on each of the examined aspects: they time, in Italy as well as abroad [11-13], a ‘minor provide indications on the critical aspects of evil’ in which methadone was justified if the the organization and on the possible actions of dose was increased and/or if it was associated improvement. with consultations, more or less psychothera- Self-assessment of MMTP can be performed peutic, and social or rehabilitative activities, following the above-mentioned model, using thus stimulating instrumental or ‘liturgical’ 272 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 273 attitudes [14]. That is, attitudes in which the or rehabilitative interventions are necessary to patient was forced to accept things that he/she cope with specific problems of the patient and did not consider necessary in order to obtain to improve the prognosis and the outcome of methadone from the health care worker. MMTP [23-26]. If methadone has to be used, this should Finally, there are situations in which the im- be done in the best way possible. This means provement of the rate of ‘responders’ is asso- that, for the therapeutic teams of addiction de- ciated with organizational or communication partments, the drug should be “at the centre of factors. The cultural reference system – that is the therapeutic program”. This means that the the epistemology with respect to methadone drug, as main intervention, has to be measured treatment – is important not only for the work- in the clinical practice also in the absence of ers but also for the patients and their environ- other interventions. ment. The influence of the peers, also with This point, which may seem obvious to respect to the credibility of the service, can be some people, is still a cause of controversy important to improve or not the outcome of which risks to feed an old problem. How can a MMTP. tool that is not trusted by the therapeutic team Similarly, to give a picture of definite and be used at the best? [15;16] reassuring rules to the patients with greater In fact, as proven by the literature, a well motivation or to strongly prevent patients managed MMTP may by itself eliminate the from breaking a positive environment with a use of other opiates and modify the life style critic or instrumental attitude may increase the and quality of life of many heroin addicts. Evi- rate of the “responders”. dence also exists [17] that interventions of psy- The problem of the “non responders” chosocial support have a good cost-benefit ra- should be dealt with according to an algorithm tio if they are of modest entity, such as generic that can be formulated as follows: counselling. More intensive interventions are 1. To identify pharmacological causes (inad- more expensive than useful where the diagno- equate dosage, necessity of greater doses sis is of drug addiction not complicated by co- for particular problems) and corrective morbidity, psychosocial situations particularly actions. compromised, or severe polyaddiction. 2. To identify organizational causes (rela- Some patients present heroin addiction as- tionship and communication with the pa- sociated with one or more of the above-men- tient) and introduce corrective actions. tioned conditions. They are the so called “non 3. To identify particular problems of the responders”, for whom MMTP does not pro- patient, such as comorbidity (organic or duce the expected results [18-20]. psychiatric), stress or situations of social Most of quality clinical practice is con- discomfort, or presence of polyaddiction cerned with these patients, who represent a and activate other medical, social, and minority of the users but who have complex psychiatric interventions (intensive if and severe clinical pictures. necessary). An important quality goal in MMTP pro- If none of the above-mentioned problems grams should be the identification of the prob- exists or if corrective actions has been success- lems of these patients and the development fully activated, the remaining cases of “non of tools to improve the services provided. For responders” represent , maybe, the not elim- example, there are cases in which the dose of inable part of the phenomenon. However, at methadone has to be increased for pharmaco- the end of the circular process of quality im- logical or clinical reasons, such as in the case provement, their number could be much more of contemporary administration of nevirapina lower than the initial one. [21] in patients with AIDS-related pathology, The diachronic study of “non responders” or in the case of severe psychiatric comorbidity in a service providing MMTP can offer an im- [22]. In other cases, complementary treatments portant representation of the characteristics of such as counselling, psychotherapy, and social the customers and of the functionality of the 272 · CHAPTER 5.1 METHADONE AND TREATMENT QUALITY. THE EFQM EXCELLENCE MODEL · 273

service, and represents a crucial element for the EFQM model of excellence, a definition of benchmarking. “good practices” continually proposed to other people working in the same field. In this continuous search for quality, many 5. Conclusions: state of the art and open issues remain open. In particular, three prob- issues lems greatly influence the daily work of addiction services. The first problem is the little flexibility of The search for quality is a never-ending, methadone, which continues to be the drug of dynamic process, and excellence itself is not choice, but which requires a daily administra- definitive. As it has been demonstrated, it is tion, with the consequent organizational prob- a circular process that has to progressively lems. With regard to this, it should be point- improve the performances but also to defend ed out that the real or presumed superiority itself from the natural entropy of not-man- of LAAM has not been tested in Italy [41]. If aged situations (it has to continually introduce LAAM is effective even in a small number of “negative entropy”). Finally, this process has patients in MMTP, the fact that it has not yet to continually take into consideration innova- been introduced means an increase of costs, in tions and new knowledges or ‘scientific evi- human, organizational and financial terms. dences’. The second problem is the need for re- In my opinion, the EFQM model is more search, innovation and experimentation in the functional than others to the activities of ad- management of non responders, the number diction services, in particular those providing of whom has to be progressively reduced. MMTP. In fact, these activities are at high rate The third problem is the problem of ‘en- of methodological uncertainty (the human fac- trusting’ methadone. The degree of reliability tor is always dominant with respect to specifi- of the patients should be better defined and cations and procedures) and require creativity better procedures, flow charts and protocols and team spirit. should be planned to decide how much meth- Moreover, this model shows the directions adone can be taken away, with what modali- to follow and the goals to achieve, while al- ties and to whom. lowing great freedom in the choice of the mo- In fact, from the therapeutic point of view, dalities to act. It is evident that an organiza- it is disadvantageous not to give a patient the tion has to harmonize individual initiative in possibility to responsibly manage its therapy. a common project. Therefore, there will not However, it is equally detrimental to trust a be individual paths to quality but paths of an patient who is not able to responsibly manage organization, and the benchmarking will be his own therapy. based on the results achieved rather than on In the prayer of the anonymous alcoholics, procedures adopted. they ask the ‘superior being’ for help to face In our case, the “state of the art” identifies what they can face, to accept what they are the organizational and operative modalities not able to face and to distinguish between the that achieve the higher rate of responders to two situations. We, therapists of drug addic- MMTP and /or greatly reduce the rate of non tion, need help in this “understanding” and responders among the more problematic pa- “distinguishing” action. 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Pharmacokinetic Monogr 106:358-364. interactions of nevirapine and methadone and 40 Phillips CD, Hubbard RL, Dunteman G, guidelines for use of nevirapine to treat injection drug Fountain DL, Czechowicz D, Cooper users. Clin Infect Dis 33(9):1595-1597. JR (1995). Measuring program performance in 22 Maremmani I, Zolesi O, Aglietti M, Marini methadone treatment using in-treatment outcomes: G, Tagliamonte A, Shinderman M (2000). an illustration. J Ment Health Adm 22(3):214-225. Methadone dose and retention during treatment of 41 White JM, Danz C, Kneebone J, La Vincente heroin addicts with Axis I psychiatric comorbidity. J SF, Newcombe DA, Ali RL (2002). Relationship Addict Dis 19(2):29-41. between LAAM-methadone preference and treatment outcomes. Drug Alcohol Depend 66(3):295-301. Index

Symbols B µ receptor Behavioural targets 148 Site binding 49 Benzodiazepine abuse 84, 111, 182 µ receptor interaction 49 Black market 101, 132 Blocking dosages 88, 89, 90, 93, 109, 110, 123, A 136 Breast-feeding 189, 193 Abuse 11 Brief motivational interventions 240 Action stage 235, 236 Addiction 11, 12, 16, 17, 78, 79, 86, 92, 95, 101, C 103, 106, 108, 112, 115, 124, 125, 126, 134, 211 Cardiac safety 120 Addiction-related crime 199 Case-planning 82 Addictive ambivalence 14 Catecholamines 73 Addictive resistance 137 Central drug addiction services 223 Admission of patients 81 Child development 193 Adverse events 117 Chronic pain 121 Affective disorders 90 Client 242 Aggressiveness 200 Clinical approach 68 Alcohol-dependent heroin addicts 170 Clinical Foundation 189 Alcoholism 168 Clinical foundation 141, 153, 181, 197, 211, 217 Alcohol abusers 90 Clinical use of urinalyses 127 Alcohol and BDZ polyabuse 184 Cocaine 76, 90, 107, 118, 121, 122, 128, 133 Alcohol dependence 169 Cocaine abuse 184 Ambivalence 82, 84, 115, 138 Cognitive-behavioural psychotherapy 251 Anti-aggressive agents 166 Collection of urine samples 128 Anti-therapeutic communities 214 Compliance 83, 84, 85, 90, 93, 94, 95, 105, 107, Anti-withdrawal dosage 98 118, 123, 131, 132, 133, 134, 137, 138, Anticraving treatment 75, 76, 90, 100, 110, 114, 139, 242 122, 132, 136 Compulsion 248 Antidepressants 156 Concern 240 Antipsychotics 163, 164 Conflicting situations 242 Antiviral Therapy 146 Constipation 118, 124, 125 Anxiety Disorders 160 Contemplation stage 234, 236 Assessment of stage status 236 Continuous quality improvement 260 Associated pathologies 34 Counselling 234 Availability of treatment options 40 Craving 75, 76, 77, 82, 84, 85, 89, 90, 100, 101,

275 276 index · 277

103, 104, 105, 106, 109, 111, 115, 119, 128, Good clinical practice 100 131, 132, 138, 139 GP setting 107 Cultural factors 106, 122 Greed 248 Group psychotherapy 252 D Group work models 242 Data collection 85 H Definitions 11 Dependence 12, 21 Habit 11 Desimipramine 165 Handling relapse 114 Detention 202 Harm reduction 33 Detoxification 75, 76, 77, 78, 88, 95, 104, 105, HCV-positive patients 145 109, 122, 123, 134, 135, 136 HCV infection 144 Diagnosis of heroin dependence 34 Healing 81, 103, 106, 124 Disulfiram 165 Heroin 21 Doctor’s surgery 219 Heroin addiction 21, 25, 27, 31 Dosage 97, 118 29 Dosage-increasing stage 25 Clinical presentation 28 Dosages in relation to pharmacology 100 Intoxication 28 Dosages in relation to phases 100 Other Opioid-induced disorders 28 Dosage increases 101 Overdose 28 Dosage of methadone 83, 97 Tolerance 28 Dosage Reductions 101 Withdrawal Syndrome 28 Drug-free 86, 88, 94, 103, 105, 106, 109, 122, Diagnosis 29 124 Etiopathogenesis 21 Dual Diagnosis 153 Natural History 24 Dual diagnosis 78, 99, 101, 114, 136 Prognosis 29 Dual diagnosis-related resistance 139 Typology 25 Dumping 251 Metabolic 27 Duration of treatment 83, 91, 92 Reactive 26 Dysphoria 200 Self-therapeutic 27 Higher dosages 100 E History of methadone treatment 75 Efficacy of psychotherapy 256 HIV infection 146 EFQM excellence model 259, 261, 265 Honeymoon stage 24 Enantiomers 51 Hypophoric syndrome 124 Endogenous opiate 72 Hypothalamic-Pituitary-Adrenal Axis 71 Engagement in treatment 242 Hypothalamus-Pituitary-Gonadal Axis 70 Enrolment in treatment 81 I Ethical principles 39 Illegal methadone 101, 123, 132, 133 F Induction dosage 98 FRAMES approach 239 Induction phase 87 Frequency of attendance 83 Infectious diseases 141 Insight 16 G Intention to change 240 Intolerance to methadone 118 General practitioner 217 GHB 170 J Global toxicity 117 Glucose metabolism 73 Jail 197 276 index · 277

L Treatment Quality 259 Methadone blood levels 88, 97, 99, 100, 118 Laboratory evaluations 85 Methadone diversion 92, 107, 132, 133 Levels of change 235 Methadone dose 78, 85, 93, 101, 102, 107, 111, Levels of intervention 31, 32 121, 122, 123, 126, 134, 139 Level of tolerance 87, 88, 94, 98, 109, 114, 123, Methadone Maintenance 102, 104, 106, 108, 109, 127, 132 117, 125, 126, 131, 134, 144, 145, 146, Liver function 120, 125 148, 154, 160, 162, 166, 168, 181, 182, Long-term perspectives 103 184, 200, 235 Long term safety 104 Methadone maintenance in different settings 94 Low-threshold MMT programmes 243 Methadone overdose 119 Lower dosages 100 Methadone tapering 109, 111, 115 M Methadone Treatment Management 247 Maintenance dosage 99, 105 Methadone treatment 75, 77, 81, 86, 87, 89, 91, Maintenance phase 91 94, 95, 102, 104, 105, 108, 112, 117, 126, Maintenance stage 236 129, 134 Malpractice 101 Methadone treatment history 75 Medically supervised withdrawal 109 Methadone treatment program Medical maintenance 106 Mission 266 Medical principles 17 Vision 266 Methadone 141 Mimic caring 251 Absorption 44 Misconceptions 78, 122 Blood concentration 63 Mood-stabilizing drugs 157 Clinical approach 68 Mood and methadone 67 Determinants of variability 67 Morphine 75, 76, 77, 120, 128 Pathological conditions 67 Mortality 104 Pharmacologic interactions 67 Motivation 235 Physiological states 67 Motivational enhancement therapy 240 Distribution 45 Motivational interventions 233, 238, 241, 243 Elimination 47 Motivational interviewing 239 Endocytosis 50 Mourning for the lost object 248 For pain in pregnant women 193 Intolerance 118 N Management during pregnancy 190 Naloxone 119, 120, 124 Metabolism 46 Naltrexone 204 Neurochemistry 43, 48 Narcotic blockade 87, 100 Neuroendocrinologic effects 69 Natural course 202 Overdose 119 Neonatal abstinence syndrome 191 Pharmacokinetics 45, 63 Neonatal strabismus 192 Pharmacological Interactions 58 Neonatal thrombocytosis 192 Pharmacological interactions 158 Neuro-hormonal Axis 69 Pharmacology 43 Non-compliance 242 Quality 266 Non-therapeutic Communities 214 Racemic 44 Normalization 77, 78, 106 Side effects 52 Specificity 49 O Stability 66 Teratogenicity 190 Opiate peptides 72 Tolerance 50 Opioidergic agents 157 Opioid agonists 157 278 index · 279

Opioid antagonists 158 R Opium 75, 76 Optimism 240 RADAR system 270 Outcome 77, 78, 83, 84, 85, 88, 92, 99, 103, 104, Rapidity criterion 82 108, 109, 113, 115, 118, 128, 134, 139, 140 Rapid metabolism 97 Overdose 107, 119, 120, 124, 125, 126, 133 Rationale of agonist maintenance 202 Recommendations 159, 166 P Reduction of infection risk 148 Refusal or interruption of treatment 41 Parental role 194 Regrets for the fusional-heroic dimension 248 Patients’ selection 34, 35 Rehabilitation 35, 91, 101, 122, 124, 134 Persistent heroin use 84 Rehabilitative paradox 212 Personality disorder 154 Rejection of the therapeutic instrument 83 Phases of treatment 87 Relapse 77, 78, 81, 82, 83, 84, 91, 92, 93, 94, 97, Polyabusers 90, 101, 119, 133, 137 99, 101, 105, 106, 109, 110, 111, 113, 114, Polyabuse patients 181 115, 120, 122, 123, 124, 126, 128, 129, Possible Integration 255 133, 137, 138, 139, 236 Precontemplation stage 234, 236 Treatment 36 Pregnancy 79, 81, 86, 100, 102, 189 Relapse handling 113 Psychological aspects 193 Relapse prevention 113 Pregnancy abnormalities 190 Repeated detoxification stage 25 Prejudice 122, 123, 133 Resistance to treatment 135, 136, 137, 138, 139 Premature withdrawal 105 Retention in treatment 242 Preparation stage 235, 236 Retention rate 107 Prevention 32 Revolving door stage 25 Primary care 106, 107, 108 Risk of relapse 92, 99, 105, 106, 109, 110, 113, Primary health care clinics 221 114, 129, 139 Principle of emergency 17 Principle of improvement 18 S Principle of prognosis 18 Principle of severity 17 Safety 75, 88, 104, 120, 125, 133 Principle of specificity 18 Self-assessment of quality 270 Principle of stabilization 17 Self-injuring behaviour 200 Prison Serum conversion 146 Safe discharge 204 Side-effects 117 Prison-based treatment 198 Social disease 211 Problem recognition 240 Social integration 35 Processes of change 235 Specificity criterion 82 Prolactin 69 Specific treatments 34 Psychiatric disorders 90, 92, 126 Stabilization dosage 99 Psychodynamically oriented therapy 249 Stabilization phase 89 Psychoeducation 227 Stage-specific Interventions 236 Psychopharmacotherapy 169 Stages of change 234 Psychosocial services 234 Starting dosage 87, 88 Psychotherapy 247, 253, 255, 256 Steady state 88 Psychotic disorders 162 Stigma 122 Public services 253 Structured motivational intervention models 239 Structured stepped model 241 Q Substitution treatment 77 Supervised abstinence 113 QTc 120, 121, 122, 125, 126 Systemic relationship psychotherapy 250 278 index · 279

T U Take-Home 131 Unsafe practices 201 Effectiveness of 132 Urinalyses 127 Guidelines for 132 Clinical Meaning 127 Tapering schedule 110, 115 Clinical use 127 Termination 81 Ensuring the reliability of results 128 Therapeutic communities 94, 211, 213, 214 Therapeutic implications 129 Therapeutic deal 40 Therapeutic dependence 78, 91 V Therapeutic heroin 76 Vasopressin 73 Therapeutic instrument 83 Violence 166 Thyroid function 72 Violent behaviour 82, 84 Toxicity 117 Training issues 243 W Transtheorethical model 234 Treatment control measures 92 Withdrawal 76, 77, 84, 87, 88, 89, 90, 92, 94, 95, Treatment duration 104 97, 98, 99, 100, 101, 105, 109, 110, 111, Treatment modality 39, 41 113, 115, 118, 120, 121, 123, 132, 136, Treatment negotiation 41 137, 138, 139 Treatment of mood disorders 154 155 Treatment rules 92 Treatment specificity 229 Treatment termination 82 Typology of heroin addicts 27 280 Printed in Pisa, Italy, December 2009 www.europad.org www.aucns.org