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Drug and Dependence 59 (2000) 287–294 www.elsevier.com/locate/drugalcdep

Combined use of - versus -naltrexone in rapid withdrawal from treatment. A comparative inpatient study

Gino Pozzi *, Gianluigi Conte, Sergio De Risio

Clinical Psychiatry and Unit, Institute of Psychiatry and Psychology, Faculty of Medicine ‘Agostino Gemelli’, Catholic Uni6ersity of the Sacred Heart, 00168 Rome, Italy

Received 11 June 1999; received in revised form 8 October 1999; accepted 12 October 1999

Abstract

Trazodone is a non-tricyclic drug with specific antagonistic activities at 5-HT2 and alpha-1 adrenoceptors. We test the efficacy of trazodone (T) compared with clonidine (C) in rapid opiate detoxification (ROD) from methadone after reduction to a daily maintenance dose 520 mg. Forty five inpatients were consecutively assigned either to T (n=30) or to C (n=15) treatment in a 7-day ROD protocol with naltrexone administration starting at day 4. The maximum daily dosage was 800 mg for T and 1.2 mg for C. The retention rate was similar in both groups (93.3%). Overall, T was as effective as C in the ROD protocol. T was slightly superior in controlling some subjective and psychological symptoms, but not under naltexone challenge. No severe adverse effects were observed. We conclude that T is effective, safe and well-tolerated in acute withdrawal from methadone. Further investigation is needed to test the effectiveness and safety of T in ultra-rapid protocols and its usefulness in long-term administration to detoxified addicts. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Opiate withdrawal; Naltrexone; Trazodone; Clonidine

1. Introduction Gossop and Strang, 1991; Kanof et al., 1993). Apart from subjective distress, such symptoms may provoke Long-term methadone maintenance is a treatment of resumption of street drug use in a high percentage of choice for large groups of opiate addicts aimed at clients. Shortening the so-called protracted or sec- stopping the use of illicit drugs, which dramatically ondary abstinence is made possible by adding improves physical health and social adjustment (Coun- antagonists, with the advantage that clients directly cil on Addiction Psychiatry, 1994). Still, the discontinu- begin a maintenance program with naltrexone. Tech- ation of methadone medication may constitute a niques that precipitate by naloxone further stage of treatment to comply with other types of or naltrexone administration without anesthesia or drug-free therapeutic intervention and/or to complete heavy sedation are currently named rapid opioid detox- rehabilitation. Clinical studies demonstrate that metha- ification (ROD). On the whole, ROD techniques are done withdrawal may cause severe symptomatology, suitable for selected clients who have failed standard including classical opioid withdrawal symptoms and a detoxification treatment or desire an expedited detoxifi- true organic mood syndrome, starting when the daily cation for psychological or social reasons (O’Connor methadone dose is decreased below 20 mg and reaching and Kosten, 1988). a maximal levels a few weeks after the methadone dose The role of presynaptic 2-adrenoceptors in reducing tapering has been completed (Gossop et al., 1987; withdrawal response at the locus coeruleus is a well-established (Aghajanian, 1978) and the 2-stimu- lant drug clonidine is commonly used as an effective * Corresponding author. Tel.: +39-6-30154573; fax: +39-6- 30154163. anti-withdrawal medication in the management of E-mail address: [email protected] (G. Pozzi) heroin addiction (Gold et al., 1978) and methadone

0376-8716/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0376-8716(99)00125-8 288 G. Pozzi et al. / Drug and 59 (2000) 287–294 withdrawal (Charney et al., 1981). Subsequently, other withdrawal signs and may be further potentiated by a 2-agonists have been tested in preclinical studies of m-CPP exerting its agonistic activity on 5-HT1 recep- a morphine dependence, such as lofexidine (Shearman et tors and on 2-adrenoceptors. Anyhow, the metabolite al., 1980), (Boccafusco et al., 1984), ti- seems to be only partially involved in the anti-with- zanidine (Pinelli et al., 1998). Lofexidine was also ad- drawal action of the parent compound and both ministered to humans for the management of molecules act at both spinal and supra-spinal levels non-precipitated opioid withdrawal in open and con- (Silvestrini and Valeri, 1986; Valeri et al., 1988, 1989, trolled studies (Schubert et al., 1984; Bearn et al., 1988; 1991b). Furthermore, 5-HT reuptake inhibition may Kahn et al., 1997), but clonidine remains the drug of play a role in the modulation of noradrenergic neurons reference in ROD treatments (Charney et al., 1986; hyperactivity at the locus coeruleus (Akaoka and As- Gold, 1993). ton-Jones, 1993). Trazodone is a triazolopyridine derivative that exerts complex effects on the CNS at different levels, partly by 1.1. Aim of the study means of its active metabolite methachlorophenylpiper- azine (m-CPP). As an antidepressant drug, trazodone is Starting from these preclinical evidences and previous devoid of the typical aminergic properties of tricyclics, open clinical studies in the management of non-precipi- showing specific adrenolytic and antiserotonergic ef- tated opiate withdrawal, we decided to test the clinical fects, moderate anti-histaminergic and very little or no efficacy of trazodone in comparison with clonidine anticholinergic and antidopaminergic activities. The under controlled conditions in a 7-day inpatient trial of a parent compound is a strong 1-antagonist with a more rapid detoxification from methadone treatment. a a than 10-fold greater affinity for 1 than for 2-adreno- ceptors; furthermore, it acts as a selective antagonist at

5-HT2 receptors and also as a 5-HT reuptake inhibitor, though over ten times less potent than fluoxetine. The 2. Materials and methods active metabolite m-CPP is a 5-HT1b agonist and a weak 5-HT2 antagonist, and seems unrelated to antide- 2.1. Sampling pressant and – effects (Taylor et al., 1980; Riblet and Taylor, 1981; Richelson and Nelson, Patients were enrolled from a waiting list of subjects 1984; Valeri et al., 1988; Richelson, 1990; Marek et al., requiring detoxification from methadone at the Drug 1992; Rotzinger et al., 1998). Trazodone and m-CPP Dependence Unit of the ‘Agostino Gemelli’ University share also antinociceptive properties, which are consid- Hospital in Rome during the period 1995–1997. The ered relevant to the antidepressant activity, exerted treatment costs were covered by the Italian National both through interactions with the opioid system and Health Service. Inpatient ROD was preceded by an through pathways not affected by naloxone (Valeri et outpatient phase of treatment aimed at tapering metha- al., 1991a). done maintenance dosage to 20 mg/day or less. Clinical The use of trazodone in the management of sub- evaluation during the preparation time was performed stance withdrawal syndromes was predicted by some of on a weekly basis, including urinanalysis for opiates its neuropharmacological activities (Riblet and Taylor, and other drugs of abuse. Low-dose psychoactive med- 1981), through different mechanisms from clonidine, ication (excluding clonidine or trazodone) was allowed a since trazodone does not downregulate presynaptic 2 in selected cases for mood and anxiety disorders, or for receptors by direct effect (Price et al., 1986). Open sleeplessness. clinical studies were performed since the late 1970s with Subjects fulfilling inclusion and exclusion criteria encouraging results in detoxification from opiates listed in Table 1 were asked for consent and were (Fedeli et al., 1979) and alcohol (Roccatagliata et al., informed that they could change their mind at any time 1980); trazodone was also proposed for the relief of about the ROD treatment. If so, as well as in case of cocaine withdrawal symptoms (Small and Purcell, failure of the treatment for any reason, they were 1985). More recently, trazodone did well in the man- re-stabilized on 20 mg/day of oral methadone and agement of dependence in open and referred to outpatient facilities without prejudice for controlled trials (Ansseau and DeRoeck, 1993; Rickels further therapy. et al., 1999). Further preclinical in vivo investigation Patients enrolled in the study were consecutively has amplified our knowledge about the role of tra- assigned either to trazodone or to clonidine treatment zodone in opioid dependence and precipitated with- on a consecutive basis with a 2:1 ratio. All patients drawal at doses similar to those employed in the underwent physical and laboratory examination at the treatment of mood disorders in humans. In particular, beginning of hospitalization. None had abnormal blood a the selective adrenolytic effects of trazodone on 1 chemistry or ECG recording that could counterindicate receptors are responsible for the suppression of opiate the ROD treatment for clinical reasons. G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294 289

2.2. Ratings The checklist was completed by a trained medical doctor who was blind to study conditions. The evalua- Withdrawal responses were measured by means of a tion took about 30 min at each rating and was per- 27-item rating scale, specifically devised for the mea- formed daily in the late morning. surement of opiate withdrawal symptomatology (Bruno and Ferracuti, 1983). This checklist has been routinely 2.3. Treatment regimen employed in our institution and proved to be helpful in the comparison of different detoxification regimens Patients entered the hospital 1 or 2 days before (Janiri et al., 1994). starting the ROD program, and received a decremental The rating scale is graded in five points and includes dose of 20–10 mg of oral methadone (according to objective, subjective and psychological signs and symp- their outpatient schedule) until day 1 of rapid detoxifi- cation. The subsequent ROD treatment regimen was as toms. The 12 objective items are: mydriasis, polypnea, follows: yawns, lachrymation, rhinorrea, sneezes, horripilation, Day 1: methadone 10 mg; perspiration, vomiting, diarrhoea, trembling, tics. The Day 2: methadone 5 mg; ten subjective items are: nausea, abdominal cramps, Day 3: methadone wash-out; anorexia, visual disturbances, shivers, motor agitation, Day 4: naltrexone 2 mg; muscular/bone pain, , thirst, asthenia. The five Day 5: naltrexone 10 mg; psychological items are: anxiety, depression, hunger for Day 6: naltrexone 25 mg; drug, tension, wish for flight. Day 7: naltrexone 50 mg. Apart from the specific opioid withdrawal items of Both methadone and naltrexone were administered the scale, further well-known symptoms typically re- orally in the morning. Trazodone or clonidine were lated to pharmacological side effects of trazodone administered according to a fixed schedule divided in (Brodgen et al., 1981) were investigated and similarly three equal oral doses per day at 08:00, 15:00, and rated, including: dizziness, drowsiness, palpitation. 22:00 h (Table 2). Nurses were instructed to refuse information about what specific medication was used in Table 1 the ROD treatment to control withdrawal symptoms. Study inclusion and exclusion criteria Medication had to be taken under supervision, to en- sure that it had all been swallowed. The standardization Inclusion criteria of the schedules was decided for practical reasons. As Age 18–45 DSM-IV diagnosis of opioid dependence in therapy with agonists for clonidine, the dosage was decided following the Good physical health and stable psychosocial condition results of Charney et al. (1986) and our earlier experi- High motivation towards abstinence ence in the management of methadone withdrawal and Post-detoxification program based upon a verified drug-free naltrexone administration (Conte et al., 1990). As for project trazodone, we adopted the maximum dosage usually Exclusion criteria employed for the management of unipolar depression, Body mass abnormalities i.e. 600 mg/day (Haria et al., 1994). Severe somatic illness (e.g. AIDS or cirrhosis) Past history of psychosis and/or current psychiatric disorders In case of abdominal pain, nausea or vomiting, anti- impairing volition or reality testing (e.g. organic brain withdrawal drugs were administered parenterally, i.e. syndromes or psychotic states) clonidine i.m. or trazodone i.v. diluted in saline. Ad- Dependence from psychoactive substances other than opioid junctive doses of trazodone (100 mg) or clonidine (150 Use of street drugs in the last 2 weeks before admission mg) were also allowed on request. In facts, such extra Previous rapid or ultra-rapid detoxification failure doses were required only on days 4 and 5, and not more than twice a day up to maximum daily amounts of Table 2 trazodone 800 mg and clonidine 1200 mg. Trazodone and clonidine fixed regimens (total amount per day except During the 7 days of ROD, oral ranitidine 150 mg extra doses on demand, see text) t.i.d. was administered as a routine to decrease gastric secretion and flurazepam 30 mg was prescribed for Day Trazodone (mg) Clonidine (mg) night-time sedation. Adjunctive medication was decided 1150 0.45 by the physicians of the medical ward if withdrawal 2 300 0.6 symptoms were severe or not tolerated, mostly vomiting 3600 0.9 or pain. In this case the patients received i.m. 4 600 0.9 antiemetic drugs, such as methoclopramide, or anal- 5 600 0.9 6450 0.75 gesic non-steroidal anti-inflammatory drugs (e.g. ke- 7300 0.6 torolac or diclofenac). Anyhow, additional treatment did not affect the evaluation of withdrawal symptoms 290 G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294

Table 3 were performed separately for objective, subjective and Characteristics of the sample (n=45) psychological symptoms and signs, according to item Male sex (N) 36 (80.0%) grouping of the opioid withdrawal scale. If differences were found within a specific item subgroup, a further 9 Age (years) 30.13 5.66 day-by-day analysis was performed for each item by Opioid abuse duration (years) 8.7695.59 means of Fisher’s exact test on true frequencies. Last methadone treatment duration (months) 11.45915.67 The same statistical analysis was repeated separately Other substances of abuse in the lifetime (N)a for adverse effects. All statistical tests were considered Alcohol 9 (20.0%) significant at the h=0.05 probability level. Statistical 19 (42.2%) analyses were processed by BMDP software (Dixon, Amphetamines 6 (13.3%) 1988). Other 9 (20.0%) Employment status (N) Employed 17 (37.8%) 3. Results Unemployed 22 (48.9%) Student 6 (13.3%) 3.1. Patients’ characteristics Li6ing arrangement (N) Alone 5 (11.4%) With partner 9 (20.4%) Patients assigned to either trazodone- or clonidine- With family of origin 25 (56.8%) treated group showed no significant difference for de- Other 5 (11.4%) mographic and clinical features. Therefore, such characteristics are presented in Table 3 for the whole a Each patient may have more than one. sample. since it was given after the administration of the rating 3.2. Retention scale. Urine specimens were collected at treatment days 1 Only three patients (6.7%) decided to abandon the and 3 for evidence of illicit drug use before the admin- treatment after naltrexone administration, equally dis- istration of naltrexone. Clients who completed the tributed in the trazodone (two patients at days 6 and 7) ROD protocol were discharged in the afternoon of day and clonidine (one patient at day 4) groups. 7. We recommended to continue naltrexone for at least 1 month if they planned to enter a controlled therapeu- 3.3. Opioid withdrawal ratings tic environment, or to maintain long-term naltrexone treatment if they did not so. Low-dose clonidine (150 After transformation of rough scores into percent- m g b.i.d.) or trazodone (50 mg t.i.d.) were allowed for a ages, a preliminary ANOVA was performed with the few days after discharge in selected cases. treatment as grouping factor on 42 cases, since incom- plete records were excluded from this calculation. The 2.4. Data handling and statistical analysis analysis showed a statistically significant difference be- tween treatments with lower scores in the trazodone Before the analysis of treatment results, the tra- group (F=4.79, PB0.05) and extreme differences for zodone- and clonidine-treated groups were preliminar- repeated measures within each group (F=39.56, PB ily compared for demographic and clinical 0.001), while the interaction of the factors was not characteristics by means of Student’s t-test for unpaired significant (treatment×repeated measure). samples and 2-tail Fisher’s exact test as appropriate. Further analyses were aimed at determining in which Signs and symptoms of withdrawal and adverse ef- item subgroup and in which day significant differences fects were preliminarily collapsed into two categories, could be found, applying both parametric (t) and non- i.e. definitely ‘absent’ when rated null or mild (0–1) and parametric (U) statistical tests. All 45 records were definitely ‘present’ if the rating score was moderate to considered in data analysis. As shown in Figs. 1–3, extreme (]2). The proportion of all signs and symp- differences between treatment groups were due to sub- toms combined for each patient occurring every day jective and psychological items only, where trazodone was converted to percentages for further data analysis did better than clonidine, but such a superiority van- and a 2-way analysis of variance (ANOVA) with re- ished at days 4 and 5, when the withdrawal opioid peated measures was performed for the two treatment distress was maximized by naltrexone challenge. As groups. statistical significance was not reached with both proce- To determine the single days when treatment groups dures (U- and t-test) in some cases, due to imperfection differed at a statistically significant level, Student’s t- in the normal distribution of transformed values, confl- tests and Mann–Whitney U-tests for unpaired samples icting results are specified in the legends. G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294 291

A final analysis was devoted to the identification of 3.4. Ad6erse effects specific signs and symptoms that could be better con- trolled by trazodone treatment in comparison with A statistical analysis of the adverse effects specifically clonidine. This point was dealt with a re-analysis of added to the rating scale (i.e. dizziness, drowsiness, rough frequencies of subjective and psychological items palpitation) was conducted in a similar way. Trazodone by means of Fisher’s exact test (2-tail). Trazodone was seems more tolerated than clonidine, showing lower superior to clonidine in reducing the following symp- symptom scores, but differences were found at days 1 toms: at day 1, thirst (PB0.001), insomnia (PB0.03); and 3 only at a weak level of statistical significance (see at day 2, thirst (PB0.001), insomnia (PB0.01); at day Table 4). 3, thirst (PB0.001), shivers (PB0.01), insomnia (P: 0.01); at day 4, thirst (PB0.01); at day 5, thirst (PB 4. Discussion and conclusions 0.001); at day 6, thirst (PB0.001), asthenia (PB0.03); at day 7, thirst (PB0.01), insomnia (PB0.03). Overall, the fixed-schedule administration of tra-

Fig. 1. Percentage of objective items scored positive during the rapid detoxification treatment.

Fig. 2. Percentage of subjective items scored positive during the rapid detoxification treatment. 292 G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294

Fig. 3. Percentage of psychological items scored positive during the rapid detoxification treatment (the difference at day 7 was statistically significant only at t-test, see text). zodone during naltrexone-precipitated opioid with- We must recognize that our procedure of data drawal was as effective as the administration of recording was parsimonious, relying on semi-structured clonidine, and even superior in the control of subjective observation and retrospective inquiry once a day, be- and psychological symptoms, though only before and/ cause we did not run a dedicated detoxification ward or a few days after the beginning of naltrexone with trained staff at our disposal. For similar reasons, it challenge. was impossible to plot a 24-h curve of blood pressure. Considering the discrepancies in the mechanism of Anyhow, since subjective factors often prevail in the action of the two drugs and the experimental observa- compliance to opioid detoxification treatments (Jasinski tion of differential withdrawal reactions in rats (Ro- et al., 1985; Gossop, 1988), the present trial retains mandini et al., 1984; Valeri et al., 1989), we expected clinical validity. some differences in the distribution of withdrawal signs As for safety and tolerability, the ROD protocol with and symptoms in the two treatment groups. This was trazodone led to encouraging results. Drop-out rates not the case apart from few subjective and psychologi- were exactly alike in the trazodone- and clonidine- cal items, such as thirst (all treatment days), insomnia treated groups. Apart from the adverse effects assessed (4 out of 7 days), asthenia and shivers (a single treat- by the check-list, we further reported only transient ment day for each of these symptoms). It should be complaints of headache in the trazodone group, poten- noticed that ratings of the symptom ‘thirst’ could be tially related to the effect of its metabolite m-CPP in confounded with the sensation of ‘dry mouth’; yet, the susceptible individuals (Brewerton et al., 1988). Since inadequacy of clonidine in controlling sleep distur- bances is consistent with the results of previous studies Table 4 a with highly specific 2-adrenoceptor agonists (Schubert Percentage of adverse effect items scored positive in the two treat- et al., 1984; Kahn et al., 1997). The lack of differences ment groups between the treatment groups in the objective items Day Adverse effects P may hinge on different reactivity in humans compared with rodents. We should first speculate that differences Trazodone Clonidine in motor behaviours specific to other species (e.g. wet- dog shakes) may not predict differential vegetative Mean S.D. Mean S.D. symptoms in humans; furthermore, as the CNS be- 111.11 20.22 24.44 32.04 B0.03a comes more integrated rostrally in primates, the sever- 2 27.78 23.30 40.00 33.81 N.S. ity of withdrawal symptoms may be substantially 3 30.00 23.73 51.11 35.34 B0.05 modulated by the level of brain-stem arousal and by 433.33 30.32 40.00 33.81 N.S. psychological responsiveness. Otherwise, the rating 538.89 30.43 52.38 33.88 N.S. 628.7435.33 38.10 36.65 N.S. scale or the statistical procedure could be inadequate to 7 21.43 30.38 23.81 27.51 N.S. catch subtle qualitative differences in the control of withdrawal symptoms by these two treatments. a Only U-test significance. G. Pozzi et al. / Drug and Alcohol Dependence 59 (2000) 287–294 293 remarkable adverse events are likely to occur early in References the course of treatment with trazodone (Haria et al., 1994), we can reasonably suppose that only uncommon Aghajanian, G.K., 1978. 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