LJMU Research Online

van Hout, MC

Medicinal products detected as Novel Psychoactive Substances: the case of intravenous use of Tropicamide http://researchonline.ljmu.ac.uk/id/eprint/8027/

Article

Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work)

van Hout, MC (2018) Medicinal products detected as Novel Psychoactive Substances: the case of intravenous use of Tropicamide. And Related Clinical Problems, 20 (5). pp. 51-53. ISSN 1592-1638

LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. You may not engage in further distribution of the material or use it for any profit-making activities or any commercial gain.

The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription.

For more information please contact [email protected]

http://researchonline.ljmu.ac.uk/ ISSN 1592-1638 (print) - ISSN 2531-4122 (on line)

20th year Vol. 20 • N. 5 • October 2018 Periodico bimestrale - Sped. in Abb. Post. - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma DCB PISA - Periodico bimestrale - Sped. in Abb. Post. D.L. 353/2003 conv. Aut. tirb. di Pisa n.5 del 9-3-2000

the official journal of

World Federation for the Europad Treatment of European Addiction Treatment Association

Per aspera ad astra since 1994 AU - CNS Association for the Application of Neuroscientific Knowledge Opiod Dependence Affiliated to INTERNATIONAL SOCIETY OF ADDICTION MEDICINE to Social Aims

Press AssociAtion for theAU-CNS ApplicAtion of neuroscientific Knowledge to sociAl Aims Founded in 1994 by Icro Maremmani and Alessandro Tagliamonte† Advert_Layout 1 25/02/2015 14:02 Page 7

Addiction is a treatable disease Millions of people worldwide are suffering from diseases of addiction

We at Indivior envision a day in which all patients around the world will have unrestricted access to quality treatments and services for the chronic relapsing conditions and co-morbidities of addiction.

Indivior Italia S.r.l. Corso di Porta Romana, 68 - 20122, Milano, Italy www.indivior.com Editorial Board

Editor in Chief Icro Maremmani VP Dole Dual Disorder Unit, Santa Chiara University Hospital, University of Pisa, Italy, EU Associate Editors Thomas Clausen SERAF, Norwegian Centre for Addiction Research, University of Oslo, Norway Pier Paolo Pani Socio Health Local Area, Sardinia Region Health Protection Trust, Olbia, Italy, EU Marta Torrens University of Barcelona, Spain, EU International Advisory Board Hannu Alho National Public Health Institute (KTL), University of Helsinki, Finland, EU Marc Auriacombe Victor Segalen University, Bordeaux, France, EU Alexander Baldacchino University of St Andrews Medical School. North Haugh, St Andrews, Scotland, United Kingdom, EU James Bell South London and Maudsley NHS FoundationTrust & Langston Centre, Sydney, Austrelia Olof Blix County Hospital Ryhov, Jönköping, Sweden, EU [Retired] Barbara Broers University Hospital of Geneva, Switzerland Miguel Casas Vall d’Hebron University Hospital, University of Barcelona, Spain, EU Michael Farrell National and Research Centre, University of New South Wales, Sydney, Australia Loretta Finnegan National Institutes of Health, Bethesda, MD, USA [Retired] Gabriele Fischer Addiction Clinic, University of Vienna, Austria, EU Carla Gambarana Department of Molecular and Developmental Medicine, University of Siena, Italy Gilberto Gerra United Nations Office on and Crime (UNODC), Vienna Gian Luigi Gessa University of Cagliari, Italy, EU [Retired] Michael Gossop King’s College, University of London, UK, EU Leift Grönbladh Institute of Addictive Diseases, University Hospital of Uppsala, Sweden, EU Lars Gunne University of Uppsala, Sweden, EU [Retired] Herman Joseph Stop Stigma Now; NAMARecovery, New York, NY, USA Andrej Kastelic Center for Treatment of Drug Addiction, University Hospital, Ljubljana, Slovenia, EU Michael Krausz St. Paul’s Hospital, University of British Columbia, Canada Mary Jane Kreek The Rockfeller University, New York, NY, USA Evgeny Krupitsky St. Petersburg Bekhterev Psychoneurological Research Institute, Saint Petersburg, Russia Mercedes Lovrecic Institute of Public Health of the Republic of Slovenia, Ljubljana, Slovenia, EU Joyce Lowinson Albert Einstein College of Medicine, The Rockfeller University, New York, NY, USA, [Retired] Angelo GI Maremmani Department of , Northern-West Tuscany Region Local Health Unit, Versilian Zone, Viareggio, Italy, EU Charles P. O'Brien University of Pennsylvania, Phildelphia, PA, USA Lubomir Okruhlica Centre for Treatment of Drug Dependencies, Bratislava, Slovak Republic, EU Matteo Pacini Institute of Behavioural Sciences, Pisa, Italy, EU Mark Parrino American Association for the Treatment of Dependence, New York, NY, USA Einat Peles Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel Giulio Perugi Department of Clinical and Experimental Medicine, University of Pisa, Italy, EU Jens Reimer University of Hamburg, Germany and Psychiatry Health North, Bremen, Germany, EU Marc Reisinger European Opiate Addiction Treatment Association, Brussels, Belgium, EU Lorenzo Somaini Addiction Treatment Center, Cossato (Biella), Italy, EU Marlene Stenbacka Karolinska Institute, Stockholm, Sweden, EU Ambros Uchtenhagen Research Foundation on Public Health and Addiction, Zurich University, Switzerland Helge Waal Center for Addiction Research (SERAF), University of Oslo, Norway, [Retired] George Woody University of Pennsylvania, Philadelphia, PA, USA Editorial Coordinator Marilena Guareschi Psychologist Association for the Application of Neuroscientific Knowledge to Social Aims, AU-CNS, Pietrasanta, Lucca, Italy, EU Coordinator Master in Addictologia, University of Pisa Assistants Silvia Bacciardi School of Psychiatry, and Master in Addictologia, University of Pisa, Italy, EU Iacopo Belcari Psychologist and Master in Addictologia, University of Pisa, Italy, EU Manuel Glauco Carbone School of Psychiatry, University of Pisa, Italy, EU Denise Gazzarrini Specialty in Psychiatry, and Master in Addictologia, University of Pisa, Italy, EU Marco Maiello School of Psychiatry, University of Pisa, Italy, EU Enrico Massimetti Specialty in Psychiatry and Master in Addictologia, University of Pisa, Italy, EU Alessandro Pallucchini School of Psychiatry, and Master in Addictologia, University of Pisa Fabio Rugani School of Psychiatry, University of Naples, Italy, EU Master in Addictologia, University of Pisa Vincenza Spera School of Psychiatry, University of Pisa, Italy, EU

Publishers

Not for profit Agency Via 20 Settembre, 83 - 55045 Pietrasanta, Lucca, Italy, EU Press Phone +39 0584 790073 - Fax +39 0584 72081 - E-mail: [email protected] AssociAtion for theAU-CNS ApplicAtion of neuroscientific Knowledge to sociAl Aims Internet:http://www.aucns.org Founded in 1994 by Icro Maremmani and Alessandro Tagliamonte†

Pacini Editore Via A. Gherardesca - 56121 Ospedaletto, Pisa, Italy, EU Phone +39 050 313011 - Fax +39 050 3130300 - E-mail: [email protected] Internet:http:// www.pacinieditore.it

Cited in: EMBASE Excerpta Medica Database SCOPUS EMCave Social Sciences Citation Index (SSCI) - Thomson Reuters

Open Access at: http://www.heroinaddictionrelatedclinicalproblems.org CONTENTS

Addiction and self-reported associated sociodemographic factors in a small province of Iran Zahra Sedaghat, Mohammad Fararouei, Gholamhosein Shahraki, Kambiz Karimzadeh Shirazi, and Roksana E. Haghighi 5

An evaluation of community pharmacist perception of the misuse and abuse of over-the- counter co-codamol in Cornwell and Devon, UK: A cross-sectional survey Ravina Barrett, and Dalmar Costa 13

Switching between lyophilized and sub-lingual formulations in opioid-dependent patients: Observations on transfer during a safety and pharmacokinetic study Kylie Reed, Alastair Knight, Shelagh Baillie, Karolina Bogdanowicz, James Bell, 19 and John Strang

The SCL90-based psychopathological structure may be applied in patients independently of the drug involved, even in heroin, alcohol and monodrug users Manuel Glauco Carbone, Marco Maiello, Vincenza Spera, Corrado Manni, 29 Alessandro Pallucchini, Angelo G. I. Maremmani, and Icro Maremmani

Comparing neurocognitive function in individuals receiving chronic or buprenorphine for the treatment of opioid dependence: A systematic review. Duncan Hill, Daniel Garner, and Alex Baldacchino 35

Medicinal products detected as novel psychoactive substances: The case of intravenous use of tropicamide. Marie Claire Van Hout 51 Medicina delle Dipendenze Italian Journal of the Organo ufficiale della Società Italiana Tossicodipendenze

Presidente Onorario Gaetano Di Chiara Presidente Luigi Stella Segretario Franco Montesano Tesoriere Riccardo Gionfriddo

Consiglio Direttivo Mauro Cibin Ernesto De Bernardis Giovambattista De Sarro Riccardo Gionfriddo Anna Loffreda Piergiovanni Mazzoli Roberto Mollica Edoardo Polidori Fabrizio Starace Eugenia Vernole

Past Presidents Gian Luigi Gessa Alessandro Tagliamonte † Gian Paolo Guelfi Pier Paolo Pani Icro Maremmani

Collegio dei Revisori Giuseppe Falcone (Presidente) Ciro D'Ambra (Membro Effettivo) Andrea Fuscone (Membro Effettivo) Domenico Cante (Membro Supplente) Bruno Aiello (Membro Supplente) HEROIN ADDICTION & RELATED CLINICAL Regular article PROBLEMS Heroin Addict Relat Clin Probl 2018; 20(5): 5-11 www.europad.org Pacini Editore & AU CNS www.wftod.org

Addiction and self-reported associated sociodemographic factors in a small province of Iran Zahra Sedaghat1, Mohammad Fararouei2, Gholamhosein Shahraki3, Kambiz Karimzadeh Shirazi4, and Roksana E. Haghighi5

1-Student Research Centre for Health Sciences, Department of Epidemiology, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran 2-HIV/AIDS Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran. 3-Social Determinants of Health Research Centre, Yasuj University of Medical Sciences, Yasuj, Iran 4-Department of Public Health, Social Determinants of Health Research Centre, Yasuj University of Medical Sciences, Yasuj, Iran 5-Shiraz University of Medical Sciences, Shiraz, Iran

Summary Background: Drug addiction is a chronic brain disorder caused by drug use. It is one of the most important social and health problems, as it is responsible for the serious deterioration of health, mental health and the socioeconomic status of individuals and the community. Aims: The aim of this study was to understand the views of drug users on the factors putatively involved in their initiation of substance use and in their propensity to make attempts to quit drug use in Yasuj, Iran. Methods: Using a self-administered questionnaire, 362 male addicted participants (selected through snowball sam- pling) provided us with the information required. Results: Among all participants, 83.6% reported that they were not aware of the health or social consequences of addiction. Also, 33.13% referred to their friends as being the main reason for their addiction and 69.46% declared that they had been introduced to drugs by a friend. was reported to be the most prevalent (92.44%) substance at first drug administration, the most common route being via eating. The most com- mon place for drug use was a friend’s home (29.52%). Among the participants, 82.34% were smokers who had started when as young as 17.57±4.90 years of age. Family members were the main factor encouraging participants to attempt to quit (63.91%). Conclusion: Based on the information provided by the addicted participants, friendship is the most important initiating factor in addiction. Friends encouraged patients and provided them with drugs and a safe place to first administer them. On the other hand, family members and family relationships seem to help patients financially and emotionally to quit substance use. As a result, keeping or restoring family relationships may be helpful factors in predict- ing and treating addiction. Key Words: Addiction; drug quitting; age of starting use of drug; self-reported

1. Introduction is estimated that 149 to 272 million economically ac- tive individuals (aged between 15 to 64 years) abuse Drug addiction is a chronic brain disorder drugs at least once in their lifetime. Moreover, about caused by drug abuse [13]. Dependency on drugs is 11 to 21 million drug abusers administer drugs via of great concern to social and health organizations injection, and run higher risks of blood transmitted because of the adverse effects of addiction, which diseases. In Iran, the prevalence of drug abuse is ris- include psychological and physiological disorders ing so sharply that addiction has become a national and socioeconomic impairment [14]. Along with the problem [12]. The types of illicit drugs that are used growing number of drug-injecting addicts, the preva- in each country are different, and the differences are lence of sexually and blood-transmitted infections is of substantial importance. For example, the drugs becoming an increasingly serious problem [9, 12]. It most commonly used in Africa are heroin and co-

Correspondence:Corresponding author: Mohammad Fararouei, HIV/AIDS Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Zand Street, 7143754188, Shiraz, Fars, Iran Phone: 00989357736583; E-mail: [email protected] 5 Heroin Addiction and Related Clinical Problems 20(5): 5-11 caine, in Europe heroin and , and in North that addicts are not easily accessible. However, there and Central America cocaine [15]. In Asia, cannabis are many addicted individuals who are frequently ar- and opium are the drugs most widely used, including rested and registered by police, or else are admitted to Iran, where the highest usage rate is that of opium de- rehabilitation camps or treatment centres. These reg- rivatives [10]. To date, the number of addicts in Iran istered individuals were not believed to be representa- is estimated to be about 1.2 million (approximately tive of the addicted community because of significant 1.6% of the total population) [10], and opium deriva- socioeconomic differences compared with the rest of tives are known to be the most commonly used illicit the addicted community. As a result, the researchers drugs [1, 4, 15]. It is estimated that every year about decided not to conduct any type of probability sam- 1,100 tons of opium are used by 4 million drug abus- pling. Instead, they decided to recruit a more repre- ers, 42% of them living in Iran. In particular, annual sentative sample of the addicted urban population, heroin use is estimated to be around 17 tons in Iran and snowball sampling was the method chosen. In (about 5% of global use). With regard to the above that regard, male addicted volunteers who had regis- facts, Iran is ranked first among countries with a high tered with police or with a rehabilitation or treatment rate of opium use [10]. centre were invited to assist in the sampling proce- Among the many factors associated with addic- dure after being trained by the research team. The as- tion, age, sex and marriage status are the most im- sistants invited known male addicted individuals aged portant. The male to female ratio for addiction has between 18 to 45 years to complete the questionnaire. been estimated at 9 to 1 [10], with 18.9% of addicts The assistants delivered the questionnaire to the par- younger than 24 years of age [10]. The adverse ef- ticipants in a private place after a short interview to fects of drug use on one hand, and situations in which strengthen the confidence felt by participants in the no access to drug users is allowed on the other, make confidentiality of the interview, and as to whether the provision of health and medical care to drug abus- they were able to read and understand the question- ers a difficult task [12]. In addition, as is true of many naire. An informed consent document was read and other countries, in Iran the illicit use of drugs is pun- signed by the participants before the interview began. ished severely. This makes addicted individuals even harder to reach when medical and social help should 2.2. Instruments be delivered to patients. This leads to a limited or zero supply of reliable information about this vulnerable A self-administered questionnaire was drawn up and hidden part of a community. Via the collection by the research team and its validity was evaluated by of data on the history of illicit drug use by filling in an expert panel consisting of a psychologist, an epide- a self-administered questionnaire, male drug abusers miologist and a public health nurse experienced in ad- in Yasuj (the capital of Kohgilooyeh and Boyerahmad diction therapy. A pilot study was also conducted on province) were selected and studied to understand 30 addicted participants who completed the question- their views on the factors putatively involved in the naire twice (with a two-week interval). According to initiation to substance use and in their later propen- the results of a test-retest analysis, the questionnaire sity to make attempts to quit. was reasonably reliable (Cronbach's alpha=0.65). The questionnaire was designed to collect information on 2. Methods the participant's educational, social and behavioural characteristics as well as the history of their addiction This descriptive study was conducted on 362 and related knowledge and behaviours. male addicts (aged 18 to 45 years of age) from March 2013 to December 2015 in Yasuj, the capital of Koh- 2.2.1. Study variables giluyeh and Boyer-Ahmad province located in the The questionnaire consisted of four sections southwestern part of Iran. covering a wide range of areas, namely: A) Factors associated with the start of drug usage, that is, age at 2.1. Sample onset of drug use, main reason for using illicit drugs, who introduced you to illicit drugs, where the drug In Iran, addiction and carrying illicit drugs come was administered for the first time, route of the first with serious social and legal consequences, no for- drug administration and type of the first drug to be mal access to drug abusers is available. As a result, no administered; B) Current use of illicit drug(s), i.e., predefined population of illicit drug users exists, so currently, with whom do you administer drugs, how

- 6 - Z. Sedaghatet al.: Addiction and self-reported associated sociodemographic factors in a small province of Iran do you obtain drugs and what type(s) of drug do you friends were the main cause of their addiction and use?; C) Knowledge and behaviour, i.e., being aware 69.46% declared that they were introduced to drugs of the consequences of addiction (yes/no question), (for the first time) by a friend. Opium was the most being aware of how HIV is transmitted (multiple common drug used on the first occasion and the most choice question), the date of the last time you were popular route of first drug use was eating (92.44%). tested for HIV, whether you use a shared syringe (yes/ Only 63.76% of the participants were buying their no question), have you been in a sexual relationship drug(s) from drug dealers. The rest obtained drugs outside marriage (yes/no question), frequency of use from friends or relatives. The most common place of condom during sexual contact (whether it is: al- to use drugs was a friend’s home (29.52%). Among ways, sometimes, never), aggressive behaviour (ask- the addicted participants, 82.34% were smokers who ing: always, sometimes, never), having a criminal had started smoking when they were as young as record (yes/no question), smoking (yes/no question) 17.57±4.90 years of age. As reported by the smoker and who encouraged you to start smoking; D) Quit- participants, 68.75% were encouraged to start smok- ting attempts, i.e., did you ever attempt to quit (yes/ ing by a family member. no question), way chosen for the first attempt to quit (multiple choice question), way chosen for second at- 3.2. Risky behaviours tempt to quit (multiple choice question), who encour- aged patient to quit the first time and the reason for Having a sexual relationship outside marriage the first attempt to quit. was reported by only 15.56% of the participants. Of the participants, 50.90% had taken no HIV test for 2.3. Data analysis longer than 3 years. Most addicts (95.51%) knew that blood transfusion, injection and having sexual rela- Descriptive methods were used to analyse data. tions are the common routes of HIV transmission, All analyses were performed using SPSS (version 20, and only 4.49% were totally unaware of the main SPSS, Chicago, IL). routs of HIV transmission. However, 56.29% of the participants reported that they did not use a condom 3. Results during sexual intercourse. About 29.62% of the par- ticipants reported that they had been aggressive, and Results are reported in table 1. 52.87 % reported that they have a criminal record or have been arrested (at least) once by police. 3.1. Addiction-related factors Based on the participants’ reported informa- tion about quitting substance use, about 71.63% of Interestingly, 83.6% (CI%: 0.78, 0.87) of the the participants had attempted to quit at least once. participants reported that they were not aware of the Job lost or other social problems were indicated as health or social consequences of addiction. However, the main reason for quitting (23.84%), and family only 11.43% of the participants reported a history of members were the main encouraging factor for par- shared syringe usage for drug injection. Among par- ticipants, 33.13% (CI: 44%, 57%) reported that their

Table 1: Baseline characteristics of addicted participants

Factors associated with start of drug usage N % Main reason for becoming addicted Advice from friends 107 33,1 To experience 34 10,5 A sense of curiosity 13 4,0 Unemployment 28 8,7 Being unaware of the consequences 27 8,4 Who introduced you to drugs? Family members 42 14,1 Friends 207 69,5 It was a personal decision 49 16,4 Who encouraged you to start smoking? Family 165 68,8

- 7 - Heroin Addiction and Related Clinical Problems 20(5): 5-11

Table 1: Baseline characteristics of addicted participants

Factors associated with start of drug usage N % Friends 75 31,3 Family / Social problems 114 35,3 Where did you use drugs for the first time? At home 43 15,9 At work 18 6,6 Parks or suburbs 64 23,6 Others 56 20,7 Friends’ home 80 29,5 Street 10 3,7 Route of first drug use Inhalation 11 3,8 Eating 269 92,4 Injection 11 3,8 Drug used the first time Opium 200 58,1 Marijuana 40 11,6 Other 104 30,2 Criminal history No 123 47,1 Yes 138 52,9 Current use of drugs N % With whom do you use drugs? I use them when I am alone 23 7,9 Friends 226 77,4 Family 43 14,7 Current use of drugs? Opium 152 50,7 Heroin 49 16,3 Glass/Ampoule 27 9,0 Others 72 24,0 Knowledge N % Were you aware of the consequences of addic- No 199 83,6 tion? Yes 39 16,4 Use of a shared syringe No 279 88,6 Yes 36 11,4 Sexual relationship outside marriage Often 49 15,6 Sometimes 74 23,5 Never 192 61,0 Use of condom during sexual contact Often 51 17,8

ticipants to attempt quitting (63.91%). drugs used, opium was the most common. This find- ing is in accordance with the studies conducted by 4. Discussion Amiri and Javanbakht [1, 5]. In the present study, eat- ing was the common route of first drug use among ad- This is a descriptive study whose aim has been to dicts. This finding is in accordance with the Christo- examine self-reported data on factors associated with: pher’s study [6]. Eating was the most commonly used first drug use, current drug use and attempts to quit. route of opium administration among Iranian addicts. In addition, participants’ knowledge about the side- That finding could be due to the ease of eating opi- effects of addiction, HIV transmission, and social and um, as no instruments are needed. When eating drugs sexual behaviours were measured. The results sug- (especially opium), there is also no smoke or smell gested that friends are the main reason for the onset at risk of being noticed by others when administer- of addiction in participants. It seems that peers play ing them, as would happen if it took place via smok- an important role in the personality and social behav- ing [2]. According to the results of the present study, iours of any individual [9]. Among all the types of addicts predominantly showed no awareness of the

- 8 - Z. Sedaghatet al.: Addiction and self-reported associated sociodemographic factors in a small province of Iran

Table 1: Baseline characteristics of addicted participants

Factors associated with start of drug usage N % Sometimes 74 25,9 Never 161 56,3 Behaving aggressively with others Often 85 29,6 Sometimes 205 36,6 Never 97 33,8 HIV is transmitted via Blood 28 11,4 Blood/Sexual contact 38 15,5 Injection 21 8,6 Injection/Blood 56 22,9 Injection/Sexual contact 61 24,9 Sexual contact 30 12,2 Other ways 11 4,5 Last time tested for HIV 1 year ago > 40 24,0 1-3 years ago 42 25,2 >3 years ago 85 50,9 Friends/Relatives 44 19,2 Drug seller 146 63,8 Quitting N % Have you ever attempted to quit? No 80 28,4 Yes 202 71,6 Way of first attempting to quit Drug 50 30,1 Camp 40 24,1 Home 48 28,9 Quitting centres 28 16,9 Way of making second attempt to quit Drug 22 25,0 Community 27 30,7 Home 15 17,1 Who first encouraged you to quit drug use? Friends 15 11,3 Family 85 63,9 Myself 33 24,8 Reason for first quitting Losing job or other social problems 31 23,8 Friends 32 24,6 Family 9 6,9 Not reported 58 44,6 health and social consequences of addiction. In the jerdi [8], which suggested that usage of methamphet- present study, most addicts knew that injection and amine as a replacement for opium is very common sexual contacts are the common routes of HIV trans- especially among young addicts [8]. The results of mission. Most addicts, however, did not use a condom the present study suggest that losing a job and other during sexual intercourse [11]. These findings are in social problems are the main reasons prompting at- accordance with the results of studies by Dariotis [3]. tempts to quit drug use. Viewed from another angle, Accordingly, drug addicts and their spouses are at a family support and encouragement provide the main higher risk of sexually transmitted diseases. inspiration for patients to actually take that decision The results of the present study also suggest that [7]. among different methods of quitting substance use, the use of replacement drugs (e.g. methadone, bupro- 5. Conclusions pion, dextoam, phetamine and ) was the most common among these participants. This Based on the information provided by the ad- is in concordance with a study conducted by Mehr- dicted participants, friendship is the most impor-

- 9 - Heroin Addiction and Related Clinical Problems 20(5): 5-11 tant initiating factor in illicit drug use. It seems that 8. Juibari T. A., Lotfi B., Ghobadi K. N., Aghaei A., Moradi friends encourage individuals to use illicit drugs for M., Najafi F., Farnia V. (2016): Factors affecting the the first time by providing the substance itself and a duration of addiction in individuals visiting drugabuse safe place to administer it. On the other hand, fam- treatment centers in Kermanshah province in 2013. Acta ily members and family relationships seem to support Medica Mediterranea. 32(885). 9. Mehrjerdi Z. A. (2013): A brief overview of patients financially and emotionally in quitting sub- methamphetamine use treatment in Iran: Intervention stance use. However, it seems that the attempts to quit and practice. J Res Med Sci. 18(12): 1018-1020. mostly ended up in relapse and failure. Independently 10. Mirahmadizadeh A. R., Majdzadeh R., Mohammad K., of what the results of an attempt to quit are, a feeling Forouzanfar M. (2009): Prevalence of HIV and Hepatitis of determination to quit addiction is a very important C Virus Infections and Related Behavioral Determinants factor in achieving success in the quitting process. It among Injecting Drug Users of Drop-in Centers in Iran. follows that family supervision during adulthood and Iranian Red Crescent Medical Journal. 11(3): 325-329. helping patients to rebuild family relationships may 11. Momtazi S., Rawson R. (2010): among help them to prevent and to quit substance abuse, Iranian high school students. Curr Opin Psychiatry. respectively. The results also suggested that most 23(3): 221-226. 12. Reback C. J., Fletcher J. B. (2014): HIV prevalence, participants were unaware of the side-effects of ad- substance use, and sexual risk behaviors among diction when they first started to use drugs. It may transgender women recruited through outreach. AIDS therefore be suggested that all individuals should be Behav. 18(7): 1359-1367. made aware of the consequences of addiction at an 13. Shekarchizadeh H., Khami M. R., Mohebbi S. Z., earlier stage (preferably while still at school). Ekhtiari H., Virtanen J. I. (2013): Oral Health of Drug Abusers: A Review of Health Effects and Care. Iran J References Public Health. 42(9): 929-940. 14. Trigo J. M., Martin-Garcia E., Berrendero F., Robledo P., 1. Amiri M., Khosravi A., Chaman R. (2010): Drug Abuse Maldonado R. (2010): The endogenous opioid system: Pattern and High Risk Behaviors among Addicts in a common substrate in drug addiction. Drug Alcohol Shahroud County of Semnan Province, Northeast Iran Depend. 108(3): 183-194. in 2009. J Res Health Sci. 10(2): 104-109. 15. Zaaijer E. R., Bruijel J., Blanken P., Hendriks V., Koeter 2. Butler S. F., Cassidy T. A., Chilcoat H., Black R. A., M. W., Kreek M. J., Booij J., Goudriaan A. E., Van Ree Landau C., Budman S. H., Coplan P. M. (2013): Abuse J. M., Van Den Brink W. (2014): Personality as a risk rates and routes of administration of reformulated factor for illicit opioid use and a protective factor for extended-release : initial findings from a illicit opioid dependence. Drug Alcohol Depend. 145: sentinel surveillance sample of individuals assessed for 101-105. substance abuse treatment. J Pain. 14(4): 351-358. 16. Ziaaddini H., Sharifi A., Nakhaee N., Ziaaddini A. (2010): 3. Dariotis J. K., Johnson M. W. (2015): Sexual discounting The Prevalence of at Least One-Time Substance Abuse among high-risk youth ages 18-24: implications for among Kerman Pre-university Male Students. Addict sexual and substance use risk behaviors. Exp Clin Health. 2(3-4): 103-110. Psychopharmacol. 23(1): 49-58. 4. Degenhardt L., Bucello C., Mathers B., Briegleb C., Ali Acknowledgements H., Hickman M., Mclaren J. (2011): Mortality among The authors would like to thank the deputy of re- regular or dependent users of heroin and other : search of Yasuj University of Medical Sciences for pro- a systematic review and meta-analysis of cohort studies. viding us with great supports in conducting the present Addiction. 106(1): 32-51. research. 5. Doremus-Fitzwater T. L., Varlinskaya E. I., Spear L. P. (2010): Motivational systems in adolescence: possible Role of the funding source implications for age differences in substance abuse and The present study was funded by the Yasuj University other risk-taking behaviors. Brain Cogn. 72(1): 114-123. of Medical Sciences. 6. Javanbakht M., Mirahmadizadeh A., Mashayekhi A. (2014): The long-term effectiveness of methadone Contributors maintenance treatment in prevention of hepatitis C Z.S., M.F., K.K., designed the study and wrote the virus among illicit drug users: a modeling study. Iran protocol. Z.S., M.F., G.S.., managed the literature searches Red Crescent Med J. 16(2): e13484. and analyses. M.F., undertook the statistical analysis, and 7. Jones C. M. (2013): Heroin use and heroin use risk all the authors discussed the results. M.F., wrote the first behaviors among nonmedical users of prescription draft of the manuscript. All authors revised the last draft. opioid pain relievers - United States, 2002-2004 and All the authors contributed to, and have approved, the final 2008-2010. Drug Alcohol Depend. 132(1-2): 95-100. manuscript.

- 10 - Z. Sedaghatet al.: Addiction and self-reported associated sociodemographic factors in a small province of Iran

Conflict of interest Authors declared no conflict of interest.

Ethics Authors confirm that the submitted study was con- ducted according to the WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. This study does not require ethics committee approval because it was carried out according to a non- interventional protocol. All patients gave their informed consent to the anonymous use of their clinical data for this independent study.

Note It is the policy of this Journal to provide a free re- vision of English for Authors who are not native English speakers. Each Author can accept or refuse this offer. In this case, the Corresponding Author accepted our service.

Received July 26, 2017 - Accepted December 27, 2017

- 11 -

HEROIN ADDICTION & Regular article RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 13-17 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

An evaluation of community pharmacist perception of the misuse and abuse of over-the-counter co-codamol in Cornwell and Devon, UK: A cross-sectional survey Ravina Barrett, and Dalmar Costa

University of Portsmouth, Portsmouth, UK

Summary Background: containing preparations have the potential to cause harm and dependence. Recent UK regulatory changes to the pack-size and printed warnings have been instituted to reduce this potential. However, there is a reported increase in the misuse of codeine containing analgesics in countries where it is available over-the-counter. This is a challenge for pharmacies and pharmacists globally. Aim: To evaluate the perceptions of community pharmacists on the nature and management of Over-The-Counter (OTC) co-codamol (paracetamol and codeine combination preparations) misuse and abuse. Methods: A self-report, postal survey was developed and posted to 65 pharmacies in Cornwall and 85 pharmacies in Devon (n=150) in the UK. Qualitative and quantitative data was analysed using descriptive statistics, hypothesis testing and thematic analysis. Results: Most pharmacists perceived their patients and community as having some challenges with the misuse of co-codamol. Pharmacists think that co-codamol is not harmful if used as indicated. The behaviours pharmacist associated with misuse were frequent to purchase and misinformation provided by the patient during consultation. Counselling and referral are the main interventions utilised by pharmacist in such circumstances. Pharmacists who have received training on co-codamol abuse know where to refer customers. Conclusions: Community pharmacists face a difficult challenge when suspecting misuse. However, pharmacists believe co-codamol abuse can be reduced by increasing the public’s awareness of the addictive potential of co-codamol. Key Words: Codeine; Misuse; Over the counter; Risk reduction; Community pharmacy

6. Introduction While the definition of ‘abuse’ is: ‘The use of drugs for nonmedical purposes is to experience their The inappropriate use of OTC is mind-altering effects, while “misuse” is applied to the referred to as misuse or abuse, due to their potential use of a drug for legitimate medical purposes, but in for addiction and dependency. Misuse and abuse can an incorrect manner’ [1]. Both definitions imply rec- sometimes be misunderstood. For the purpose of this reational use. Although these definitions are limited study, the definitions are adopted from EU commis- to codeine abuse and misuse, we use these definition sioned report [18] concerning codeine use, misuse as they are relevant to co-codamol use. and dependence. In the UK, there are three categories of licenced The definition of ‘misuse’ is: ‘The problematic medicines for human use: 1. General Sales List (GSL) consumption of codeine where risks and adverse con- medicines, which can be readily purchased from re- sequences outweigh the benefits, and which includes tailers, often containing a small quantity of analgesics use of codeine with or without prescription, outside and other preparations (not codeine-based). 2. Phar- of acceptable medical practice or guidelines, for rec- macy (P) medicines, which can be purchased OTC reational reasons, when self-medicating, with higher from a registered pharmacy where a registered phar- doses and for longer than advisable’ [3]. macist oversees the sale (can be codeine-based). 3.

Corresponding author: Ravina Barrett, University of Portsmouth, St Michael's building, PO1 2DT, Portsmouth, Hampshire, United Kingdom Phone: +44 (023) 9284 3683; E-mail: [email protected]; 13 Heroin Addiction and Related Clinical Problems 20(5): 13-17

Prescription only medicines (POM), which must be what do community pharmacists think about co-co- supplied only against a valid prescription. Codeine damol misuse and abuse?) preparations are sold OTC as P medicines or on a pre- The secondary aim was to understand how com- scription. Some examples of other commonly abused munity pharmacists suspect and manage co-codamol medications include , z-drugs and misuse or abuse (research question: how do commu- opioid painkillers. nity pharmacists manage the phenomenon?) The misuse and abuse of OTC medicines is a worldwide problem [4, 17]; the five key groups of 7. Methods abuse range from laxatives, cough products, seda- tive antihistamines, decongestants and codeine based The survey was developed from Carney et al’s analgesics [4, 9]. This is due to looser regulations, [2] study. This study investigated views on regulatory greater availability and self-medication [18, 16]. The changes, strategies used to identify misuse of codeine misuse of codeine containing compound analgesics and how community pharmacists managed them. (normally in combination with ibuprofen or paraceta- To improve internal validity and reliability, the mol) is increasing in countries where it can be pur- survey instrument was piloted, and cognitive testing chased OTC [10]. Codeine containing analgesics are (read aloud) was conducted on the final instrument. commonly associated with abuse and dependence due The feedback confirmed that the questions were in- to the addictive and euphoric properties of codeine terpreted properly. Accompanying the survey was a [18]. participant information sheet, that highlighted the Associated with this euphoric effect is the con- purpose of the study and invited participation. Tak- sequence of overconsumption of the compounded an- ing part in the study was voluntary and anonymous. algesic such as paracetamol. The potential health risk A pre-paid, self-addressed envelope was included as a direct consequence of paracetamol overdose is to facilitate survey responses. Implied consent was hepatotoxicity [8] related to the chronic use of such assumed if surveys were returned. The duration of products [6, 5, 8]. Similarly, when codeine is com- data collection was approximately 3 months from bined with ibuprofen, overdose can result in nephro- 25/11/2016. toxicity and gastric irritation. These health harms are Community pharmacies in Cornwall (n=65) and amplified with dose escalation, which is commonly Devon (n=85) were surveyed, a sample representing observed with chronic codeine misuse [16], because approximately 60% of pharmacies in both counties. patients build tolerance to that dose of codeine and Devon had previously run a codeine awareness cam- need a greater amount of codeine to generate the paign and Cornwall had not. Community pharmacies same euphoric effect, while sustaining damage from registered on NHS choices website were targeted. paracetamol and ibuprofen overdose. Registered and preregistration pharmacists were in- The initial use of such agents is often genuine vited to complete the questionnaire. 32 completed and for appropriate indicated conditions. However, surveys (out of 150) were returned (response rate eventually it is taken for non-medical reasons and bor- 21%) from Devon (20) and Cornwall (12). 56% male ders on dependency [8, 4, 15]. Some studies suggest and 44% females responded. 59% of respondents had that codeine dependence is subtly different to other eight years or more practice experience. 66% of these opioid dependence. It requires different types of treat- were full-time pharmacist. ment, abusers have different mental health problems, Quantitative data were analysed using SPSS [7] and they have more similarities to the general popula- software and qualitative data were analysed using tion [11, 13]. Similarly, individuals mainly abusing NVivo [14] for thematic analysis. codeine, labelled themselves as ‘social and economi- cally active and different from illicit substance misus- 7.1. Ethics statement ers’ [4]. Additionally, individuals have described their codeine abuse as the ‘blurring’ between therapeutic Prior to data collection, favourable ethical opin- and problematic use, whereby they think they are us- ion was received from the School of Pharmacy and ing it to relieve pain, while in fact they are using it to Biomedical Sciences Research Ethics Committee on prevent opioid withdrawal symptoms [12]. (Reference number: 2016.17 – 005, Date submitted: Aims: The primary aim was to investigate the 24-10-2016). This study is in line with declaration of perceptions of community pharmacists on the misuse Helsinki-ethical principles for medical research in- and abuse of OTC co-codamol (research question: volving human subjects.

- 14 - R. Barrett & D. Costa: An evaluation of community pharmacist perception of the misuse and abuse of over-the-counter co-codamol in Cornwell and Devon, UK: A cross-sectional survey

treatment. All respondents that received training with 8. Results co-codamol abuse know where to refer customers for abuse support. Hence, Devon’s public health cam- 88% of respondents reported knowing custom- paign seems to have worked. 63% of all respondents ers who regularly purchased co-codamol, with 44% would like to receive further training. purchasing co-codamol once or twice a week. 84% of respondents did not routinely recommend co-co- 9. Discussion damol for pain relief. Of these, 38% actively avoid- ed recommending co-codamol for pain. 94% of all Most of the responders were full-time phar- responders had offered alternatives to co-codamol macists working in communities they perceived as during an OTC sale. 91% had denied prior sales of upper-middle-class areas. The obstacles they face co-codamol to individual customers. 47% of respond- included low-level co-codamol abuse. The Pearson ers believe that OTC use of co-codamol is harmful. chi-squared test suggests that poorer communities Of these, 41% believed it encouraged the risk of ad- that face challenges of co-codamol abuse/misuse are dictive behaviour, 28% believed there was a risk of doubly disadvantaged because the community phar- paracetamol overdose, a similar percentage believe macist lacks sufficient knowledge to be able to refer there was a risk of endorsing abuse, 22% believed patients appropriately to address their addiction. Con- there was a risk of liver damage with chronic high versely, respondent working in upper-middle-class or paracetamol intake. However, 72% of responders in- middle-class backgrounds are more aware of appro- dicated that co-codamol should not be reclassified as priate referral pathways. a prescription only medicine (POM). Pharmacist attempted to safeguard patients by 47% of respondents believed they served ‘low- asking questions and providing counselling for safe er-middle-class’ patients in their shop. 63% believed and appropriate use. They also shied away from rec- they knew where to refer customers for the treatment ommending co-codamol and actively discourage its of co-codamol abuse. A Pearson chi-squared test sta- use. Many respondents had mixed opinions on the tistic of 14.264 (p=0.002) rejects the null hypothesis harm of OTC use of co-codamol. Most respondents that there is no association between perceived lower concurred that OTC sale may risk ‘encouraging’ ad- socio-economic status of patients and pharmacist’s dictive behaviour. knowledge of referral. Regardless of these harms, it must be stressed Thematic analysis of the challenges associated that respondent-pharmacists do not believe that co- with OTC co-codamol sale identified the following codamol should be reclassified as prescription only, themes: 1. Patients, 2. Abuse, 3. Pharmacies. Patients: and many do not believe that the OTC use of co- patients repeatedly requesting co-codamol, failed to codamol is harmful. These recommendations are in understand the impact of their abuse on their health. line with the recent studies that suggest raising public Abuse: respondents reported patient abuse towards awareness and education is needed as the first step them including aggressiveness, defensiveness and in combating this problem. This education should not abusive language and actions. Pharmacies: some re- just be for co-codamol, but include all OTC codeine spondents would rather make a supply, even when containing products. they suspect abuse to secure revenues. The main limitation of this study is the small Thematic analysis of how patient’s health is safe- sample size, where results are not generalisable. guarded considering the above challenges revealed: 1. However, it provides a snapshot into current phar- Use, 2. Patients, 3. Staff. Use: advice around safe use macy practice. There was a high completion rate for is given. Patients: patients are routinely questioned on most questions, however, responder bias is possible. their use of co-codamol. Staff: staff are locally made Further in-depth study is warranted given the global aware of frequent customers and the risk of abuse by status of the . individual patients. 66% of respondent had received no training on 10. Conclusions helping customers with co-codamol abuse. A Pearson chi-squared test statistic of 8.119 (p = 0.004) reject- Community pharmacists face a difficult chal- ed the null hypothesis that there was no association lenge in gaining the right balance of safe co-codamol between pharmacists that had received training and use. Community pharmacists in Devon and Cornwall pharmacists who knew where to refer customers for believe that abuse can be reduced by raising public

- 15 - Heroin Addiction and Related Clinical Problems 20(5): 13-17 awareness and training pharmacist to spot the early 6. Craig DGN, Bates CM, Davidson JS, Martin KG, Hayes signs of abuse. The magnitude of this challenge re- PC, Simpson KJ. Overdose pattern and outcome in mains small according to the respondent and pharma- paracetamol-induced acute severe hepatotoxicity. Br J cists do not believe reclassification to POM is war- Clin Pharmacol. 2011 Feb;71(2):273–82. ranted. 7. IBM Corp. IBM SPSS Statistics for Windows. Armonk, NY; 2014. Co-codamol abuse is a complex and difficult 8. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani challenge, which can be reduced via policy or public E, Hynan LS, et al. Acetaminophen-induced acute liver health promotion. Pharmacist believed that mandato- failure: results of a United States multicenter, prospective ry counselling with co-codamol sale is essential. This study. Hepatol Baltim Md. 2005 Dec;42(6):1364–72. could be achieved in several ways: having a desig- 9. Lessenger JE, Feinberg SD. Abuse of Prescription and nated ‘codeine’ staff, who is the single point of con- Over-the-Counter Medications. J Am Board Fam Med. tact for codeine sales and is themselves additionally 2008 Jan 1;21(1):45–54. trained for issues around addiction. There could be 10. McAvoy BR, Dobbin MDH, Tobin CL. Over-the-counter barcode scanned prompts at point of sale for essen- codeine analgesic misuse and harm: characteristics of tial counselling with each sale. Further, local training cases in Australia and New Zealand. N Z Med J [Internet]. 2011 Nov 25 [cited 2017 Jan 20]; 124 (1346): 29-33. and awareness of pharmacists and their support staff Available from: https://www.nzma.org.nz/journal/ via e-learning courses could further raise awareness read-the-journal/all-issues/2010-2019/2011/vol-124- amongst pharmacy professionals, including local no-1346/article-mcavoy signposts for addiction support counselling services. 11. Nielsen S, Cameron J, Lee N. Characteristics of a Patients are made aware of the risk of addiction nontreatment-seeking sample of over-the-counter on the packaging: in the UK, printed warning for safe codeine users: implications for intervention and use of three days as a maximum and pack sizes are prevention. J Opioid Manag. 2011 Oct;7(5):363–70. restricted to a maximum of three-day supply. Further 12. Nielsen S, Cameron J, Pahoki S. Over the counter codeine OTC opioid-analgesics awareness programs could be dependence, Final Report 2010. Victoria, Australia: run by the government. Turning Point Alcohol and Drug Centre; 2010 Jun p. 79. Available from: http://atdc.org.au/wp-content/ Safety as a quality can be linked to medication uploads/2011/02/OTC_CODEINE_REPORT.pdf and their safe use. Safety, can also be linked to patient 13. Nielsen S, Murnion B, Dunlop A, Degenhardt L, qualities and characteristics, where some patients Demirkol A, Muhleisen P, et al. Comparing treatment- have a greater propensity for safety versus addiction. seeking codeine users and strong opioid users: Findings It is this second group, which benefits most from from a novel case series: Comparing codeine and strong these safer modalities exercised by pharmacy. opioid users. Drug Alcohol Rev. 2015 May;34(3):304–11. 14. NVivo qualitative data analysis Software. QSR References International Pty Ltd.; 2015. 15. Roussin A, Bouyssi A, Pouché L, Pourcel L, Lapeyre- 1. Albsoul-Younes A, Wazaify M, Yousef A-M, Tahaineh L. Mestre M. Misuse and Dependence on Non-Prescription Abuse and Misuse of Prescription and Nonprescription Codeine Analgesics or H1 Antihistamines by Drugs Sold in Community Pharmacies in Jordan. Subst Adults: A Cross-Sectional Investigation in France. PLOS Use Misuse. 2010 Jul;45(9):1319–29. ONE. 2013 Oct 3;8(10):e76499. 2. Carney T, Wells J, Bergin M, Dada S, Foley M, McGuiness 16. Tobin CL, Dobbin M, McAvoy B. Regulatory responses P, et al. A Comparative Exploration of Community to over-the-counter codeine analgesic misuse in Pharmacists’ Views on the Nature and Management Australia, New Zealand and the United Kingdom. Aust of Over-the-Counter (OTC) and Prescription Codeine N Z J Public Health. 2013 Oct 1;37(5):483–8. Misuse in Three Regulatory Regimes: Ireland, South 17. United Nations Publication. The non medicinal use of Africa and the United Kingdom. Int J Ment Health prescription drugs. Discussion paper [Internet]. 2011 Addict. 2016 Aug;14(4):351–69. [cited 2017 Jan 24]. Available from: https://www. 3. Casati A, Sedefov R, Pfeiffer-Gerschel T. Misuse of unodc.org/documents/drug-prevention-and-treatment/ Medicines in the European Union: A Systematic Review nonmedical-use-prescription-drugs.pdf of the Literature. Eur Addict Res. 2012;18(5):228–45. 18. Van Hout, MC. Bergin, M. Foley, M. Rich, E. Rapca, 4. Cooper RJ. ‘I can’t be an addict. I am.’ Over-the-counter AI. Harris, R. Norman I. A Scoping Review of Codeine medicine abuse: a qualitative study. BMJ Open [Internet]. Use, Misuse and Dependence, final report [Internet]. 2013 Jun 17;3(6). Available from: http://bmjopen.bmj. CODEMISUSED Project European Commission 7th com/content/3/6/e002913.abstract Framework Programme, EU. Brussel; 2014. Available 5. Cooper RJ. Over-the-counter medicine abuse – a review from: http://codemisused.org/uploads/files/Van_Hout_ of the literature. J Subst Use. 2013 Apr;18(2):82–107. et_al_Scoping_Report_23-03-2015.pdf

- 16 - R. Barrett & D. Costa: An evaluation of community pharmacist perception of the misuse and abuse of over-the-counter co-codamol in Cornwell and Devon, UK: A cross-sectional survey

Acknowledgements Conflict of interest Thank you to Dr Nicola Barnes for providing edito- Authors declared no conflict of interest. rial guidance. Ethics Role of the funding source Authors confirm that the submitted study was con- This study was funded by the University of Ports- ducted according to the WMA Declaration of Helsinki - mouth. Ethical Principles for Medical Research Involving Human Subjects. All patients gave their informed consent to the Contributors anonymous use of their clinical data for this independent All authors were involved in the study design, had study. full access to the survey data and analyses, and interpreted the data, critically reviewed the manuscript and had full Note control, including final responsibility for the decision to It is the policy of this Journal to provide a free re- submit the paper for publication. vision of English for Authors who are not native English speakers. Each Author can accept or refuse this offer. In this case, the Corresponding Author preferred not to use our service.

Received September 8, 2017 - Accepted February 9, 2018

- 17 -

HEROIN ADDICTION & Report RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 19-28 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

Switching between lyophilized and sub-lingual buprenorphine formulations in opioid-dependent patients: Observations on medication transfer during a safety and pharmacokinetic study Kylie Reed 1,2, Alastair Knight 3, Shelagh Baillie 4, Karolina Bogdanowicz 1, James Bell 1,2, and John Strang 1,2

1-King’s College London, National Addiction Centre (Institute of Psychiatry, Psychology & Neuroscience), London, UK 2-Addictions Services, South London & Maudsley NHS Foundation Trust, London, UK 3-Evicom Ltd, Twickenham, UK 4-Martindale Pharmaceuticals Ltd, High Wycombe, Buckinghamshire, UK

Summary Background: A new lyophilized, rapid-disintegrating buprenorphine tablet (“bup-lyo”) has been developed to potentially enhance adherence compared to conventional sublingual tablets (“bup-SL”) but with a higher bioavailability of buprenor- phine. Aim: To examine the pharmacokinetics, efficacy and safety of switching between formulations. Methods: Within a randomized trial of opioid-dependent subjects, one arm received “bup-lyo”. After 2 weeks of treatment, all subjects switched back to standard sublingual “bup-SL” over 1-4 days in preparation for transfer back to their treating clinician. Observations were made of any change in clinical situation on transfer, or need for dose adjustment. Measurements included dose titration, treatment retention and within-subject comparisons of; pharmacokinetics (buprenorphine and norbuprenorphine), subjective scores of medication hold and dose adequacy, and safety assessments. Results: Subjects (N=23) were titrated to an effective and safe daily dose of “bup-lyo” (10.8 ± 4.85 mg) (N=22) and then returned to the same dose of “bup-SL” (N=21). There had been no significant difference in dose, medication hold and dose adequacy be- tween formulations on optimized treatment. Bloods were provided by 5 “bup-lyo” subjects for pharmacokinetic analysis: despite within-subject similar dosing, buprenorphine Cmax and AUC0-3hr (mean ± SD) were significantly higher with “bup-lyo” than when switched to “bup-SL” (relative Cmax 185.8 ± 88.2%, AUC0-3hr 169.8 ± 62.0 %). However, for nor- buprenorphine which is more associated with respiratory depression, the differences were not significant (relative Cmax 109.6 ± 42.2%, AUC0-3hr 105.0 ± 39.4 %). Adverse event incidence was slightly higher with "bup-lyo" but events were mild to moderate. Conclusion: Switching from “bup-lyo” to “bup-SL” did not require clinical adjustment of daily dose de- spite observed higher buprenorphine levels with “bup-lyo”. The bioavailability of the metabolite norbuprenorphine, which is a more potent respiratory than buprenorphine, was comparable between formulations. This may explain the absence of clinical difference in vital signs or other adverse events observed on switching formulations. Key Words: Buprenorphine; switching; lyophilized; pharmacokinetics

1. Introduction Poor adherence and diversion of supplies are common obstacles to the success of opioid replace- Buprenorphine is a widely-approved replace- ment therapy (ORT). Supervised dosing of standard ment therapy of opioid addiction [7]. Evidence sug- sublingual buprenorphine [2] can take 5–10 min for gests it is a safer treatment than other opioids such tablets to dissolve and hence requires extended su- as methadone although deaths, possibly associated pervision which can be impractical, particularly in with respiratory depression [1] due to buprenorphine prisons and busy community pharmacies. The de- overdose, are still reported in clinical and forensic velopment of rapidly dissolving or rapid-dispersal practice. formulations, such as combination buprenorphine/

Corresponding author: John Strang, King’s College London, National Addiction Centre (Institute of Psychiatry, Psychology & Neuroscience), Denmark Hill, London SE5 8BB, UK and Addictions Services, South London & Maudsley NHS Foundation Trust, London, UK, United Kingdom E-mail: [email protected] 19 Heroin Addiction and Related Clinical Problems 20(5): 19-28 naloxone film [11, 6] and rapid-dispersal tablets spe- the ethics committee although safety was routinely cifically designed for virtually instant disintegration monitored during the course of the trial by the Prin- [3, 12], may be beneficial in busy community phar- cipal investigator (Prof John Strang) and one of two macies and custodial settings as it will enable wider Medical safety advisors; Dr John St Clair Roberts and prescribing of buprenorphine in these settings. Dr Robert Miller who were otherwise not involved in We [12] undertook a randomized, group com- the study. Subjects in this one arm of the trial were parison trial in opioid-dependent subjects comparing initially randomized to a new lyophilized (rapid-dis- standard sublingual buprenorphine (“bup-SL”) [Sub- integrating) buprenorphine (“bup-lyo”). It was then utex®, Indivior UK Ltd, Slough, UK] to a new lyo- necessary for all participating patients to be switched philized (rapid-disintegrating) buprenorphine (“bup- back to standard “bup-SL” during an extension period lyo”) [Espranor®, Martindale Pharmaceuticals Ltd, in preparation for transfer back to their treating clini- High Wycombe UK] and established complete disin- cian. Importantly, this part of the study included addi- tegration by 3 min for more than 75% of “bup-lyo” tional pharmacokinetic (PK) data from a sub-group of administrations versus less than 25% of “bup-SL” subjects consenting to blood sampling for PK analysis administrations. Comparative safety and efficacy of for up to 180 min post-dose “bup-lyo” and “bup-SL” these formulations was assessed against an observed treatment, in effect providing within-subject (cross- suprabioavailability of “bup-lyo”. Further pharma- over), PK comparison data. Through the research op- cokinetic analysis of these data [13] included assess- portunity afforded by the clinical necessity to switch ment of norbuprenorphine, the of these patients from “bup-lyo” to standard “bup-SL”, buprenorphine which has a greater potency for respir- along with supplementary analysis of this arm of the atory depression than buprenorphine and may be the study we examine further the clinical practicalities of main cause of the observed deaths on buprenorphine switching between these buprenorphine formulations. [5, 10]. This additional analysis provided evidence to The following information was utilized; dosing com- suggest that the reason respiratory depression was not parability, subject retention, efficacy (subjective Lik- observed with suprabioavailable buprenorphine was ert scores (1=best, 4=worst) for adequacy of ‘hold’, because buprenorphine is only minimally directly de- withdrawals symptoms and intensity of craving) and pressing respiration and may indirectly be protective safety data (adverse event reports and vital signs), to- by competing for receptor occupancy with the active gether with new PK data. metabolite norbuprenorphine and its greater depres- The study design and methods undertaken sive effect on ventilation [8]. The purpose of this within the group comparison arms of the trial have study was to examine further this hypothesis by com- been described previously [12, 13]. In summary, con- paring the two buprenorphine formulations amongst senting subjects already treated with or suitable for subjects in the randomized arm who received “bup- ORT, were screened for their suitability for the trial. lyo” for 14 days and were then switched to “bup-SL”, Subjects were then randomized directly onto the as- utilising within-subject pharmacokinetic data for both signed study medication, either to standard sublin- buprenorphine and norbuprenorphine and examining gual buprenorphine or to a new lyophilized (rapid- dosage comparability through clinical outcome and disintegrating) buprenorphine (“bup-lyo”). To enable safety assessments. a buprenorphine-free PK profile at the start of ran- domization, subjects received no buprenorphine or 2. Methods methadone replacement therapy for a minimum of one-day prior to randomization. Following randomi- This supplementary report describes additional zation, subjects proceeded to a titration period of up to data from one arm of a randomized, open-label, group 7 days during which their dose of buprenorphine was comparison trial in ORT subjects [12] which was ap- increased in a step-wise manner from 1-2 mg daily proved by Brent Research Ethics Committee, UK based on post-dose safety data and efficacy data from with trial number UK/H/5385/01-02/DC. The study Likert scores and validated opioid-withdrawal signs was subsequently, registered with EudraCT number: and symptom scales (Objective Opiate Withdrawal 2012-003560-49 and conducted according to the Dec- Scale [OOWS] and Subjective Opiate Withdrawal laration of Helsinki which required patients to sign Scale [SOWS]), [4]. Thereafter, subjects proceeded informed consent to enter the documented screening to a maintenance period of 7 days during which they process. As this was a small open-label study a sepa- were assessed 24 hr post-dose at end of day 1 and rate data monitoring committee was not required by 7 for safety and efficacy, and a sub-group also pro-

- 20 - K. Reed et al.: Switching between lyophilized and sub-lingual buprenorphine formulations in opioid-dependent patients: Observations on medication transfer during a safety and pharmacokinetic study vided blood samples for PK analysis after dosing. each on different doses of buprenorphine but on the This was then the end of the group comparison study same formulation dose within subjects, the % change period. To ensure subjects returned safely back to a of Cmax and AUC0-3hr on “bup-lyo” treatment com- licensed formulation of buprenorphine (“bup-SL”) at pared to “bup-SL” treatment were determined for an optimal dose, subjects then entered an extension each subject and absolute values compared by paired period which included a switching period of up to 4 t-test and summarized for all subjects as a mean % days where subjects were weaned-off “bup-lyo” onto relative change. Corresponding Likert scores on “bup-SL” using daily safety and Likert score data to “bup-lyo” and “bup-SL” were compared statistically guide clinician judgement of buprenorphine dose. using ANOVA. Safety data during the “bup-lyo” ti- After this switching period subjects were maintained tration phase was assessed daily and included periods on the same dose of “bup-SL” for the rest of the ex- at sub-optimal dosing. To compare safety data at op- tension period and reassessed on day 14 from start of timal dosing of both formulations only the adverse switching for efficacy and safety, at which point the events (AEs) recorded during the maintenance phase same sub-group provided an additional series of PK (Day 2 and Day 7) on “bup-lyo” and the extension samples post-dose. period after switching (Extension Day 4 or last day PK profiles of each subject within the PK sub- of switching and Extension Day 14) for “bup-SL” are group at the end of the maintenance period on “bup- reported. The incidence of all AEs, independent of lyo” and at the end of the extension data on “bup-SL” dosing status, have been previously reported [12]. (treatment for 14 days including optimal maintenance dosing for at least 7 days) were, where available, com- 3. Results pared and Phoenix WinNonlin 6.3 (Certara USA Inc., Princeton, USA) software utilised to determine the The flow of and number of subjects recruited Cmax, AUC0-3hr and Tmax parameters of buprenor- and randomized to the “bup-lyo” arm of a single-blind phine and the metabolite, norbuprenorphine for each study and then switched to “bup-SL” are detailed in buprenorphine formulation. Since PK subjects were Figure 1. A total of 55 subjects were screened over a

Opioid-dependent Subjects Screened N = 55 Screen Failures N = 17: 16 Failed incl. / exc. criteria : 1 Screening incomplete, DNA Randomized (2:1) No buprenorphine or methadone treatment within 1 day N = 36*

“bup-lyo” “bup-SL” N = 23 (PK = 8) N = 13 TITRATION PERIOD 7 days N = 22 (PK = 7)

MAINTENANCE PERIOD 7 days N = 21 (PK = 6)

“bup-SL” N = 21 (PK = 6) SWITCH PERIOD ≤ 4 days N = 20 (PK = 5)

EXTENSION PERIOD up to 14 days N = 20 (PK = 5)

* 2 subjects were randomized but not treated (1 Lost to follow-up and 1 Withdrew consent). PK = Pharmacokinetic study population, DNA = Did Not Attend

Figure 1. Study flow and subject numbers

- 21 - Heroin Addiction and Related Clinical Problems 20(5): 19-28 two-week period. Thirty-eight were eligible for ran- 3.2. Dosing domization (2:1) and excluded any ORT (buprenor- phine/methadone) for a minimum of one day prior to The mean ± SD “bup-lyo” maintenance dose randomization. Of these, 23 were randomized and was 10.8 ± 4.85 mg (2-20 mg) and on switching back commenced “bup-lyo” study treatment, including 8 to “bup-SL” at the end of the extension 10.5 ± 4.98 who consented to PK blood sampling. These sub- mg (2-20 mg). These small dosing differences were jects formed the cohort for this additional analysis. not significantly different. Eighteen of 22 subjects The other 13 subjects were randomized to continued (81.8%) were titrated to an optimal dose of “bup-lyo” maintenance on “bup-SL” and their outcomes have within 3 days, the others within 7 days. On switch- been previously reported [12]. Of the 23 randomized ing from “bup-lyo” to “bup-SL” all subjects were and receiving “bup-lyo” medication, one subject switched to the same dose of “bup-SL” as the dose withdrew consent during the titration period and one of “bup-lyo” to which they had been titrated and on withdrew consent during the maintenance period. A which they had been maintained for the second week total of 21 subjects completed the “bup-lyo” main- of the study. tenance period. These subjects were then switched back to conventional “bup-SL” as part of an extension 3.3. Pharmacokinetics period of the trial. This included a ‘switching’ pe- riod of up to 4 days for dose adjustment, if required. Eight subjects formed the PK sub-group which One subject was lost to follow-up during ‘switching’, included PK sampling for buprenorphine and nor- resulting in a total of 20 subjects who entered and buprenorphine while on “bup-lyo” on Day 7 of the completed the switch to “bup-SL” extension period of maintenance period. Five of these also had PK sam- the trial. No subjects withdrew due to adverse events. pling while being treated with “bup-SL” at the end of the extension period. Three subjects did not have 3.1. Demographics and medical history of the sampling performed at the end of extension (2 insuf- “switch to bup-SL” subjects ficient samples to establish PK profile due to cannula blockage, 1 withdrew (lost to follow-up)). The PK The demographics of the 23 subjects who were comparisons of the 5 paired PK assessments at the randomized, received “bup-lyo” and then expected to end of comparable durations of treatment, are de- switch to “bup-SL” as part of the protocol, are de- tailed for each patient and summarised in Table 1. scribed in detail in a previous publication [12]. In Each subject had different doses of buprenor- summary there were 20 males and 3 females with a phine but within subject dosing for the buprenorphine mean ± SD age of 42.0 ± 8.0 years. The majority were formulations were the same. Significant increases Caucasian (65.2%). They reflect a typical population in mean ± SD buprenorphine Cmax and AUC0-3hr of opioid users with 22 of the 23 subjects including were observed with “bup-lyo” relative (%) to “bup- a history of opioid use >2 years, with a mean ± SD SL” (Cmax 185.8 ± 88.2%, AUC0-3hr 169.8 ± 62.0 duration of opioid use of 16.6 ± 11.3 years. Mean %) P<0.001, but the variation between subjects was ± SD age at first opioid use was 25.4 ± 8.7 years. great. Interestingly, for norbuprenorphine, a bu- Medical history for psychiatric disorders included; prenorphine metabolite, the relative % mean ± SD PK mild to moderate depression in 11 (6 ongoing), alco- parameter differences were not significantly differ- hol dependence in 2 (1 potentially ongoing as failed ent when comparing “bup-lyo” to “bup-SL” (Cmax an initial screen test) and anxiety in 1 (ongoing). relative 109.6 ± 42.2%, AUC0-3hr 105.0 ± 39.4 %). Medical history for infections included 7 with Hepa- Tmax ranges for buprenorphine and norbuprenor- titis C (3 ongoing). At the start of screening, 15 of the phine were similar between formulations. A longer randomized cohort were treated with buprenorphine, maximal Tmax range for norbuprenophine (120 min) 6 with methadone and 2 had no treatment. No sub- compared to buprenorphine (60 min) was observed as jects had positive screens for but 13 had would be expected for this metabolite. positive screens for opioids at start of screening and were requested to stop use. Within the cohort being 3.4. Subjective assessments - Medication hold and treated with “bup-SL” one subject stated they were a dose adequacy regular user of therapy. The others stated they were non-regular users of benzodiazepine. Mean (SD) subjective scores for medication hold, intensity of withdrawal symptoms and intensity

- 22 - K. Reed et al.: Switching between lyophilized and sub-lingual buprenorphine formulations in opioid-dependent patients: Observations on medication transfer during a safety and pharmacokinetic study 5 (%) (%) 96.0 69.0 69.0 96.0 75.0 AUC AUC 0-3hr 0-3hr 166.0 105.0 119.0 166.0 39.35 ”bup-SL” ”bup-SL” 5 (%) (%) 78.0 60.0 60.0 163.0 109.6 109.0 138.0 163.0 Cmax Cmax 42.18 109.09 "bup-lyo” “bup-lyo” AUC 0-3hr 731.435 417.240 505.270 192.620 401.005 208.020 229.700 293.710 346.328 220.303 (min.ng/mL) Norbuprenorphine 5 60 120 120 (min) 5.504 2.572 3.315 1.217 2.794 1.373 1.681 1.998 2.238 1.566 Tmax Cmax (ng/mL) “bup-SL” 5 60 60 60 60 60 60 60 120 120 120 120 120 120 (min) (min) Tmax Tmax “bup-lyo”’ 5 (%) (%) AUC AUC 0-3hr 0-3hr 169.8 267.0 156.0 108.0 108.0 156.0 188.0 267.0 130.0 61.99 ”bup-SL” ”bup-SL” 5 (%) (%) 185.8 315.0 146.0 103.0 103.0 146.0 237.0 315.0 128.0 Cmax Cmax 88.17 "bup-lyo” "bup-lyo” mL) AUC 0-3hr (min.ng/ 934.423 670.338 168.810 351.715 318.018 382.993 938.395 499.568 1012.520 1047.803 Buprenorphine 5 60 60 60 (min) Tmax Cmax 8.729 5.681 8.964 1.281 8.312 2.554 3.039 3.272 8.044 4.198 (ng/mL) “bup-SL” 5 60 60 60 60 60 60 60 60 60 60 60 60 60 (min) (min) Tmax Tmax “bup-lyo” 4 8 4 8 16 12 16 12 10 10 (mg) Dose D7 D7 D7 D7 D7 Visit Maintenance Maintenance Maintenance Maintenance Maintenance Extension End Extension End Extension End Extension End Extension End “bup-SL” “bup-SL” “bup-SL” “bup-SL” “bup-SL” “bup-lyo” “bup-lyo” “bup-lyo” “bup-lyo” “bup-lyo” Treatment n 5 4 3 2 1 SD Min Max Mean Summary Statistics AUC0-3hr = area under the curve from 0 to 3 hours, Cmax = maximum concentration, PK = pharmacokinetic, Tmax = time to maximum concentration from 0 to 3 hours, Cmax = maximum concentration, PK = pharmacokinetic, under the curve AUC0-3hr = area and “bup-SL” for subjects completing “bup-lyo” AUC0-3hr % Cmax and Relative Subject Median Comparative pharmacokinetics of buprenorphine and norbuprenorphine at the end of 14 days treatment with “bup-lyo” and “bup-SL”. and “bup-SL”. at the end of 14 days treatment with “bup-lyo” and norbuprenorphine pharmacokinetics of buprenorphine 1. Comparative Table

- 23 - Heroin Addiction and Related Clinical Problems 20(5): 19-28

"bup-lyo" "bup-SL" Screening Titration Period Maintenance Period Switch Period Extension Period Day -3 - -1 Day 1 - 7 Day 8 - 14 Day 1 - ≥ 4 Day ≥4 - 14 4

3.5 P = 0.603

3 SD) SD) Worst, 4= 1 = Best ± 2.5

2 Adequacy of Hold (Mean (Mean Hold of Adequacy

1.5

1 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Day of Treatment

Figure 2a. Likert categorical assessment scores for Adequacy of hold during buprenorphine formulation switching

"bup-lyo" "bup-SL" Screening Titration Period Maintenance Period Switch Period Extension Period Day -3 - -1 Day 1 - 7 Day 8 - 14 Day 1 - ≥ 4 Day ≥4 - 14 4

3.5 P = 0.062

3 SD) 4= 4= SD) Most, 1 Least = ± 2.5

2 Intenisty of Withdrawal (Mean 1.5

1 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Day of Treatment

Figure 2b. Likert categorical assessment scores for Withdrawal symptoms during buprenorphine formulation switch- ing

- 24 - K. Reed et al.: Switching between lyophilized and sub-lingual buprenorphine formulations in opioid-dependent patients: Observations on medication transfer during a safety and pharmacokinetic study

"bup-lyo" "bup-SL" Screening Titration Period Maintenance Period Switch Period Extension Period Day -3 - -1 Day 1 - 7 Day 8 - 14 Day 1 - ≥ 4 Day ≥4 - 14 4

3.5 P = 0.269

3 SD) SD) Most,4= 1 = Least ± 2.5

2 Intensity of Craving (Mean

1.5

1 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Day of Treatment

Figure . Likert categorical assessment scores for Craving during buprenorphine formulation switching of craving at the end of screening on “bup-SL”, on 3.6. Adverse events switching to “bup-lyo” during a titration period and a dose maintenance period, and on switching back A summary of all AEs reported with each for- to “bup-SL” during a switching period and an exten- mulation during stable optimal dosing for at least a sion period are detailed in Figure 2a-c. All assess- week are detailed in Table 2. There was a slightly ments were performed 24 hr post-dose. Following larger number of AEs reported on “bup-lyo” than a stable dose of buprenorphine for 7 days none of “bup-SL” which was also reflected in a larger pro- the differences between buprenorphine formulation portion of subjects reporting AEs on “bup-lyo”. The scores were statistically significant. The higher Lik- most frequently reported TEAEs by system organ ert scores observed during the initial days of the ti- class were from clinical “Investigations” followed tration period reflected what would be expected for by “Musculoskeletal and connective disorders”. The sub-optimal dosing. proportion of subjects treated reporting these events was greater on “bup-lyo”. The most common AE was 3.5. Vital signs headache reported in 3 subjects (“bup-lyo” 2 subjects and “bup-SL” 1 subject), followed by athralgia, and Vital signs were assessed at each subject visit ECG abnormalities reported each in 2 subjects (“bup- 24 hr post-dose and included respiratory rate. There lyo” only). The majority of AEs were mild in both were no significant differences between formulations groups. No serious or severe adverse events were in respiratory rate or blood pressure at the end of the reported, and no subjects withdrew or discontinued maintenance period on “bup-lyo” and end of the ex- from the study due to adverse events. tension period on “bup-SL”, despite the higher Cmax observed with “bup-lyo”. 4. Discussion

Utilising within-subject, pharmacokinetic, com- parative analysis this study supports the view from our

- 25 - Heroin Addiction and Related Clinical Problems 20(5): 19-28

Table 2. Adverse events by buprenorphine treatment

"bup-lyo" "bup-SL" N=22 N=21 System Organ Class Preferred Term n (%) n (%) Total AEs Overall 21 15 At least one AE per subject Overall 16 (72.7) 6 (28.6) Gastrointestinal disorders Overall 1 (4.5) 3 (14.3) Constipation 1 (4.8) Hypoaesthesia oral 1 (4.5) Nausea 1 (4.8) Toothache 1 (4.5) 1 (4.8) Vomiting 2 (9.5) General disorders and administration Overall 1 (4.5) 2 (9.5) site Fatigue 1 (4.8) Influenza like illness 1 (4.8) Vessel puncture site reaction 1 (4.5) Infections and infestations Overall 1 (4.5) 1 (4.8) Cellulitis 1 (4.8) Influenza 1 (4.5) Injury, poisoning and procedural com- Overall 1 (4.5) 1 (4.8) plications Arthropod bite 1 (4.8) Laceration 1 (4.5) Muscle strain 1 (4.5) Investigations Overall 4 (18.2) 2 (9.5) Blood creatinine phosphokinase 1 (4.5) increased Blood pressure diastolic de- 1 (4.5) creased Blood pressure increased 1 (4.8) Electrocardiogram abnormal 2 (9.1) Platelet count decreased 1 (4.8) Musculoskeletal and connective disor- Overall 4 (18.2) ders Arthralgia 2 (9.1) Muscular weakness 1 (4.5) Musculoskeletal chest pain 1 (4.5) Myalgia 1 (4.5) Nervous system disorders Overall 2 (9.1) 1 (4.8) Headache 2 (9.1) 1 (4.8) Psychiatric disorders Overall 1 (4.8) Depressed mood 1 (4.8) Respiratory, thoracic and mediastinal Overall 1 (4.5) disorders Oropharyngeal pain 1 (4.5) Rhinorrhoea 1 (4.5) Skin and subcutaneous tissue disorders Overall 1 (4.5) 1 (4.8) Hyperhidrosis 1 (4.8) Skin irritation 1 (4.5) Vascular disorders Overall 1 (4.5) 1 (4.8) Hot flush 1 (4.8) Hypotension 1 (4.5)

- 26 - K. Reed et al.: Switching between lyophilized and sub-lingual buprenorphine formulations in opioid-dependent patients: Observations on medication transfer during a safety and pharmacokinetic study previous group comparison, dose-normalized analy- worse on initial titration day assessments with low sis, that buprenorphine bioavailability with “bup-lyo” starting doses compared to those at higher mainte- is higher than with “bup-SL” while norbuprenorphine nance dosing. bioavailability is similar [12, 13]. It can be postulated that a higher buprenorphine bioavailability with “bup- 5. Conclusions lyo” will require a lower dosing than conventional “bup-SL”: however, this study provides efficacy and In conclusion, this study suggests that opio- safety evidence to suggest that the dosing of the two id-dependent subjects can be switched between “bup- formulations are comparable across a dose range of lyo” and conventional “bup-SL” therapy using similar 4-16 mg when adopting an initial dose-titration prac- dosing despite pharmacokinetic evidence suggesting tice over a period of up to 7 days. No risk of any comparative suprabioavailability of buprenorphine. respiratory depression was observed when switch- The bioavailability of the metabolite norbuprenor- ing between “bup-lyo” at the same dose of “bup-SL” phine, which is a more potent respiratory depressant despite the higher bioavailability of buprenorphine. than buprenorphine, was comparable between formu- It has been proposed that norbuprenorphine, a bu- lations. This may explain the absence of clinical dif- prenorphine metabolite with a known respiratory de- ference in vital signs or other adverse events observed pressant potency up to 10 times that of buprenorphine on switching formulations. in animal studies [9] is the likely mediator of any res- piratory depression in buprenorphine tablet overdos- References ing. This view is indirectly supported in this study by the lack of respiratory depression observed with 1. Cowan A., Doxey J.C., Harry E.J. (1977): The animal “bup-lyo” at comparable dosing and the similarity pharmacology of buprenorphine, an oripavine analgesic of norbuprenorphine bioavailability between the for- agent. Br J Pharmacol. 60: 547–554. mulations at the same dose. Adverse event incidence 2. Department of Health (England) and the Devolved Administrations (2007): Drug Misuse and Dependence: did appear to be slightly greater with “bup-lyo” than UK Guidelines on Clinical Management. London, “bup-SL” at the same dose but all AEs observed were Department of Health. graded mild or moderate and none were classified as 3. Fischer A, Jönsson M, Hjelmström P. (2015): severe or serious. Pharmaceutical and pharmacokinetic characterization Buprenorphine is comparable to methadone in of a novel sublingual buprenorphine/naloxone tablet suppressing opioid use but there is evidence to sug- formulation in healthy volunteers. Drug Dev Ind gest it is slightly less effective in retaining patients Pharm.41:79-84. as an ORT [7]. The use of a lyophilized formula- 4. Handelsman L., Cochrane K.J., Aronson M.J., Ness R., tion reduces the potential for concealment and sub- Rubinstein K.J., Kanof P.D. (1987): Two new rating sequent diversion and abuse and thereby is expected scales for opiate withdrawal. Am J Drug Alcohol Abuse. 13: 293-308. to increase medication adherence and retention in 5. Kintz P. (2002): A new series of 13 buprenorphine-related treatment. Furthermore, it may make buprenorphine deaths. Clin Biochem. 35: 513–516. prescription more feasible in settings where time-con- 6. Lintzeris N., Leung S.Y., Dunlop A.J., Larance B., White suming supervision proves an obstacle e.g. treatment N., Rivas G.R., et al (2013): A randomised controlled in prison, or in a busy clinic. This study demonstrates trial of sublingual buprenorphine-naloxone film versus that switching from conventional sub-lingual therapy tablets in the management of opioid dependence. Drug is relatively simple and although a titration period of Alcohol Depend. 131: 119–126. 7 days was utilized the vast majority of subjects were 7. Mattick R.P., Breen C., Kimber J., Davoli M. (2014): switched across to a comparable dose after 3 days, Buprenorphine maintenance versus placebo or thus mitigating this risk. methadone maintenance for opioid dependence. In: Mattick RP, editor. Cochrane Database of Systematic Although the sample size is small and limits the Reviews. Chichester, UK: John Wiley & Sons, Ltd. strength of the observations made, it does highlight 8. Megarbane B., Hreiche R., Pirnay S., Marie N., Baud F.J. that clinical trials with a high frequency of hospital (2006): Does high-dose buprenorphine cause respiratory visits in opioid-dependent subjects are feasible and depression?: possible mechanisms and therapeutic can produce meaningful qualitative outcome scores consequences. Toxicol Rev. 25: 79–85. which are sensitive to changes in therapy dosing. 9. Ohtani M., Kotaki H., Nishitateno K., Sawada Y., Iga T. This was highlighted by the recording of differences (1997): Kinetics of respiratory depression in rats induced between Likert categorical assessments which were by buprenorphine and its metabolite, norbuprenorphine.

- 27 - Heroin Addiction and Related Clinical Problems 20(5): 19-28

J Pharmacol Exp Ther. 281: 428-433. Contributors 10. Pirnay S., Borron S.W., Giudicelli C.P., Tourneau J., A.K., J.S., designed the study and wrote the proto- Baud F.J., Ricordel I. (2004): A critical review of the col. K.R., A.K., S.B., K.B., J.B., J.S., managed the litera- causes of death among post-mortem toxicological ture searches and analyses. K.R., A.K., S.B., K.B., J.B., investigations: analysis of 34 buprenorphine-associated J.S., undertook the statistical analysis, and all the authors and 35 methadone-associated deaths. Addiction. 99: discussed the results. K.R., A.K., S.B., J.S., wrote the first 978-988. draft of the manuscript. All authors revised the last draft. 11. Strain E.C., Harrison J.A., Bigelow G.E. (2011): All the authors contributed to, and have approved, the final Induction of opioid-dependent individuals onto manuscript. buprenorphine and buprenorphine/naloxone soluble- films. Clin Pharmacol Ther. 89: 443–449. Conflict of interest 12. Strang J., Reed K., Bogdanowicz K., Bell J., van der Waal J.S. is a researcher and clinician and has worked with R., Keen J., et al (2017): Randomised Comparison of a a range of types of treatment and rehabilitation service-pro- Novel Buprenorphine Oral Lyophilisate versus Existing viders. He has contributed to the work of various govern- Buprenorphine Sublingual Tablets in Opioid-Dependent mental and non-governmental organisations. He has also Patients: A First-in-Patient Phase II Randomised Open worked with pharmaceutical companies to seek to identify Label Safety Study. Eur Addict Res. 23: 61–70. new or improved treatments (including, last 3 years, Mar- 13. Strang J., Knight A., Baillie S., Reed K., Bogdanowicz tindale, Indivior, MundiPharma, Rusan/iGen, Braeburn/ K., Bell J. (2018): Norbuprenorphine and respiratory Camurus) from whom he and his employer (King’s Col- depression: exploratory analyses with new lyophilised lege London) have received honoraria, travel costs, consul- buprenorphine and sublingual buprenorphine. Int J Clin tancy payments or trial medications. Funding provided by Pharmacol Ther. 56: 81-85. Martindale Pharma includes funding to the King’s Health Partners Clinical Trials Office for conduct of this study and Acknowledgements also payment to J.S.’s university employer for consultancy We are grateful to all patients who participated in the input for his contribution to this work. Fuller detail of JS’s study and to clinical colleagues who helped with referrals; interests is given at http://www.kcl.ac.uk/ioppn/depts/ad- we thank Elka Giemza and her staff on the Clinical Tri- dictions/people/hod.aspx. J.B. has held consultancy agree- als Facility at King’s College Hospital for working with ments with Reckitt-Benckiser, Britannia Pharmaceuticals us. Alli Sellors and Stuart Hatcher from the KHP-CTO and Martindale Pharmaceuticals Ltd, and is PI on research (King’s Health Partners Clinical Trials Office) were a con- grants funded by Reckitt-Benckiser and Martindale Phar- stant source of guidance and support, and we also thank Dr maceuticals Ltd. S.B. is Medical Director of Martindale John St Clair Roberts and Dr Robert Miller for their inputs. Pharmaceuticals Ltd who have developed the study medi- cation (“bup-lyo”) and A.K. is employed by Martindale Role of the funding source Pharmaceuticals Ltd for specialist statistical advice on Funding for the study was provided by Macarthys conduct and analyses of the study data. No other authors Laboratories Ltd (trading as Martindale Pharma, Bucking- have a conflict of interest. hamshire, UK). J.S. is an NIHR Senior Investigator and is supported by the Biomedical Research Centre in Mental Ethics Health at SLaM NHS Foundation Trust and King’s College Authors confirm that the submitted study was con- London. ducted according to the WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects.

Received January 10, 2018 - Accepted March 2, 2018

- 28 - HEROIN ADDICTION & Regular article RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 29-34 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

The SCL90-based psychopathological structure may be applied in Substance Use Disorder patients independently of the drug involved, even in heroin, alcohol and cocaine monodrug users Manuel Glauco Carbone 1, Marco Maiello 1, Vincenza Spera 1, Corrado Manni 1, Alessandro Pallucchini 1, Angelo G. I. Maremmani 2,3,4, and Icro Maremmani 3,4,5

1. School of Psychiatry, University of Pisa, Italy 2. Department of Psychiatry, North-Western Tuscany Region NHS Local Health Unit, Versilian Zone, Viareggio, Italy, EU 3. Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS), Pietrasanta, Lucca, Italy, EU 4. G. De Lisio Institute of Behavioural Sciences, Pisa, Italy, EU 5. Vincent P. Dole Dual Disorders Unit, Department of Specialty Medicine, Psychiatric Unit 2, Santa Chiara University Hospital, University of Pisa, Italy, EU

Summary Background. Using the SCL90 checklist, we previously showed that a cluster of five psychopathological symptoms could be found in Heroin Use Disorder patients. This aggregation demonstrated a high degree of stability, as it proved to be independent of addiction-related conditions such as treatment chosen, intoxication status, and presence of psychiatric problems. It was also applied, in patients with polysubstance use, independently of the drug involved (alcohol, cocaine or heroin). In this study, we have restricted the analysis to patients using only one substance of abuse by excluding patients with polysubstance use. Methods. 256 subjects with alcohol (AUD), heroin (HUD), or cocaine use disorder (CUD) and without a secondary substance of use were assigned to one of the five clusters (worthlessness-being trapped, somatic symptoms, sensitivity-psychoticism, panic anxiety, and violence-suicide). Differences between AUD, HUD and CUD patients in their psychopathological typology and its severity were analysed at univariate and multivariate level. Results. Despite some demographic distinctions, no differences were observed regarding psychopathological typology or its se- verity among AUD, HUD and CUD patients. Conclusions. This study further supports the independence of the proposed SCL90 five-dimensional structure of the various substances considered.

Key Words: Alcohol Use Disorder; Heroin Use Disorde; Cocaine Use Disorder; psychopathology specific to substance use disorder

6. Introduction (HUD) subjects, using factor analysis on all the 90 items included in the SCL90 questionnaire, a 5-fac- Psychiatric conditions of addictive diseases im- tor solution had been found. The first factor defined a ply severe burdens. Psychopathological symptoms in depressive worthlessness and being trapped (W/BT) Substance Use Disorder (SUD) patients are usually dimension. The second factor picked out a somatic viewed as being assignable to the context of a person- symptoms (SS) dimension. The third identified a ality trait or comorbidity, so precluding the presence sensitivity-psychoticism (S/P) dimension. The fourth of specific psychopathology that could only be relat- isolated a panic anxiety (PA) aspect; and the fifth a ed to the addiction process. The V.P. Dole Research ‘violence-suicide’ (V/S) dimension [14]. Group at the University of Pisa, Italy, has studied the The W/BT dimension shows depressive, obses- possible definition of a specific psychopathological sive and psychotic features, and is characterized by dimension in SUD patients. In Heroin Use Disorder feelings of being trapped, and uselessness. SUD sub-

Corresponding author: Icro Maremmani, Vincent P. Dole Dual Disorders Unit, Department of Specialty Medicine, Psychiatric Unit 2, Santa Chiara University Hospital, University of Pisa, Italy, EU, Via Roma, 67, 56100, Pisa, Italy, EU Phone: +39050993045; E-mail: [email protected]; 29 Heroin Addiction and Related Clinical Problems 20(5): 29-34 jects report feelings of guilt and inferiority, interper- HUD, AUD (alcohol use disorder) and CUD (cocaine sonal sensitivity, irritability, excessive worries, pho- use disorder) patients were analysed in terms of the bic anxiety and no sex drive. Obsessive-compulsive frequency of the five clusters and their severity. The symptoms focus mainly on patients’ doubts about association between the secondary abuse of alcohol their capabilities, the decisions they must take and and cocaine and the five groups was also consid- their actions. The SS domain is marked out by sev- ered in a subsample of HUD patients. We confirmed eral anxious and somatic symptoms that are typical a positive association of the SS dimension with the of opiate withdrawal. These patients report back pain, condition of HUD versus CUD and of the S/P and muscle aches, weakness and tiredness, heavy legs and PA that successfully discriminated between patients arms, paraesthesia and loss of sensitivity somewhere as being AUD, HUD or CUD patients. In the subsam- in the body. Cold shivers and hot flushes are possible ple of HUD patients, no significant differences were too, even aching stomach and nausea. Sleeping is dif- observed. The available evidence given by our results, ficult and, as a rule, even when sleep does come, it is taken as a whole, seems to support the extension of then disrupted. The S/P factor features psychoticism the psychopathological structure previously found in and sensitivity. These subjects show suspiciousness, opioid addicts to the population of AUD and CUD nuanced paranoid ideas, self-reference and persecu- patients [18]. tion. They think people do not respect them because These results permit the delineation of a trait of their perspective. These behaviours can be consid- nature rather than a state nature in the perception of ered as psychotic when patients feel sure that others the structure of these five-factor psychopathological influence, control, or read their thoughts. The PA fac- dimensions. tor comprises fear of going around alone, travelling Aims: To further support the hypothesis that the by bus, train, and subway (agoraphobia), sensations SCL90-based five-dimensional structure may be ap- of dizziness and episodes of critical anxiety and fear plied independently of the drug involved, we decided of feeling sick. Generalized fear is present, with the to compare heroin, alcohol and cocaine monodrug need to avoid activities or places to prevent acute user patients. anxiety. The fifth factor (V/S) includes aggressive- ness directed against others as well as self-directed 7. Methods aggressiveness. Rage, anger, and impulsiveness are the critical components of this dimension. These pa- 7.1. Design of the study tients have a habit of arguing with others and showing high energy levels, together with returning to ideas The Evaluation of the Therapeutic Community about death. Treatments and Outcomes cohort study was con- These psychopathological dimensions were ducted in 2008-2009, after recruiting a total of 2,533 closely linked with the behavioural covariate of crav- patients who were admitted to a Therapeutic Commu- ing in HUD patients [2, 5, 9-11] and were able to nity (TC) treatment for a substance use disorder in 8 distinguish patients affected by addiction from those Italian regions [15]. In the present analysis only base- affected by psychiatric diseases such as major depres- line data were used, implementing a cross-sectional sive disorder [7] and obesity [6]. The possibility of approach. differentiating between HUD patients and Pathologi- The study was conducted according to the cal Gamblers, using only the SS typology, suggests WMA Declaration of Helsinki – Ethical Principles the applicability of these five dimensions even to a for Medical Research Involving Human Subjects. All non-substance-related addictive disorder, bringing subjects examined filled in an informed consent form further support to the hypothesis that there is a psy- to participate in this study. The local pertinent ethics chopathology that is specific to addiction [8]. committees approved both the consent form and the Our previous studies shed light on a specific ag- experimental procedures. gregation of psychopathological symptoms in cases of SUD. We can say that these syndromes are stable 7.2. Sample regardless of demographic and clinical characteristics [12], kind of treatment chosen [19], active involve- Inclusion criteria were: to be at least 18 years ment in substance use [17], lifetime psychiatric prob- old, with a diagnosis of heroin, cocaine or alcohol lems [16] and the substance chosen [18]. dependence based on a clinical judgement, and infor- As to the substance chosen, differences between mation collected from the SCL90 questionnaire. Re-

- 30 - M.G. Carbone et al.: The SCL90-based psychopathological structure may be applied in substance use disorder patients independently of the drug involved, even in heroin, alcohol and cocaine monodrug users flecting these criteria, the sample consisted of 2,314 significance, at multivariate (discriminant analysis) subjects. Each participant was included in the sample level. Discriminant analysis is used to statistically once only. 256 patients, 207 (80.8%) males and 49 distinguish between two or more groups of cases. We (19.2%) females, (mean age±SD = 39.40±9.4) were used the stepwise procedure to select the best dis- alcohol, cocaine or heroin monodrug. Out of 449 criminating variables. (19.4%) AUD patients, 114 (25.4) were alcohol mon- The numbers of patients belonging to each of odrug users (mean age±SD = 44.05±8.9; 92, 81.4% the five subgroup clusters were then compared using males); out of 670 (28.9%) CUD patients 57 (8.50%) the chi-square test, with Bonferroni’s correction, be- were cocaine monodrug users (mean age±SD = tween alcohol, heroin or cocaine monodrug use pa- 435.73±9.0); in addition, out of 1,195 (51.6%) HUD tients. In cases of univariate statistical significance, a patients, 85 (7.11%) were heroin monodrug users stepwise multinomial logistic regression analysis was (mean age±SD = 35.71±7.6). then programmed with heroin, cocaine or alcohol as monodrug-dependent variable and the psychopatho- 7.3. Instruments logical subgroups as predictors, including sociode- mographic and clinical variables as confounding fac- 7.3.1. Self-Report Symptom Inventory (SCL-90) tors (age, gender, marital status, detoxification status, First developed by Derogatis and colleagues living condition). [3], the SCL90 consists of 90 items, each rated on All analyses were performed using SPSS v. 4.0 a 5-point scale of severity. Among heroin-dependent (SPSS, Chicago, IL, USA). Statistical significance patients, the 90 questions reflected the five primary was set at the p= 0.05 level. symptom dimensions that are believed to underlie the vast majority of symptom behaviours observed 8. Results in this kind of patient: Worthlessness-Being trapped, Somatic Symptoms, Sensitivity-Psychoticism, Panic 8.1. Sociodemographic and addiction characteristics Anxiety, Violence-Suicide [14]. In previous studies these five dimensions were In the overall sample (n=256), mean age was empirically established and validated [12, 17, 19]. 39.40 ± 9.4 years. 207 (80.8%) of the subjects were In the present study, SCL90 was administered to our male, 208 (81.2%) were single, 60 (23.5%) had a sample of patients within 15 days, counting from the high educational level (with duration over 8 years), day of entry into TC. 183 (71.5%) of subjects were unemployed, and 67 (27.3%) lived alone. When looking at differences 7.3.2. Other instruments between alcohol, heroin and cocaine mono-user pa- Information on the sociodemographic and clini- tients, mean age was 44.05±8.9 in alcohol mono- cal characteristics of the patients included in the study user, 35.61±7.6 in heroin mono-user, and 35.73±9.0 was recorded through a questionnaire administered at in cocaine mono-user patients. This difference was the time of entering TC. The secondary substance of statistically significant (F = 30.38; p < 0.001), with abuse (whether one or more) was self-reported by the heroin and cocaine mono-users proving to be younger patient. than alcohol mono-users. As regards marital status, the frequency of singles was 87.7% among patients 7.4. Data analysis with alcohol mono-dependence, 84.7% among those with heroin mono-dependence, and 63.2% among SCL-90 factors were standardized into z-scores those with (chi-square = 16.04; to compare scores. We assigned each subject to one p < 0.001). Heroin and Cocaine mono-users were less of the five subgroups on the basis of the highest “z frequently living alone (19.3% and 18.9%, respective- score” achieved. This procedure allows us to classify ly) than alcohol mono-users (37.6%). This difference patients according to their foremost symptomatologi- was statistically significant (chi-square = 10.42; p = cal cluster, so overcoming the problem of identifying 0.005). Gender (chi-square = 2.83; p=0.243), educa- a cut-off point for typifying patients. These subtypes tional level (chi-square = 4.00; p = 0.135), and being are distinct [14]. unemployed (chi-square = 1.97; p = 0.373) showed The severity of the SCL90 5-dimensions was no statistically significant differences between the compared by identifying the monodrug used sub- groups. stance at univariate (T-Test) and, in cases of statistical

- 31 - Heroin Addiction and Related Clinical Problems 20(5): 29-34

Table 1. SCL90-based psychopathological factor severity at treatment entry in heroin, alcohol and cocaine mono-user patients Only Only Only Alcohol Heroin Cocaine N=114 N=85 N=57 SCL90-based factors M±sd M±sd M±sd F p 1.Worthlessness-Being Trapped 1.04±0.7 1.02±0.8 0.81±0.6 2.04 0.131 2. Somatic Symptoms 0.92±0.6 0.91±0.7 0.74±0.6 1.37 0.256 3. Sensitivity-Psychoticism 0.74±0.5 0.66±0.6 0.56±0.4 1.85 0.158 4. Panic Anxiety 0.42±0.5a 0.34±0.5a,b 0.20±0.3b 3.66 0.027 5. Violence-Suicide 0.61±0.6 0.64±0.6 0.55±0.4 0.31 0.731 a,b Scheffe’s post-hoc procedure p<0.05; DF1=Wilks lambda=0.95 df 10 p=0.249; DF2: Wilks lambda=0.99 df 4 p=0.748

8.2. Psychopathological dimensions 9. Discussion

Table 1 shows differences in psychopathological Patients with alcohol, heroin and cocaine mono- severity between alcohol, heroin and cocaine mono- dependence differ in some demographic characteris- user patients. The only statistically significant differ- tics investigated in the present study. Differences were ence observed between the three groups was that in observed in age, in the frequency of “single” mari- the severity of the PA dimension. Panic anxiety symp- tal status and the “living alone” condition. Alcohol toms were more severe in alcohol mono-user than in mono-dependent patients were older and lived alone cocaine mono-user patients. Heroin mono-user pa- more often than heroin or cocaine mono-dependents. tients were found to be in an intermediate position. Cocaine mono-users were less frequently single than No differences were observed, at univariate level, heroin or alcohol mono-users. Only marital status dif- in regarding the other dimensions, or at multivariate fered from what we have observed in polydrug us- level. ers [18]. The differences found were consistent with Table 2 shows differences in psychopathologi- the sociodemographic characteristics of the various cal typology between alcohol, heroin or cocaine mo- populations of addicts reported in previous studies [4, no-user patients. PA was the most frequent (around 13, 21]. 29.0%) psychopathological typology in all three At univariate level, considering the severity of groups of patients. V/S was the least frequent psy- psychopathological symptoms of mono-dependent chopathological dimension in the alcohol mono-user patients at treatment entry, PA symptoms showed the (7.9%) and heroin mono-user (11.8%) groups. W-BT highest severity in alcohol monodrug and the lowest was the least frequent typology for the cocaine mono- in cocaine monodrug users. It is not easy to explain user patients (8.8%). No statistically significant dif- the higher severity induced by alcohol mono-depend- ferences were observed between groups. ence than by cocaine mono-dependence in regarding PA symptoms. We have already observed this phe- nomenon in polydrug users typified according to the primary substance of use (alcohol, heroin or cocaine)

Table 2. SCL90-based psychopathological typology at treatment entry in heroin, alcohol and cocaine mono-user patients Alcohol Heroin Cocaine Mono-users Mono-users Mono-users N=114 N=85 N=57 SCL90-based factors N (%) N (%) N (%) Chi-square P 1.Worthlessness-Being Trapped 17 (14.9) 12 (14.1) 5 (8.8) 2. Somatic Symptoms 26 (22.8) 18 (21.2) 13 (22.8) 3. Sensitivity-Psychoticism 30 (26.3) 20 (23.5) 11 (19.3) 4. Panic Anxiety 32 (28.1) 25 (29.4) 17 (29.8) 5. Violence-Suicide 9 (7.9) 10 (11.8) 11 (19.3) 5.27 0.617 Post hoc test (Bonferroni’s procedure): no differences

- 32 - M.G. Carbone et al.: The SCL90-based psychopathological structure may be applied in substance use disorder patients independently of the drug involved, even in heroin, alcohol and cocaine monodrug users

[18]. In this case too we can say that anxiety is a com- ous studies that had shown the great stability of the mon symptom of , whereas in five-factor structure observed in HUD patients, sup- alcohol-dependent patients anxiety is expressed dif- port its extension to the population of SUD patients, ferently, as a component of withdrawal, even in mild independently of the drug involved. forms of alcohol dependence. Moreover, we have also to keep in mind that anxiety related to alcohol with- References drawal may last for months [1, 20]. Unlike what we observed in polydrug users [18], the differences ob- 1. Carlson R. W., Kumar N. N., Wong-Mckinstry E., served at univariate level were not confirmed at mul- Ayyagari S., Puri N., Jackson F. K., Shashikumar S. tivariate level. In alcohol, heroin and cocaine mon- (2012): Alcohol withdrawal syndrome. Crit Care Clin. odrug users, therefore, psychopathological severity 28(4): 549-585. 2. Della Rocca F., Maremmani A., Rovai L., Bacciardi S., seems to be more homogeneous. Lamanna F., Maremmani I. (2017): Further evidence Looking at previous analyses carried out on of a specific psychopathology of Heroin Use Disorder. samples of heroin-dependent patients only, no differ- Relationships between psychopathological dimensions ence emerged in the use of alcohol or cocaine as the and addictive behaviors. Heroin Addict Relat Clin Probl. secondary substance of abuse, either in the severity or 19(6): 13-20. the frequency of the five psychopathological SCL90 3. Derogatis L. R., Lipman R. S., Rickels K. (1974): The dimensions [18]. Only polydrug use would, therefore, Hopkins Symptom Checklist (HSCL). A self report lead to differences in the severity of psychopathology symptom inventory. Behav Sci. 19: 1-16. related to SUDs. This last consideration is also sup- 4. Lopez-Goni J. J., Fernandez-Montalvo J., Arteaga A. ported by the fact that, in this study, no differences (2015): Differences between Alcoholics and Cocaine Addicts Seeking Treatment. Span J Psychol. 18: E2. in psychopathological typology were observed in the 5. Maremmani A. G., Rovai L., Bacciardi S., Massimetti E., monodrug users. Gazzarrini D., Pallucchini A., Pani P. P., Maremmani I. This lack of psychopathological differences (in (2016): Relationships between addictive behaviours and severity and typology) may further be attributed to a dual disorders, as found in heroin use disorder patients at psychic structure present in SUD patients that is com- treatment entry. Heroin Addict Relat Clin Probl. 18(2): mon to the various forms of dependence, so that this 5-12. structure is independent of the specific drug used. 6. Maremmani A. G. I., Cerniglia L., Cimino S., Bacciardi This result convinces us, so much so that addiction S., Rovai L., Pallucchini A., Spera V., Perugi G., can now be defined as a unitary condition. Maremmani I. (2017): Further evidence of a specific psychopathology of addiction. Differentiation from other psychiatric psychopathological dimensions (such Limitations as obesity). Int J Environ Res Public Health. 14(943). 7. Maremmani A. G. I., Cerniglia L., Cimino S., Bacciardi The cross-sectional design does not allow us to S., Rovai L., Rugani F., Massimetti E., Gazzarrini D., be sure whether the previous presence and severity of Pallucchini A., Pani P. P., Akiskal H. H., Maremmani I. symptoms included in our five-dimension psychopa- (2015): Towards a specific psychopathology of heroin thology are a predictor of, or act as a predisposition addiction. Comparison between Heroin Use Disorder to use, specific substances. Likewise, we cannot say and Major Depression patients. Heroin Addict Relat whether, conversely, the use of, or a dependence on Clin Probl. 17(6): 9-16. these substances may condition the development of 8. Maremmani A. G. I., Gazzarrini D., Fiorin A., Cingano the specific psychopathological picture. Other limi- V., Bellio G., Perugi G., Maremmani I. (2018): Psychopathology of addiction: Is the SCL90-based five tations on the validity of the SCL90 based psycho- dimensional structure applicable to a non-substance- pathological 5-dimension solution were commented related addictive disorder such as Gambling Disorder? on in our previous studies [14, 17-19] Ann Gen Psychiatry. 17(3): 1-9. 9. Maremmani A. G. I., Rovai L., Bacciardi S., Bertoni S., 10. Conclusions Massimetti E., Gazzarrini D., Rugani F., Pallucchini A., Maremmani I. (2016): Addictive behaviours in Heroin Looking only at the population consisting of Use Disorder patients. Correlation with heroin-craving monodrug alcohol, heroin and cocaine users, no sub- patients’ self-evaluation. Heroin Addict Relat Clin Probl. stantial differences in the severity and no differences 18(1): 9-18. in the typology of the psychic structure were demon- 10. Maremmani A. G. I., Rovai L., Bacciardi S., Massimetti E., Gazzarrini D., Pallucchini A., Rugani F., Pani P. P., strated. These findings, together with those of previ-

- 33 - Heroin Addiction and Related Clinical Problems 20(5): 29-34

Maremmani I. (2016): Psychopathological dimensions Psychiatry. 15:13. and addictive behaviours in Heroin Use Disorder patients. 19. Pani P. P., Trogu E., Vigna-Taglianti F., Mathis F., Heroin Addict Relat Clin Probl. 18(6): 43-50. Diecidue R., Kirchmayer U., Amato L., Davoli 11. Maremmani A. G. I., Rovai L., Bacciardi S., Massimetti M., Ghibaudi J., Camposeragna A., Saponaro A., E., Gazzarrini D., Rugani F., Pallucchini A., Piz L., Faggiano F., Maremmani A. G., Maremmani I. (2014): Maremmani I. (2015): An inventory for assessing the Psychopathological symptoms of patients with heroin behavioural covariates of craving in heroin substance addiction entering opioid agonist or therapeutic use disorder. Development, theoretical description, community treatment. Ann Gen Psychiatry. 13(1): 35. reliability, exploratory factor analysis and preliminary 20. Roelofs S. M. (1985): Hyperventilation, anxiety, craving construct validity. Heroin Addict Relat Clin Probl. 17(5): for alcohol: a subacute alcohol withdrawal syndrome. 51-60. Alcohol. 2(3): 501-505. 12. Maremmani A. G. I., Rovai L., Maremmani I. 21. Swendsen J., Conway K. P., Degenhardt L., Dierker (2012): Heroin addicts' psychopathological subtypes. L., Glantz M., Jin R., Merikangas K. R., Sampson N., Correlations with the natural history of illness. Heroin Kessler R. C. (2009): Socio-demographic risk factors Addict Relat Clin Probl. 14(1): 11-22. for alcohol and drug dependence: the 10-year follow-up 13. Maremmani I., Pani P. P., Mellini A., Pacini M., Marini of the national comorbidity survey. Addiction. 104(8): G., Lovrecic M., Perugi G., Shinderman M. (2007): 1346-1355. Alcohol and cocaine use and abuse among opioid addicts engaged in a methadone maintenance treatment program. Acknowledgements J Addict Dis. 26(1): 61-70. None 14. Maremmani I., Pani P. P., Pacini M., Bizzarri J. V., Trogu E., Maremmani A. G. I., Perugi G., Gerra G., Dell'osso Role of the funding source L. (2010): Subtyping Patients with Heroin Addiction at Authors state that this study was financed with inter- Treatment Entry: Factors Derived fron the SCL-90. Ann nal funds. No sponsor played a role in study design; in the Gen Psychiatry. 9(1): 15. collection, analysis and interpretation of data; in the writ- 15. Mathis F., Vigna-Taglianti F., Decidue R., Kirchmayer ing of the report; and in the decision to submit the paper U., Piras G., Amato L., Ghibaudi J., Camposeragna for publication. A., Saponaro A., Faggiano F., Trogu E., Pani P. P. (2013): Studio “Valutazione dell’Offerta e dell’Esito Contributors dei trattamenti in Comunità Terapeutiche (VOECT), A.G.I.M. and I.M., designed the study and wrote the Ministero della Salute, Ricerca finalizzata. Monografia protocol. M.G.C., M.M., V.S., C.M., A.P., managed the n. 1, Analisi descrittiva della coorte arruolata. Centro literature searches and analyses. I.M., undertook the sta- Stampa Regione Sardegna, Cagliari. tistical analysis, and all the authors discussed the results. 16. Pani P. P., Maremmani A. G. I., Trogu E., Vigna-Taglianti A.G.I.M., wrote the first draft of the manuscript. All au- F., Mathis F., Diecidue R., Kirchmayer U., Amato L., thors revised the last draft. All the authors contributed to, Davoli M., Ghibaudi J., Camposeragna A., Saponaro A., and have approved, the final manuscript. Faggiano F., Maremmani I. (2016): Psychic Structure of Opioid Addiction: Impact of Lifetime Psychiatric Conflict of interest Problems on SCL-90-based Psychopathologic Authors declared no conflict of interest. IM served as Dimensions in Heroin-dependent Patients. Addict Disord board member for D&A, Molteni, Indivior, Gilead, Merck, Their Treatment. 15(1): 6-16. CT Sanremo 17. Pani P. P., Maremmani A. G. I., Trogu E., Vigna-Taglianti F., Mathis F., Diecidue R., Kirchmayer U., Amato L., Ethics Davoli M., Ghibaudi J., Composeragna A., Saponaro A., Authors confirm that the submitted study was con- Faggiano F., Maremmani I. (2015): Psychopathological ducted according to the WMA Declaration of Helsinki - symptoms in detoxified and non-detoxified heroin- Ethical Principles for Medical Research Involving Human dependent patients entering residential treatment. Heroin Subjects. Addict Relat Clin Probl. 17(2-3): 17-24. 18. Pani P. P., Maremmani A. G. I., Trogu E., Vigna-Taglianti F., Mathis F., Diecidue R., Kirchmayer U., Amato L., Note Ghibaudi J., Camposeragna A., Saponaro A., Davoli M., It is the policy of this Journal to provide a free re- Faggiano F., Maremmani I. (2016): Psychopathology of vision of English for Authors who are not native English addiction: May a SCL-90 based five dimensions structure speakers. Each Author can accept or refuse this offer. In be applied irrespectively of the involved drug? Ann Gen this case, the Corresponding Author accepted our service.

Received February 3, 2018 - Accepted May 14, 2018

- 34 - HEROIN ADDICTION & Regular article RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 35-49 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. Duncan Hill1,2, Daniel Garner3, and Alex Baldacchino3,4

1. Addictions Services, NHS Lanarkshire, Motherwell, Scotland, UK 2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK 3. School for Medicine, University of St Andrews, Fife, Scotland, UK 4. NHS Fife, Queen Margaret Hospital, Whitefield Road, Dunfermline, Fife, Scotland, UK

Summary Introduction: Agonist Opioid Treatments (AOT) have been, in comparison to healthy controls, associated with neuro- cognitive impairment in different domains. This review identifies differences in neurocognitive function as a result of treatment with either buprenorphine or methadone. Method: A qualitative and systematic literature review of published articles from 1946 to 29/2/2016 on neurocognitive function of patients prescribed buprenorphine or methadone and com- pared with healthy patients utilising the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Results: The limited data demonstrate buprenorphine as presenting with fewer neurocognitive impairments, in cognitive impulsivity, cognitive flexibility and attention domains when compared with methadone. However both treatments mo- dalities presented with more impairments in neurocognitive function domains, including short term memory, attention, cognitive flexibility, cognitive impulsivity, motor impulsivity and non planning impulsivity, when compared with healthy control groups. Discussion: The lack of published papers in comparing neurocognitive impairment between the treatment modalities limit interpretation of this systematic review. Conclusion: Further methodologically rigid and higher quality research into the neurocognitive effects of these treatment modalities in the opioid dependent populations, especially when in treatment, is urgently required. Key Words: Neurocognitive Impairment; buprenorphine; methadone; treatment; opioid dependence

11. Introduction also display by altering the brains behavioural circuits. The receptors affected by Treatment for opioid (and opiate) addiction us- opioids, are located through the brain and spinal cord, ing agonist opioid treatments (AOT) (i.e. methadone including the thalamus, hypothalamus, hippocampus, and buprenorphine) have been associated with neuro- amygdala and the cerebral cortex [12],which are im- cognitive impairment in comparison to healthy con- portant for neurocognitive function, but are also con- trols. nected to the reward and reinforcement area in the For the purposes of this review we will use the brain, the nucleus accumbens. term opioids to encompass both and opioids. Opioid use has been demonstrated in the brain to Opioids are widely used both legally in treatment, for increase oxidative stress, which contributes to neuro- their analgesic effects, and illicitly, for the psycho- toxicity leading to neurocognitive impairment [7, 33]. tropic effects. The neurocognitive impairments asso- In the review by Büttner and Mall, they noted re- ciated with opioid use have already been documented duced neuronal density in majority of patients dying [4] from heroin overdoses due to respiratory depression Opioids are known to alter receptor sensitivity and associated brain hypoxia [6]. and expression, demonstrating a tolerance effect, but Consideration of other contributing factors other

Corresponding author: Duncan Hill, Specialist Pharmacist in Substance Misuse, NHS Lanarkshire, Airbles Road Centre, 49-59 Airbles Road, ML1 2TP, Motherwell, Scotland, UK Phone: 01698266717; Mobile: 07920711131; E-mail: [email protected],nhs.uk 35 Heroin Addiction and Related Clinical Problems 20(5): 35-49 than the direct opioid toxic effects on neurocognitive ability to recall and make new memories. The Atkin- impairment needs to be considered. This can include son-Shiffrin model of memory proposes three distinct bacterial and viral infection and other potential neu- ‘stores’ of memory: sensory memory (lasting a few ropathological insults [10]. These factors will not be milliseconds: providing a buffer for sensory informa- reviewed in this systematic review. tion and allows us to address information when re- To measure neurocognitive function in individu- quired), short-term memory (lasting 12-30 seconds als the precise function being tested must be defined. without rehearsal: primarily auditory in nature, can Muriel Lezak, the author of the first book exploring store around seven chunks of information for a few neuropsychological assessment, wrote ‘Direct obser- seconds without rehearsal [22] duration of storage vation of the fully integrated functioning of living hu- can be increased with the use of a phonological loop), man brains will probably always be impossible’ [18]. and long term memory which can be indefinite (abil- Therefore, to assess neuropsychological function in ity to store information for a lifetime [2] and can be the context of assessment, three domains (and sub- further split into declarative memory requiring con- sequent sub-domains based on neurocognitive tests) scious though and procedural memory requiring no need to be clearly defined to allow the objective ob- thought). servation of neurocognitive function in individuals: A recent meta analysis looking at the effects of • Intelligence chronic methadone use identified global impairments • Executive Function in neurocognitive function relative to healthy partici- • Memory and Learning pants [5]. The use of an intelligence assessment allows an This article aims to determine if there are dif- estimate the premorbid IQ of an individual. A vocab- ferences in the effects on the neurocognitive function ulary test is the primary assessment method use, e.g of patients being treated with either buprenorphine or Shipley Institute of Living Scale (SILS) or Wechsler methadone. Adult Intelligence Scale – Revised & III [31, 38]. High level neurocognitive functions, known as 12. Methods Executive functions, allow for the control of behav- iour to achieve a targeted outcome, this includes cog- 12.1. Literature Search nitive flexibility, cognitive planning, cognitive impul- sivity, working memory and attention [5, 11, 36]. A literature review identified articles relating Memory and learning assesses an individual’s to the neurocognitive effects of either buprenorphine

Table 1: Inclusion and exclusion criteria for studies used in the review

Inclusion Exclusion Participants aged eighteen or over with chronic opioid de- Cohorts with current uncontrolled poly-drug use ( pendence and currently engaged in an opioid maintenance excluding). programme Individuals needed to be compared to either healthy Cohorts with a diagnosis of any Axis-1 psychiatric ill- controls, abstinent individuals or another maintenance pro- ness (excluding substance related disorders) as defined gramme (methadone vs. buprenorphine) through the use of by DSM-IV/V (American Psychiatric Association 2000; validated neuropsychological assessments. American Psychiatric Association 2013).

Neuropsychological assessments needed to be identi- Cohorts with previous serious head injury. fied and validated to allow for them to be classified into domains. If novel assessments were used a description of the cognitive functions assessed was used to classify by comparison to a defined assessment. Identified papers need to be of adequate quality match- Articles with poor quality methodology, ing the control/abstinent group to the maintained cohort, matching criteria should include: age, sex, years of educa- tion and years of heroin dependence Papers needed to report separate results for each cohort Cohorts including participants who were HIV serotype and test, papers which combined maintenance cohorts positive were excluded as it was not possible to extract the results required.

- 36 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review.

Table 2: Search Subject Headings

opioid related neuropsychological tests/impair- methadone OR disorders OR ments/deficits substance related disorders OR OR buprenorphine OR chronic drug AND AND dependence OR Subutex OR neurocognitive tests/deficits/im- substance pairments withdrawal syn- Suboxone drome or methadone on patients receiving Agonist Opioid function were used from articles comparing either of Treatment (AOT) for opioid dependence. The cohorts the two therapeutic intervention against a healthy pa- chosen where either direct comparison between indi- tient control group. The results of these studies were viduals treated with methadone or buprenorphine or used to comment on the potential for neurocognitive those compared against a healthy control group. The impairment from the treatment with ORT against a Meta-analysis of Observational Studies in Epidemi- control group. ology (MOOSE) guidelines were employed and the inclusion and exclusion criteria used have been tabu- 13.2. Assessment of study quality lated in Table 1. An electronic based search using a number of The vast majority of selected articles for this re- databases and incorporating articles published from view were assessed as fair in quality using the NIH 1946 to 29/2/2016 were used. The databases used Quality Framework for case-control studies (Table 3) where Ovid MEDLINE (1946 to 29/2/2016); EM- (NIH 2014) with others ranging in quality from poor BASE (1974 to 29/2/2016); PUBMED (1964 to (2 articles) to good (1 article). All studies were obser- 29/2/2016); PsychINFO (1980 to 29/2/ 2016). There vational case control studies. were no language constraints employed. The articles were identified using the search 13.3. Number of articles identified headings in Table 2. The search terms ‘neuropsychological tests’ and The initial literature search identified 426 ar- ‘neurocognitive tests’ were then replaced with the ticles from literature and other sources. Once du- sub-titles of neurocognitive domains e.g. Short Term plicates were removed the total number of relevant Memory, Long Term Memory, Attention, Cognitive manuscripts was reduced to 179. Titles and abstracts Flexibility, Cognitive Impulsivity, Motor Impulsivity of 31 articles included in the accepted abstracts were and Non-Planning Impulsivity. screened for eligibility with an additional six articles As this article is a literature review there was included in the full text screening (Figure 1: QUO- no requirement for ethical approval in relation to the RUM). The full text of the remaining 36 articles was study. assessed using the inclusion and exclusion criteria on Table 1. This assessment excluded a further 20 arti- 13. Results cles which failed to meet the inclusion criteria in the full text with the remaining 16 articles included in 13.1. Data analysis and study detail this review.

The literature search provided very few articles 13.4. Cohorts identified published on the comparison of effects of treatment on the neurocognitive function of patients being treat- The included articles described results from the ed with buprenorphine or methadone. direct comparison of 60 buprenorphine maintained With the very limited number of published arti- individuals to 74 methadone maintained individu- cles offering direct comparisons (3 articles identified) als from 3 published articles. When the search was between buprenorphine and methadone, a wider but extended to compare either methadone or buprenor- indirect comparison of the effects on neurocognitive phine maintained patients to a healthy control, there

- 37 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

(IQ) RST3) WCST Measured WAIS-III; WAIS-III; TT15; DR2; logical Tests logical Tests DSST; TMT DSST; (A&B); 2BT; (A&B); 2BT; GT; ST; SILS ST; GT; Neuropsycho - WMSR (PAL- Q1; FAT; LL5; Q1; FAT; I& II, VR-I & II I& II, RCFT; COWAT; COWAT; RCFT; subtests); CVLT; subtests); CVLT; ART-2020 (MAT; (MAT; ART-2020 92.6 94.0 (2.8) Mean (-11.1) IQ (sd) 11.7 12.1 Educa - tion (yrs) / / Sex Sex 12F 11F (intelligence) 18M 10M (nM/nF) Healthy Controls Healthy Age 35.2 34.9 (yrs) Mean Matched for age, sex and score in MAT and score in MAT Matched for age, sex N 30 21 78.6 45.7 67.2 dose done (mg) daily Mean metha - 1.55 3.78 (yrs) dian) 5 (me - Metha - done use 4.28 15.3 Mean mum) Opioid 5 (mini - Use (yrs) IQ n/a (sd) 91.5 87.4 (2.7) Mean (10.4) Methadone Group yrs tion 11.2 11.8 ment High Junior attain - Modal School Educa - / / / 6F 9M 7M Sex Sex 12F 11F 18M (nM/nF) Age 35.8 25.8 37.6 (yrs) Mean N 30 15 18 ity Fair Fair Fair Qual - States

United Austria Country Australia Study Schin - (2000) (2004) al (2002) dler et al. Mintzer et Abbreviations: n= Number of Participants; yrs = Years; nM/nF= Number Male/ Number Female; IQ = Intelligence quotient; sd= standard deviation; mg= milligrams; WAIS-III = Wechsler Wechsler = WAIS-III mg= milligrams; nM/nF= Number Male/ Female; IQ = Intelligence quotient; sd= standard deviation; Years; yrs = n= Number of Participants; Abbreviations: learning test; RCFT; California verbal Reproduction; CVLT= Visual VR-I&II= Associate Learning; Paired PAL-I&II= Memory Scale-Revised; Weschler WMSR; Adult Intelligence Scale; DSST= Tast; Scale; GT= Gambling Institute of Living SILS= Shipley Test; Card Sorting Wisconsin WCST= association test; Controlled oral word COWAT= Test; Figure Complex Rey Reten - Visual Benton BVRT= Adult Intelligence Scale - Revised; Wechsler WAIS-R= Test; ST= Stroop Test; Back Two 2BT= Test; Making Trail TMT= Test; Digit Symbol Substitution Semantic SAVF= Test; RRLET= Remote and Recent Life Event Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test; CPT= Continuous Performance Test; tion FTT= Time; Reaction CRT=Choice Test; CBT= Corsi Block World;; Three Dimensional Block Construction Model; SpTW= Spot the Real 3DBCM= Fluency; Verbal Association of AGN= Task; CGT= Cambridge Gambling Test; Adult Reading National NART= Attention; SS= Stop Signal; PES= Post Error Slowing; of Variables of Test TOVA= Test; Tapping Finger Act ART-2020= Test; Gambling Animals; IGT= Iowa Fruits and FAS= Test; Digit FDT= Five Austine Maze; n/a= not available; AM= Go/No Go; SOC= Stockings of Cambridge; Affective Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Measuring the TT15=Test Ability, Test, Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, specific Perception Traffic- Measuring the TT15=Test Test, Vision (PVT= Peripheral Test Act React Scale. KMSK= Kreek–McHugh–Schluger–Kellogg in a Dynamic Environment) DR2= Decision and Reaction Behaviour Darke et al. Darke Characteristics of articles identified comparing methadone maintenance patients to healthy controls. 3: Characteristics of articles identified comparing methadone maintenance patients to healthy Table

- 38 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. IGT. DR2) BVRT WCST SS; PES 3DBCM arithmetic, R(digit span, COWAT; ST; ST; COWAT; WAIS-R (IQ); WAIS-R SAVF; WAIS- SAVF; Test; Proverbs ART-90 (PVT; (PVT; ART-90 WAIS-III (IQ); WAIS-III BVRT; WCST; WCST; BVRT; SOMT; WSLT; WSLT; SOMT; SILS (IQ); GT; SILS (IQ); GT; symbol); Reitan BVRT; RRLET; RRLET; BVRT; TT15; Q1;RST3; NART (IQ); NART AGN; CGT; SOC n/a n/a n/a 104 92.1 12.2 (3.39) (-13.2) (-3.42) 118 (5.1) 9.3 13.6 15.5 10.9 15.4 (n=9) attain - Modal school leaving leaving general ment was ment was certificate 15.4 / / / / / 8F 7F 1F 0F n/a 11F 21M 14M 14M 22M 64M 28M / 0F 37 34 34 34 29.8 36.8 24.1 19 29 21 25 23 64 28 66 56 36 45 61.6 73.8 55.8 n/a 0.5 8.3 0.5 6.44 1.73 mum) (mini - 1.3 11 0.5 15.1 15.5 13.9 14.3 mum) (mini - 8.8 85 n/a n/a n/a 83.8 8.05 (9.7) (2.19) 109 (7.6) 13 8.6 was was “O” 12.2 8.37 10.3 ment levels levels attain - Modal (n=10) 10.6 / / / / / 6F 1F 8F 1F 0F n/a 23M 29M 16M 26M 65M 29M / 0F 35 32 42.3 37.9 36.8 40.2 27.3 18 29 30 24 27 65 29 Fair Fair Fair Fair Fair Poor Good Italy States States United United Taiwan Taiwan Germany United Kingdom - ham- (2004) (2011) (2012) (2014) Rother Lin et al. Pirastu et al. (2006) al. (2006) Prosser et Liao et al. Abbreviations: n= Number of Participants; yrs = Years; nM/nF= Number Male/ Number Female; IQ = Intelligence quotient; sd= standard deviation; mg= milligrams; WAIS-III = Wechsler Wechsler = WAIS-III mg= milligrams; nM/nF= Number Male/ Female; IQ = Intelligence quotient; sd= standard deviation; Years; yrs = n= Number of Participants; Abbreviations: learning test; RCFT; California verbal Reproduction; CVLT= Visual VR-I&II= Associate Learning; Paired PAL-I&II= Memory Scale-Revised; Weschler WMSR; Adult Intelligence Scale; DSST= Tast; Scale; GT= Gambling Institute of Living SILS= Shipley Test; Card Sorting Wisconsin WCST= association test; Controlled oral word COWAT= Test; Figure Complex Rey Reten - Visual Benton BVRT= Adult Intelligence Scale - Revised; Wechsler WAIS-R= Test; ST= Stroop Test; Back Two 2BT= Test; Making Trail TMT= Test; Digit Symbol Substitution Semantic SAVF= Test; RRLET= Remote and Recent Life Event Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test; CPT= Continuous Performance Test; tion FTT= Time; Reaction CRT=Choice Test; CBT= Corsi Block World;; Three Dimensional Block Construction Model; SpTW= Spot the Real 3DBCM= Fluency; Verbal Association of AGN= Task; CGT= Cambridge Gambling Test; Adult Reading National NART= Attention; SS= Stop Signal; PES= Post Error Slowing; of Variables of Test TOVA= Test; Tapping Finger Act ART-2020= Test; Gambling Animals; IGT= Iowa Fruits and FAS= Test; Digit FDT= Five Austine Maze; n/a= not available; AM= Go/No Go; SOC= Stockings of Cambridge; Affective Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Measuring the TT15=Test Ability, Test, Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, specific Perception Traffic- Measuring the TT15=Test Test, Vision (PVT= Peripheral Test Act React Scale. KMSK= Kreek–McHugh–Schluger–Kellogg in a Dynamic Environment) DR2= Decision and Reaction Behaviour Fuller et al. Soyka et al. Soyka Characteristics of articles identified comparing methadone maintenance patients to healthy controls. 3: Characteristics of articles identified comparing methadone maintenance patients to healthy Table Baldac - chino et al. (2014)

- 39 -

Heroin Addiction and Related Clinical Problems 20(5): 35-49

Measured

logical Tests Tests logical

- Neuropsycho Ruff DR2) RST3) ART-90 ART-90 RBANS WAIS-III WAIS-III Q1;RST3; FAT; LL5; FAT; ART-2020 ART-2020 COG; DT; COG; DT; (MAT; Q1; (MAT;

BNT; VFT; VFT; BNT; TAVT; VIG TAVT; TT15; DR2; (IQ); BVRT; (IQ); BVRT;

WCST; IGT; IGT; WCST; (PVT; TT15; (PVT; RAVLT; CTT; CTT; RAVLT;

Mean IQ (sd) IQ Mean n/a n/a n/a

104

(-3.39) Education (yrs) Education n/a 10.9 11.5 (n=9) attain -

Modal school leaving leaving general

ment was ment was certificate Sex (nM/nF) Sex / / / / (intelligence) 7F 7F

6F 11F

14M 27M 84M 114M Mean Age (yrs) Age Mean

34

35.7 29.8 37.1 n Matched for age, sex and score in MAT and score in MAT Matched for age, sex

21 34 25 90 Healthy Controls Healthy

dose (mg) dose buprenorphine buprenorphine

9 Mean daily daily Mean 10

7.7 6.78 10.4

use (yrs) use Buprenorphine Buprenorphine

5.4 5.5 0.93 0.67 0.19

Use (yrs) Use Mean Opioid Opioid Mean

n/a 13.3 3.63 12.8 11.6 Mean IQ (sd) IQ Mean n/a n/a n/a n/a

89.3

(-3.45) Education (yrs) Education 11 n/a 8.72 High (n=9) (n=9) Junior attain -

Modal school or “O” School leaving leaving general

tainment tainment Level at - Level ment was ment was Modal at - certificate Sex (nM/nF) Sex / / / / /

1F 3F 2F

5M 10F 11F 17M 15M 11M 28M Mean Age (yrs) Age Mean

25 33

36.5 34.2 36.6 n

15 18 18 22 11 Buprenorphine Group Quality

Fair Fair Fair Fair Poor Country Italy

Greece Austria

Germany Germany Study (2006) (2011) al. (2004) al. (2009) Shmygalev Shmygalev Messinis et Abbreviations: n= Number of Participants; yrs= Years; nM/nF= Number Male/ Number Female; IQ= Intelligence Quotient; sd= Standard Deviation; mg- Milligrams; WAIS-III= Wechsler Wechsler WAIS-III= mg- Milligrams; nM/nF= Number Male/ Female; IQ= Intelligence Quotient; sd= Standard Deviation; Years; yrs= n= Number of Participants; Abbreviations: Matricies System (MAT= Test Act React ART-2020= Task; Gambling IGT= Iowa Task; Card Scoring Wisconsin WCST= Test; Retention Visual Benton Adult Intelligence Scale; BVRT= Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test, Vision Selec - Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; tive Soyka et al. Soyka Schindler et et al. (2011) Pirastu et al. Characteristics of articles identified comparing buprenorphine maintenance patients to healthy controls. buprenorphine maintenance patients to healthy 4: Characteristics of articles identified comparing Table

- 40 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review.

-

Tests Measured Tests Neuropsychological DR2) RST3) RST3) ART-90 ART-90 WAIS-III WAIS-III

Q1;RST3; FAT; LL5; FAT; ART-2020 ART-2020 FAT; LL5; FAT; ART-2020 ART-2020 (MAT; Q1; (MAT; (MAT; Q1; (MAT;

TT15; DR2; TT15; DR2; (IQ); BVRT; (IQ); BVRT; WCST; IGT. WCST; (PVT; TT15; (PVT;

done dose (mg) dose done

- metha daily Mean

66 56

45.7 52.7 Methadone Use (yrs) Use Methadone

8.3 0.4 1.55 1.94

(yrs) Mean Opioid Use Use Opioid Mean

11

4.28 6.09 15.53 Mean IQ (sd) IQ Mean

85 n/a n/a n/a Education (yrs) Education n/a 8.37 High Methadone Group levels levels Junior Modal Modal (n=10) School

was “O” was

attainment attainment Sex (nM/nF) Sex / / / /

6F 1F 8F

9M 7M 13F 29M 16M Mean Age (yrs) Age Mean

35 32

25.8 27.9 n

15 30 20 24

(mg) prenorphine dose dose prenorphine

9 - Mean daily bu daily Mean 10

13.4 10.4

(yrs) Buprenorphine use use Buprenorphine

5.4 0.93 1.43 0.19

(yrs) Mean Opioid Use Use Opioid Mean

5.8

3.63 11.6 13.28 Mean IQ (sd) IQ Mean n/a n/a n/a

89.3

(-3.45) Education (yrs) Education n/a 8.72 Buprenorphine Group High (n=9) (n=9) Junior attain -

Modal school or “O” School leaving leaving general

tainment tainment Level at - Level ment was ment was Modal at - certificate Sex (nM/nF) Sex / / / /

1F 8F

5M 10F 11F 17M 12M 11M Mean Age (yrs) Age Mean

25 33 27

34.2 n

15 18 20 22 Quality Fair Fair Fair Poor

- Country

Ger Italy many

Austria Austria Study dler wert Bae - et al. et al. et al. et al. Soyka Soyka ing Ability, TT15=Test Measuring the Traffic- specific Perception Ability, DR2= Decision and Reaction Behaviour in a Dynamic Driving Environment, RST3= Reactive Stress Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, specific Perception Traffic- Measuring the TT15=Test Ability, (PVT= ing Test Act React ART-90= Test; Gambling IGT= Iowa Test; Card Sorting Wisconsin WCST= Test; Retention Visual Benton Adult Intelligence Scale; BVRT= Weschler WAIS-III= Test, DR2= Decision and Stess Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test, Vision Peripheral Available. n/a= Not in a Dynamic Environment); Reaction Behaviour Abbreviations: n=Number of Participants; yrs= Years; nM/nF= Number Males/Number Females; IQ= Intelligence Quotient; sd= Standard Deviation; mg=Milligrams; ART-2020= Act ART-2020= mg=Milligrams; nM/nF= Number Males/Number Females; IQ= Intelligence Quotient; sd= Standard Deviation; Years; yrs= n=Number of Participants; Abbreviations: Structur Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Matricies System (MAT= Test React Schin - (2004) (2006) (2007) (2011) Pirastu Characteristics of articles identified comparing buprenorphine maintenance patients to methadone patients. 5: Characteristics of articles identified comparing Table

- 41 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

Records identified Records identified through literature through other sources. search. (n=208) (n=218)

Records Excluded (n=142)

Abstracts screened after duplicates removed. Poly Drug Use (n=23) (n=179) No Control (n=25) Participants Under 18 (n=14) Current Heroin Users (n=3) HIV Positive (n=17) Axis-1 Illness (n=4) No Neuropsychological Tests (n=23) No Maintenance Therapy (n=21) No English Article Available (n=2) Full-text Articles Assessed for Eligibility Animal Study (n=1) (n=37) Acute Effects of Opioids (n=9)

Articles Excluded (n=20)

Poly Drug Use (n=7) Head Injury (n=3) Mixed Results Group (n=3) No Control (n=2) Acute Effects (n=2) Control Group Seeking Psychological Treatment for Pain (n=1) No English Article Available (n=1) Only Abstract Available (n=1)

Articles included in the Final Review N= 16

Methadone Vs. Methadone Vs. N =Buprenorphine 17 Vs. Buprenorphine Vs. Buprenorphine Vs. Healthy Control Abstinence Healthy Control Abstinence Methadone

n = 10 n = 4 n = 5 n = 1 n = 3

Figure 1. QUORUM were the neurocognitive assessments of 279 metha- In the articles directly comparing patients on done maintained individuals from 10 published arti- ORT treatment [1, 25, 34], all except one domain cles and 84 individuals maintained on buprenorphine (cognitive impulsivity) showed no significant differ- compared to healthy controls from 5 published papers ences between cognitive functioning in methadone [34], although one article is included in each com- and buprenorphine treated individuals. parison in the table as it compared healthy controls against methadone and buprenorphine and in ad- 13.5.1. Cognitive impulsivity dition a direct comparison between methadone and Buprenorphine maintained individuals scored buprenorphine groups. significantly better (p<0.05) on measures of cognitive The papers included are shown in table 6. impulsivity than methadone maintained individuals in all three selected studies [1, 25, 34]. This is also 13.5. Neurocognitive impairments between groups supported by all other selected studies measuring this

- 42 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. - n/a n/a n/a n/a n/a n/a n/a (Copy) ↓ - RCFT ↓ - RCFT Impulsivity Non Planning n/a n/a n/a n/a n/a n/a n/a Motor (Phase 1) (Phase 2) (Phase 3) ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 Impulsivity n/a n/a n/a ↓ - GT ↓ - GT ↓ - GT ↓ - DR2 ↓ - DR2 Cognitive Impulsivity n/a TT15 WCST (errors) ↓ - TMT ↓ - ↓ - TT15 ↓ - ⟷ - LL5, Cognitive ↓ - WCST WCST ↓ - Flexibility — - WCST — - ↓ - COWAT, ↓ - COWAT, — - COWAT - R n/a n/a rect) — - ST — - FAT — - PVT — - PVT ↓ - DSST Attention — - WAIS- — - ↓ - Q1 (cor ↓ - DR2, Q1 ↓ - WAIS-III ↓ - n/a n/a n/a n/a n/a n/a SAVF CVLT Memory Long Term Long Term ↓ - WSMR, ↓ - — - RRLET, — - RRLET, n/a n/a Methadone Maintenance Papers SAVF CVLT, WSLT, WSLT, SOMT, SOMT, RRLET, RRLET, Memory ↓ - TT15 ↓ - — - 2BT ↓ - BVRT ↓ - BVRT Short Term Short Term ↓ - WMSR, ↓ - — - BVRT, — - BVRT, n/a — - SILS — - SILS — - MAT Intelligence ↓ - WAIS-III ↓ - ↓ - WAIS-III ↓ - ↓ - WAIS-III ↓ - — - WAIS-III - — 30 21 29 19 21 25 23 Type and Type Number (n) (See Demo - graphic Table) graphic Control Group Matched CON 30 18 23 18 15 30 24 27 Outcome Group and Number (n) 2011 2000 2002 2006 2004 2004 2006 Article Fuller et al. Darke et al. Soyka et al. Rotherham- Pirastu et al. Prosser et al. Mintzer et al. Lin et al. 2012 mance Test; WAIS-R Weschler Adult Intelligence Scale - Revised; SS= Stop Signal; PES= Post Error Slowing; FDT= Five Digit Test; Ruff= Ruff Selective Attention Test; CTT= Color Test; Attention Selective Ruff Ruff= Test; Digit FDT= Five SS= Stop Signal; PES= Post Error Slowing; Adult Intelligence Scale - Revised; Weschler WAIS-R Test; mance BNT= Making Test; TMT= Trail Card Sorting Task; Wisconsin WCST= Association Test; Controlled Word Oral COWAT= Test; Vigilance VIG= Attention Test; COG= - Affec Test; Trails AGN= Test; Tapping FTT= Finger Test; CGT= Cambridge Gambling Test; Perception; GT= Gambling Tachistoscopic TAVT= Test; Fluency Verbal VFT= Test; Boston Naming Matrices System (MAT= Test Act React ART-2020= AM=Austine Maze; SOC=Stockings of Cambridge; Test; Figure Complex RCFT= Rey Test; Go/No Go; DT=Determination tive Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stress Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test Vision Selective Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; Abbreviations: n= Number of Participants; MMT= Methadone Maintenance Programme; CON= Healthy Control; ABST= Protracted Abstinence; BUP= Buprenorphine Maintenance; Abstinence; BUP= ABST= Protracted Control; MMT= Methadone Maintenance Programme; CON= Healthy n= Number of Participants; Abbreviations: Memory Scale Weschler WSMR= Test; Adult Reading National NART= Test; = Matrices Scale; MAT Institute of Living Adult Intelligence Scale; SILS= Shipley Weschler WAIS-III= Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test;; Retention Visual Benton BVRT= Test; Back Two 2BT= Test; Test; Learning Figure Complex RCFT= Rey - Revised; Verbal Auditory Rey RAVLT= Test Learning Verbal Californian CVLT= Fluency; Verbal Association of Semantic SAVF= Test; RRLET= Remote and Recent Life Event CPT=Continuous Perfor Test; ST= Stroop Test; Animals; DSST= Digit Symbol Substitution Fruits and Assessment of Neurological Status; FAS= Repeatable Battery for the RBANS= Schindler et al. Articles included, comparison groups and neurocognitive domain 6. Articles included, comparison groups and neurocognitive Table

- 43 - Heroin Addiction and Related Clinical Problems 20(5): 35-49 - n/a n/a n/a n/a n/a n/a n/a n/a ↓ - SOC n/a n/a n/a n/a n/a Time) Reaction (Phase 1) (Phase 2) (Phase 3) — - AGN ↓ - RST-3 ↓ - RST-3 ↓ - RST-3 — - RST3 — - RST-3 — - RST-3 ↓ - DT (Mean n/a n/a n/a ↑ - GT — - GT ↑ - DR2 ↓ - CGT — - DR2 — - DR2 n/a n/a VFT TT15 TT15 - BNT, - BNT, ⟷ - LL5, ⟷ - LL5, ↓ - TT15 — - TAVT — - WCST — - WCST n/a n/a n/a FAT - Ruff - Ruff ↓ - Q1 ↓ - PES ↑ - DR2 — - Q1, — - SS , (Correct) ↓ - CTT2 — - PVT incorrect) — - COG ↓ - Q1 (% - DR2, FAT - DR2, FAT parison Group) n/a n/a n/a n/a n/a n/a n/a n/a n/a Buprenorphine Papers n/a n/a n/a n/a n/a RBANS ↓ - TT15 ↓ - BVRT — - BVRT ↓ - RAVLT, ↓ - RAVLT, n/a n/a n/a n/a — - MAT — - MAT ↓ - NART ↓ - WAIS-III — - WAIS-III 28 64 21 34 25 30 20 90 Papers (See Demo - Comparison graphic Table) Matched CON 15 29 65 18 18 22 18 20 11 (Per- 11 (Per- protocol) Group (n) No Significant Difference in score. (Outcome Group vs. Control or Com - Score (p<0.05), ↑ Significant Higher ⟷ No Difference ↓ Significantly Lower Comparison Key: 2004 2009 2006 2011 2006 2007 al. 2014 al. 2011 Soyka et al. Soyka Pirastu et al. Pirastu et al. Shmygalev et Shmygalev Baewert et al. Baewert Messinis et al. mance Test; WAIS-R Weschler Adult Intelligence Scale - Revised; SS= Stop Signal; PES= Post Error Slowing; FDT= Five Digit Test; Ruff= Ruff Selective Attention Test; CTT= Color Test; Attention Selective Ruff Ruff= Test; Digit FDT= Five SS= Stop Signal; PES= Post Error Slowing; Adult Intelligence Scale - Revised; Weschler WAIS-R Test; mance BNT= Making Test; TMT= Trail Card Sorting Task; Wisconsin WCST= Association Test; Controlled Word Oral COWAT= Test; Vigilance VIG= Attention Test; COG= - Affec Test; Trails AGN= Test; Tapping FTT= Finger Test; CGT= Cambridge Gambling Test; Perception; GT= Gambling Tachistoscopic TAVT= Test; Fluency Verbal VFT= Test; Boston Naming Matrices System (MAT= Test Act React ART-2020= AM=Austine Maze; SOC=Stockings of Cambridge; Test; Figure Complex RCFT= Rey Test; Go/No Go; DT=Determination tive Measuring the TT15=Test Ability, Structuring Visual for Test LL5= Attention Flexibility, for Test intelligence), Q1=Attention Under Monotonous Circumstances, FAT= (non-verbal Test Test (PVT= Peripheral Act React ART-90= Test); Stress Environment, RST3= Reactive in a Dynamic Driving DR2= Decision and Reaction Behaviour Ability, Perception Traffic-specific Test, DR2= Decision and Reaction Stress Attention Under Monotonous Circumstances, RST3= Reactive Q1= Ability, Perception Traffic-specific Measuring the TT15=Test Test Vision Selective Ruff=Ruff Test; Trails CTT=Color Test; Learning Verbal Auditory RAVLT=Rey Test; Fluency Verbal VFT= Test; BNT= Boston Naming in a Dynamic Environment); Behaviour Available. n/a= Not Test; VIG=Vigilance Perception; TAVT=Tachistoscopic DT=Determination Test; Attention Test; COG= Attention Test; Abbreviations: n= Number of Participants; MMT= Methadone Maintenance Programme; CON= Healthy Control; ABST= Protracted Abstinence; BUP= Buprenorphine Maintenance; Abstinence; BUP= ABST= Protracted Control; MMT= Methadone Maintenance Programme; CON= Healthy n= Number of Participants; Abbreviations: Memory Scale Weschler WSMR= Test; Adult Reading National NART= Test; = Matrices Scale; MAT Institute of Living Adult Intelligence Scale; SILS= Shipley Weschler WAIS-III= Test; Sequence Learning Word WSLT= Test; SOMT= Six Object Memory Test;; Retention Visual Benton BVRT= Test; Back Two 2BT= Test; Test; Learning Figure Complex RCFT= Rey - Revised; Verbal Auditory Rey RAVLT= Test Learning Verbal Californian CVLT= Fluency; Verbal Association of Semantic SAVF= Test; RRLET= Remote and Recent Life Event CPT=Continuous Perfor Test; ST= Stroop Test; Animals; DSST= Digit Symbol Substitution Fruits and Assessment of Neurological Status; FAS= Repeatable Battery for the RBANS= Baldacchino et Schindler et al. Liao et al. 2014 Articles included, comparison groups and neurocognitive domain 6. Articles included, comparison groups and neurocognitive Table

- 44 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. cognitive domain and compared with healthy con- nificantly impaired (p<0.05) relative to healthy con- trols [3, 23, 25, 28, 30, 34]. There was however no trols in both methadone and buprenorphine cohorts. significant difference found in cognitive impulsivity Four of the identified studies found a significant im- between buprenorphine maintained individuals and pairment (p<0.05) when methadone maintained indi- healthy controls [25, 30, 34]. viduals were compared to healthy controls [3, 8, 25, 27]. Three of the studies comparing buprenorphine 13.5.2. Cognitive flexibility to healthy controls showed significant impairment In the three studies directly comparing metha- (p<0.05) in short term memory [21, 25, 34]. done to buprenorphine treatment there were no sig- nificant differences in cognitive flexibility scores 14. Discussion reported. However cognitive flexibility was more fre- quently reported as significantly impaired (p<0.05) in 14.1. Summary of findings patients maintained on methadone, than those on bu- prenorphine when compared to healthy controls. Four Buprenorphine maintained individuals demon- of the ten selected studies [8, 23, 25, 34], showed im- strate reduced impairment of cognitive impulsivity pairment for methadone maintained individuals com- compared to those maintained on methadone. This pared to healthy control. In comparison only one of was the most reliable conclusion drawn from the re- five studies that reviewed cognitive flexibility in bu- sults as a significant difference was observed both in prenorphine treated individuals identified impairment papers directly comparing methadone with buprenor- [34],with the other 4 papers finding no impairment in phine and comparisons with control groups. this domain in comparison to healthy controls. The attention domain shows that buprenorphine patients are less impaired than patients on metha- 13.5.3. Motor impulsivity done in the direct comparative studies. However, in In the three papers conducting the direct com- the articles comparing methadone or buprenorphine parison between methadone treatment and buprenor- to healthy controls, both treatments were shown to phine treatment, there were no reported differences in cause equal impairment. The differences between the motor impulsivity. However in the studies looking buprenorphine and methadone in relation to the at- at comparison to healthy controls, both methadone tention domain could be due to the increased sedation and buprenorphine treated cohorts exhibited impair- experienced with a full opioid agonist in comparison ments in motor impulsivity when compared to healthy to a partial agonist [29]. controls [32, 34]. Cognitive flexibility was reported to be sig- nificantly less impaired (p<0.05) in buprenorphine 13.5.4. Attention maintained cohorts than methadone when compared One measure (DR2) in relation to the attention to healthy controls. However this was not replicated domain found buprenorphine individuals were less in articles that directly compare the domain between impaired than methadone in the papers comparing methadone or buprenorphine maintained patients. treatments against each other directly [1]. However the same paper found no significant difference on two 14.2. Significance other assessments of attention (Q1 & FAT). Soyka [34] also found no significant difference in attention As the literature search demonstrated, using the test scores when comparing methadone to buprenor- strict criteria employed in this review, there is little phine. Five articles that compared methadone to evidence available currently to directly compare both healthy controls identified a significant impairment in buprenorphine and methadone maintenance therapies attention [8, 19, 23, 30, 34] with four buprenorphine in relation to neurocognitive function. The articles comparison papers showed an impairment (p<0.05) that have been included highlights that there are dif- in the attention domain [30, 21, 32, 34]. ferences between treatments and these may provide benefits for patients increasing the success of their 13.5.5. Short term memory treatment. However there is a lack of consistency in From the two direct comparison articles between the tests employed in the research to date. methadone and buprenorphine cohorts that reported on Short Term Memory, there was no significant dif- 14.3. Strength and Limitations ference found [25, 34]. Short term memory was sig-

- 45 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

The literature search found no Randomised tems. A large degree of heterogeneity existed between Control Trials (RCTs) and all articles included are studies, e.g. mean opioid use ranged from six months case-control studies. The lack of randomized blinded to over fifteen years between methadone cohorts [25, studies limits result reliability due to the possibility of 28]. Other demographics followed similar trends, e.g. increased bias [15]. Due to methodological difficul- mean buprenorphine dose ranged from 6.78mg [21] ties, patients were not blinded to their interventional to 13.4mg [1]. There were significant differences re- group with only two articles used a single blinded ported between comparable populations within indi- methodology [1, 30]. vidual selected studies. There were discrepancies in Articles were excluded if they included indi- age, gender and educational attainment between pop- viduals affected by simultaneous illicit drug use or ulations [3, 20, 25, 27]. Significant differences in the medication that might affecting neurocognitive func- completed educational years could have a profound tion to minimise the effect of compounding factors. effect on the neurocognitive test scores reported by Most articles used different definitions of simulta- these groups in the intelligence domain. Matching neous drug use, showing a differing application of controls based on an estimate of their pre-morbid in- exclusion criteria between papers. Some conducted telligence (IQ) will reduce this bias. urinalysis over a period of months and others allowed The time between administration of the mainte- for positive urine test if the individual was not expe- nance dose and conducting the neurocognitive assess- riencing acute effects. The most commonly identified ments needs to be considered as variations in the time additional substance was benzodiazepines, which are delay may have different impairments on neurocogni- known to have effects on neurocognitive function [8, tive function due to the acute sedative effects of the 28, 34, 37]. These mitigate the acute effects of ben- treatment modality used [5]. One paper analysed the zodiazepines on the result of the neurocognitive tests difference in scores between peak levels (1.5 hours and question the cause of any reported neurocogni- after administration) and trough levels (20 hours after tive impairments in these studies. This becomes more administration) for both methadone and buprenor- important when comparing buprenorphine due to the phine. The combined results showed that individuals limited number of papers available covering this area. at trough levels performed significantly worse on the The less robust exclusion criteria used in Soyka’s [34] RST3 assessment of motor impulsivity [1]. In this re- paper reduces the reliability of the results from this view, the majority of studies included did not specify study. The results mirror those from the other three the time between administration of the last dose and papers making this comparison [1, 25, 30], reducing neuropsychological test which impacts on repeat- the likelihood that benzodiazepine use caused these ability and result interpretation. The large variation results. However it must be noted that benzodiazepine in duration of action means that individuals main- use is frequent amongst active heroin users, as well as tained on different opioids may experience the onset those enrolled in maintenance opioid agonist replace- of withdrawal symptoms, at different times which ment programmes. [16]. None of the studies consid- may affect the neurocognitive assessment. Thus, if ered the potential neurocognitive sequelae of chronic the assessment is conducted at the same time post ad- nicotine and/or cannabis use in this treatment seeking ministration; the methadone maintained cohort may population. collectively experience withdrawal symptoms earlier The selected articles sample size lack consist- than the buprenorphine maintained cohort in direct ency across the five studies investigating buprenor- comparison studies. Some studies screened for opioid phine. They included 84 individuals, contrasting to withdrawal at the time of testing ensuring participants 279 methadone maintained individuals across 10 were not in withdrawal [30, 37], whilst others con- selected studies. Potential root causes of this differ- ducted assessments well within the duration of action ence in articles identified are; (a) the limited period of treatments [3, 17]. of time that buprenorphine preparations have been Multiple different cognitive domains are de- licensed for use in opioid dependence (mid-1990s scribed and used in the literature. For the purposes of for buprenorphine as opposed to methadone’s avail- this enquiry the domains set out by Baldacchino et al. ability since the 1960s) and (b) methadone being the [4] were used. preferential use of methadone as a first line treatment Until a standardised system of domains and as- to opioid dependence [39]. sessment exists there will always be discrepancies The published articles are using small numbers and variations in the tests used and subsequent result studying individuals attending diverse treatment sys- classification, damaging the integrity of conclusions

- 46 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review. drawn from these studies heavy machinery. However for some patients a degree It is important to consider compounding factors of cognitive impairment may be beneficial. E.g. states affecting neurocognition, including head injury, alco- of increased boredom and “problematic thoughts that hol use and overdose. Regression analysis was used can increase the risk of relapse” [35]. This observation by some papers to correct for variations of these fac- should be taken with extreme caution as this system- tors. The rigorous inclusion criteria applied to papers atic review has highlighted the urgent need to conduct is a strength of the review, and provides clear results methodologically sound, unbiased and well powered comparing methadone/buprenorphine to a control or studies to be able to identify better significant corre- each other. This allowed a large array of data to be ex- lation between observed neurocognitive impairments tracted from included papers. The majority of papers and type of agonist opioid treatment used with clini- did not directly compare methadone to buprenorphine cal practice. and further research into this area could address this factor. 15. Conclusions Decreased neurocognitive test scores for both treatments were demonstrated in comparison to In conclusion, this systematic review of - healthy controls. The comparison of each treatment lished literature into the neurocognitive function of option against healthy controls allows some infer- individuals on methadone or buprenorphine mainte- ence to the effects of each treatment on the neuro- nance treatment shows that there are fewer than ex- cognitive impairments experienced. The differences pected reports of impaired neurocognitive function observed between the neurocognitive impairment and when patients are prescribed buprenorphine in com- the prescribed treatment modality validates the need parison to methadone. There is a need for more rigor- for further direct comparison research between the ous and larger well matched longitudinal studies to treatment options. reduce the variances caused due to opioid withdrawal influencing the result and to measure neurocognitive 14.4. Clinical relevance impairment of pharmacologically maintained indi- viduals over time. The relevance of this review can be demonstrat- ed in the application to driving ability. It is illegal to References drive whilst impaired under the influence of any drug. England and Wales have a blood concentration limit 1. Baewert A., Gombas W., Schindler S. D., Peternell- for methadone of 500mcg/L of blood [9]. Buprenor- Moelzer A., Eder H., Jagsch R., Fischer G. (2007): phine has no defined concentration limit. Therefore Influence of peak and trough levels of opioid maintenance if supported by further research and one treatment is therapy on driving aptitude. Eur Addict Res. 13(3): 127- 135. proven to provide improved scores this could influ- 2. Bahrick H. P., Bahrick P. O., Wittlinger R. P. (1975): ence treatment choice. Therefore this review helps to Fifty Years of Memory for Names and Faces: A Cross- identify better the current knowledge base when mak- Sectional Approach. J Exp Psychol Gen. 104(1): 54-75. ing clinical decisions on choice of opioid used for 3. Baldacchino A., Balfour D. J., Matthews K. (2015): ORT to improve road safety and treatment retention. Impulsivity and opioid drugs: differential effects of The effect on neurocognitive function could be heroin, methadone and prescribed analgesic medication. extrapolated to other functions and abilities and as- Psychol Med. 45(6): 1167-1179. sist in making treatment choices for patients which 4. Baldacchino A., Balfour D. J., Passetti F., Humphris G., are better suited and many patients report to a “clear Matthews K. (2012): Neuropsychological consequences head” with buprenorphine as opposed to “clouding” of chronic opioid use: a quantitative review and meta- analysis. Neurosci Biobehav Rev. 36(9): 2056-2068. with methadone [14, 29, 35]. This subjectively based 5. Baldacchino A., Armanyous M., Balfour D. J., Humphris reduced neurocognitive impairment would be of G., Matthews K. (2017): Neuropsychological functioning greater benefit to the patients recovery and treatment and chronic methadone use: A systematic review and on the grounds of the limited evidence identified. E. meta-analysis. Neurosci Biobehav Rev. 73: 23-38. g. decreased neurocognitive impairment would be 6. Buttner A., Mall G., Penning R., Weis S. (2000): The preferential for patients who are currently employed neuropathology of heroin abuse. Forensic Sci Int. 113(1- or actively seeking employment, those with a carers’ 3): 435-442. role for either children or physically unwell individ- 7. Cunha-Oliveira T., Rego A. C., Oliveira C. R. (2008): uals or those needing to be able to drive or operate Cellular and molecular mechanisms involved in the

- 47 - Heroin Addiction and Related Clinical Problems 20(5): 35-49

of opioid and psychostimulant drugs. heroin abusers on naltrexone hydrochloride therapy. Brain Res Rev. 58(1): 192-208. Hum Psychopharmacol. 24(7): 524-531. 8. Darke S., Sims J., Mcdonald S., Wickes W. (2000): 22. Miller G. A. (1956): The magical number seven plus or Cognitive impairment among methadone maintenance minus two: some limits on our capacity for processing patients. Addiction. 95(5): 687-695. information. Psychol Rev. 63(2): 81-97. 9. Department for Transport (2013): Drug Driving. Available 23. Mintzer M. Z., Stitzer M. L. (2002): Cognitive at: https://www.gov.uk/government/collections/drug- impairment in methadone maintenance patients. Drug driving#table-of-drugs-and-limits [Accessed April 6, Alcohol Depend. 67(1): 41-51. 2016]. 24. Nih (2014): Quality Assessment of Case-Control Studies. 10. Enevoldson T. P. (2004): Recreational drugs and Available at: http://www.nhlbi.nih.gov/health-pro/ their neurological consequences. J Neurol Neurosurg guidelines/in-develop/cardiovascular-risk- reduction/ Psychiatry. 75 Suppl 3: iii9-15. tools/case-control [Accessed March 2, 2016]. 11. Ersche K. D., Sahakian B. J. (2007): The neuropsychology 25. Pirastu R., Fais R., Messina M., Bini V., Spiga S., of amphetamine and opiate dependence: implications Falconieri D., Diana M. (2006): Impaired decision- for treatment. Neuropsychol Rev. 17(3): 317-336. making in opiate-dependent subjects: effect of 12. Fine P. G., Portenoy R. K. (2004): A Clinical Guide to pharmacological therapies. Drug Alcohol Depend. 83(2): Opioid Analgesia Vendome Group Healthcare Division, 163-168. New York, NY, USA. 26. Prosser J., Cohen L. J., Steinfeld M., Eisenberg D., 13. Gould T. J. (2010): Addiction and cognition. Addict Sci London E. D., Galynker, Ii (2006): Neuropsychological Clin Pract. 5(2): 4-14. functioning in opiate-dependent subjects receiving and 14. Hill D., Conroy S., Afzal A., Lang D., Steele S., following methadone maintenance treatment. Drug Campbell D. (2015): A comparison of methadone and Alcohol Depend. 84(3): 240-247. buprenorphine–naloxone as opioid substitution therapy: 27. Prosser J., London E. D., Galynker, Ii (2009): Sustained the patient perspective in NHS Lanarkshire. J Subst attention in patients receiving and abstinent following Abuse. 20(3): 168-177. methadone maintenance treatment for opiate dependence: 15. Hróbjartsson A., Emanuelsson F., Skou Thomsen A. S., performance and neuroimaging results. Drug Alcohol Jørgen Hilden Stig Brorson J. (2014): Bias due to lack Depend. 104(3): 228-240. of patient blinding in clinical trials. A systematic review 28. Rotheram-Fuller E., Shoptaw S., Berman S. M., London of trials randomizing patients to blind and nonblind E. D. (2004): Impaired performance in a test of decision- sub-studies. , 43(4), 1272-1283. Int J Epidemiol. 43(4): making by opiate-dependent smokers. Drug 1272-1283. Alcohol Depend. 73(1): 79-86. 16. Jones J. D., Mogali S., Comer S. D. (2012): Polydrug 29. Royal College of General Practitioners (2004): Guidance abuse: a review of opioid and benzodiazepine for the use of substitute prescribing in the treatment of combination use. Drug Alcohol Depend. 125(1-2): 8-18. opioid dependence in primary care. RCGP, UK. 17. Levy-Gigi E., Keri S., Shapiro A. R., Sason A., Adelson 30. Schindler S. D., Ortner R., Peternell A., Eder H., M., Peles E. (2014): Methadone maintenance patients Opgenoorth E., Fischer G. (2004): Maintenance therapy show a selective deficit to reverse positive outcomes in with synthetic opioids and driving aptitude. Eur Addict drug-related conditions compared to medication free Res. 10(2): 80-87. prolonged opiate abstinence. Drug Alcohol Depend. 31. Shipley W. C. (1940): A Self-Administering Scale for 144: 111-118. Measuring Intellectual Impairment and Deterioration. 18. Lezak M. D. (1983): Neuropsychological Assessment. The Journal of Psychology. 9(2): 371-377. Oxford University Press, Oxford, UK. 32. Shmygalev S., Damm M., Weckbecker K., Berghaus 19. Liao D. L., Huang C. Y., Hu S., Fang S. C., Wu C. S., G., Petzke F., Sabatowski R. (2011): The impact of Chen W. T., Lee T. S., Chen P. C., Li C. S. (2014): long-term maintenance treatment with buprenorphine Cognitive control in opioid dependence and methadone on complex psychomotor and cognitive function. Drug maintenance treatment. PLoS One. 9(4): e94589. Alcohol Depend. 117(2-3): 190-197. 20. Lin W. C., Chou K. H., Chen H. L., Huang C. C., Lu C. 33. Skrabalova J., Drastichova Z., Novotny J. (2013): H., Li S. H., Wang Y. L., Cheng Y. F., Lin C. P., Chen as a Potential Oxidative Stress-Causing Agent. C. C. (2012): Structural deficits in the emotion circuit Mini-Reviews in Organic Chemistry. 10(4): 367-372. and cerebellum are associated with depression, anxiety 34. Soyka M., Limmer C., Lehnert R., Koller G., Martin and cognitive dysfunction in methadone maintenance G., Kufner H., Kagerer S., Haberthur A. (2011): A patients: a voxel-based morphometric study. Psychiatry comparison of cognitive function in patients under Res. 201(2): 89-97. maintenance treatment with heroin, methadone, or 21. Messinis L., Lyros E., Andrian V., Katsakiori buprenorphine and healthy controls: an open pilot study. P., Panagis G., Georgiou V., Papathanasopoulos Am J Drug Alcohol Abuse. 37(6): 497-508. P. (2009): Neuropsychological functioning in 35. Tanner G. R., Bordon N., Conroy S., Best D. (2011): buprenorphine maintained patients versus abstinent Comparing methadone and Suboxone in applied

- 48 - D. Hill et al.: Comparing neurocognitive function in individuals receiving chronic methadone or buprenorphine for the treatment of opioid dependence: A systematic review.

treatment settings: the experiences of maintenance patients in Lanarkshire. J Subst Use. 16(3): 171-178. 36. Tolomeo S., Gray S., Matthews K., Steele J. D., Baldacchino A. (2016): Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence. Psychol Med. 46(13): 2841- 2853. 37. Verdejo A., Toribio I., Orozco C., Puente K. L., Perez- Garcia M. (2005): Neuropsychological functioning in methadone maintenance patients versus abstinent heroin abusers. Drug Alcohol Depend. 78(3): 283-288. 38. Wechsler D. (1997): WAIS-III administration and scoring manual. Psychological Corporation, New York, NY, USA. 39. Whelan P. J., Remski K. (2012): Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds. J Neurosci Rural Pract. 3(1): 45-50.

Acknowledgements The authors would like to acknowledge the Medical School at the University of St Andrews for their support in preparing the article.

Role of the funding source Financial support for the implementation of this re- view was provided by internal funds.

Contributors The authors contributed equally to this review.

Conflict of interest Authors declared no conflict of interest.

Received December 7, 2017 - Accepted March 1, 2018

- 49 -

HEROIN ADDICTION & Short Communication RELATED CLINICAL Heroin Addict Relat Clin Probl 2018; 20(5): 51-53 PROBLEMS www.europad.org Pacini Editore & AU CNS www.wftod.org

Medicinal products detected as novel psychoactive substances: The case of intravenous use of tropicamide. Marie Claire Van Hout

Public Health Institute Liverpool John Moores University, Liverpool, United Kingdom

Summary Use and abuse of novel psychoactive substances (NPS) remains a public health and law enforcement challenge across Eu- rope and bordering countries. Increasingly NPS detected on the drug market include those with legitimate use as medicines or active pharmaceutical ingredients in medicines. This Short Communication wishes to draw attention to reports on the concerning upward trend of intravenous (IV) use of eyedrops containing tropicamide by problematic opiate users. Since 2013, trends of diversion by IV route are identified as a new phenomenon in Europe. Sales in Russia and Eastern Europe in particular have increased significantly in the past five years. Key indicators of suspected misuse include online interest particularly from Russia, Ukraine and other Eastern European countries, and pharmacovigilance and clinical alerts from Turkey , Italy, France, Georgia, Russia, Tajikistan, and Kazakhstan. Tropicamide is injected as secondary to the primary opiate addiction, and reportedly occurs as self-sufficient means to get high amongst opiate injectors when primary opiates such as heroin are not available, and as poly-substitute to further enhance the opiate effect and manage heroin (and to a lesser extent methadone) withdrawals . Anecdotally, injection of tropicamide is known as the ‘seven monther’ in relation to the length of time it takes to kill the user. The diversion of tropicamide is high risk, concentrated within problematic drug user networks, and conducted by individuals who may not be engaging with social and medical systems. Aside from dependence and physical/psychiatric harms, the risk pertaining to this injecting phenomenon as potential contribution toward virus transmission (HIV, Hepatitis C) within injecting networks are present. The Short Communication presents extant literature on the topic, and discusses implications for and service delivery. Key Words: Novel Psychoactive Substance; Tropicamide; eyedrops

Use and abuse of novel psychoactive substances available. The EU legal framework of Council De- (NPS) remains a public health and law enforcement cision 2005/387/JHA also defines NPS as including challenge across Europe and bordering countries [18]. human or veterinary medicinal products. Increasingly NPS notified to the EU Early Warning System (EWS) NPS detected on the drug market include those with continue to rise, with the World Health Organisation legitimate use as medicines or active pharmaceutical reporting on a global rise of 55% in 2015. The United ingredients in medicines. The European Medicines Nations Office on Drugs and Crime (UNODC) and Agency (EMA) and the European Monitoring Cen- the European Union (EU) define NPS as “substances tre for Drugs and Drug Addiction (EMCDDA) cur- of abuse, either in a pure form or a preparation, that rently exchange information around abuse of medici- are not controlled by the 1961 Single Convention on nal products. Recent examples include those notified Drugs or the 1971 Convention on Psycho- under the Council Decision and detected by the EU- tropic Substances, but which may pose a public health EWS (, , cafentanyil, , threat” [17]. Of note is that UNODC extends the con- etaqualone, zopiklone and tropicamide) [6-7]. cept of NPS to emerging drug trends, not necessar- This Short Communication wishes to draw at- ily new designer drugs, but also substances recently tention to reports on a concerning upward trend of

Corresponding author: Marie Claire Van Hout, Public Health Institute Liverpool John Moores University, 2nd Floor Henry Cotton Campus 15-21 Webster Street , L32ET, Liverpool, United Kingdom. Phone: +44 151 231 4542; Fax: +44 151 231 4552; E-mail: [email protected] 51 Heroin Addiction and Related Clinical Problems 20(5): 51-53 intravenous (IV) use of eyedrops containing tropi- Russia have been reported in the media and on drug camide by problematic opiate users. Tropicamide is fora [3, 4, 16]. a mydriatic atropenic ophthalmic drug indicated for The diversion of tropicamide is high risk, con- therapeutic or diagnostic procedures to dilate the pu- centrated within problematic drug user networks, and pils [12]. It is administered for very short-term expo- conducted by individuals who may not be engaging sure periods, at starting doses of one drop (150 μg of with social and medical systems [11]. Aside from tropicamide) and not exceeding 3 ml of the solution. dependence and physical/psychiatric harms, the risk Effects at higher dosages include visual hallucina- pertaining to this injecting phenomenon as potential tions, confused states, sedation and delirium [1, 9]. contribution toward virus transmission (HIV, Hepati- Since 2013, trends of diversion by IV route are iden- tis C) within injecting networks are present. Given the tified as a new phenomenon in Europe. Sales in Rus- fluctuations in opiate and diverted opioid availability sia and Eastern Europe in particular have increased in regions where tropicamide is used, this remains significantly in the past five years [13-14, 19]. Key concerning, even though primary tropicamide abuse indicators of suspected misuse include online interest is not commonly reported, and it appears situated particularly from Russia, Ukraine and other Eastern within poly substance use as ‘top up’ drug. Tropi- European countries [3, 11], and pharmacovigilance camide’s craving’s specificity appears to get lost in and clinical alerts from Turkey [5], Italy [3, 15], addictive processes, with poly-substance abuse of France [11], Georgia [2], Russia [3, 19], Tajikistan tropicamide in opiate dependency going far beyond [8, 10, 20], and Kazakhstan [13-14]. cross-tolerance mechanisms. Tropicamide is injected as secondary to the pri- The rising reports in Russia and Eastern Europe, mary opiate addiction, and reportedly occurs as self- and more recently in France and Italy, of tropicamide sufficient means to get high amongst opiate injectors abuse by known injecting networks of drug users when primary opiates such as heroin are not availa- therefore warrants a careful response, instigated by ble, and as poly-substitute to further enhance the opi- country and EU wide risk assessment. Gauging the ate effect, and to manage heroin (and to a lesser extent public health risks within countries experiencing this methadone) withdrawals [2, 4, 5, 10, 15, 19, 20]. Ad- injecting phenomenon is difficult, and yet are neces- ditional factors supporting the rapid diffusion of this sary to underpin further development and coverage new injecting phenomenon within Russia and Eastern of pharmaco and addicto-vigilance regulatory sys- Europe are observed by Bersani and colleagues [4] tems. National early warning systems are uniquely in their mini-review and centre on rapid onset of ef- positioned to identify early and continued levels of fect, ease of availability and low cost, and visibility of abuse of this diverted medicinal product, particularly user interest and experiences online. Prilutskaya and within existing problem drug user networks. Given Kuliev [14] also speculate that tropicamide’s popular- the cross over between pharmacy and street supply ity is due to its readiness for injection, in contrast to of tropicamide, a multi-disciplinary approach to inte- other pharmacy sourced medicinal products such as grate regulation, enforcement, and surveillance of di- codeine, and which require version and suspected abuse is imperative to monitor some level of home preparation prior to injecting (for and respond to this type of medicinal diversion. Rou- example ‘Krokodil’, see [18]). Tropicamide eyedrops tine forensic detection, monitoring and surveillance can easily be bought online and in pharmacies [4]. of a broad reach of potential information sources both Acute intoxication characterised by hallucina- inside and outside countries experiencing this trend tions (‘open eye dreams’), dizziness, hyperthermia, are therefore necessary. For countries experiencing tremors, convulsions, suicidal ideation, psychomotor this form of medicinal diversion, training of health, agitation, tachycardia and psychosis, diagnosis of an- pharmacy and medical professionals in the detection ticholinergic syndrome and adverse chronic health of suspected abuse and appropriate clinical respons- problems (severe weight loss, cognitive impairment, es for those experiencing tropicamide related health cardiovascular toxicity, renal or liver failure, post problems and dependence are warranted [3, 5, 11, injection purulent soft tissue complications, viral 14-15]. Research efforts can assist in the garnering transmission and both physical and psychological of understanding tropicamide as relatively new drug dependence) are reported [3-5, 11, 13-15]. Anecdo- situated within problem drug user populations, and tally, injection of tropicamide is known as the ‘seven can help support the development of targeted preven- monther’ in relation to the length of time it takes to tion and initiatives. Within the wider kill the user [3]. In the past five years, fatalities in EU domain, the regular surveillance of online drug

- 52 - M.C. Van Hout: Medicinal products detected as novel psychoactive substances: The case of intravenous use of tropicamide fora and trend interest in tropicamide (and other phar- drops in open eyes. J Ocul Pharmacol Ther 8, 632–5. maceuticals with abuse liability) should continue. 13. Prilutskaya, M.V., Kuliev, R.S. (2014). Clinico-dynamic features of withdrawal symptoms in patients with References polydrug addiction of opioids and tropicamide. Voprosy Mentalnoy Medetsiny i Ecologii 3(67), 3–4. 14. Prilutskaya, M.V., Kuliev, R.S. (2015). Analysis of 1. Akkaya, C. (2008). Cyclopentolate abuse. Reactions, clinical characteristics of non-medical use of tropicamide 1228, 15. by drug addicts in the Republic of Kazakhstan. ESJ. 2, 2. Alavidze, S., Balanchivadze, N., Batselashvili, 159–162. L., Duchidze, N., Javakhishvili, J., Kikvidze, T., 15. Spagnolo, P. A., Badiani, A., Nencini, P. (2013). Polydrug Otiashvili, D., Razmadze, M., Sturua, L., Tabatadze, abuse by intravenous use of heroin and tropicamide- M., Tsertsvadze, V. (2015) Drug Situation in Georgia containing eyedrops. Clin Neuropharmacol, 36(3), 2013. Tbilisi: Global Initiative on Psychiatry/Alternative 100-101. Georgia. 16. The Independent (2011) The squalid, lonely death of 3. Bersani, F. S., Corazza, O., Simonato, P., Mylokosta, A., Ivan Kanev. Abuse of prescription drugs is claiming Levari, E., Lovaste, R., Schifano, F. (2013). Drops of thousands of young lives. 21 August 2011. Available madness? Recreational misuse of tropicamide collyrium; at: http://www.independent. co.uk/news/world/europe/ early warning alerts from Russia and Italy. Gen Hosp the-squalid-lonely-death-of-ivan-kanev-2341191. Psychiatry, 35(5), 571-573. 17. United Nations Office for Drugs and Crime (UNODC) 4. Bersani, F. S., Imperatori, C., Prilutskaya, M., Kuliev, (2013). World Drug Report. New York: United Nations R., Corazza, O. (2015). Injecting eye-drops: a mini- Publications. review on the non-clinical use of tropicamide. Hum 18. Van Hout, M. C. (2014). Kitchen chemistry: A scoping Psychopharmacology Clin Exp 30(4), 262-264. review of the diversionary use of pharmaceuticals 5. Bozkurt, M., Karabulut, V., Evren, C., Seker, M., Kan, for non-medicinal use and home production of drug H. (2015). Intravenous abuse of tropicamide in opioid solutions. Anal 6 (7–8), 778–87. use disorder: presentation of 2 cases. Subst Abuse, 19. Vladimirov, V., Kaimak, Y (2012). Increasing use of 36(2), 170-173. the eye drop preparation “Tropicamide ”as an injection 6. European Monitoring Centre for Drugs and Drug narcotic drug. Biosphere, 4(1), 86-89. Addiction (EMCDDA)-Europol (2013). EMCDDA– 20. Zule, W., Latypov, A., Otiashvilli, D., Kirtadze, I., Europol 2013 Annual Report on the implementation Ibragimov, U., Bobabshev, G (2015). Factors that of Council Decision 2005/387/JHA. Lisbon: European influence the characteristics of needles and syringes Monitoring Centre for Drugs and Drug Addiction. used by people who inject drugs in Tajikistan. Harm 7. European Monitoring Centre for Drugs and Drug Reduct J 12, 37. Addiction (EMCDDA) (2014). European Drug Report 2014: trends and developments, 2014. Lisbon: European Monitoring Centre for Drugs and Drug Addiction. Acknowledgements 8. Latypov,., A., Otiashvilli, D., Zule, W. (2014). Drug None scene, drug use and drug-related health consequences and responses in Kulob and Khorog, Tajikistan. Int. J. Role of the funding source Drug. Policy. 25, 1204–1214 Financial support for the implementation of this re- 9. Munhoz, R.P., Moscovich, M.M., Filla, L., Carneiro, view was provided by internal funds. MCB. (2010). Topical tropicamide induced delirium and psychosis: case report. J Brasileiro Psiq 59, 74–6. Conflict of interest 10. Otiashvili, D., Latypov, A., Kirtadze, I., Ibragimov, U., Author declared no conflict of interest. Zul, M. (2016). Drug preparation, injection, and sharing practices in Tajikistan: a qualitative study in Kulob and Ethics Khorog. Subst Abuse Treat Prev Policy. 11, 21. Author confirm that the submitted study was con- 11. Ponté, C., Pi, C., Palmaro, A., Jouanjus, E., Lapeyre- ducted according to the WMA Declaration of Helsinki - Mestre, M and on behalf of the French Addictovigilance Ethical Principles for Medical Research Involving Human Network (2017). Early signal of diverted use of Subjects. tropicamide eyedrops in France. Br J Clin Pharmacol 83(8), 1791-1800. Note 12. Portes, A.J., Barbosa, A.C., de Mello, G.L., Lopes, M.A, It is the policy of this Journal to provide a free re- Cavalcanti, R.S. (2012). Tropicamide 1% mydriatic vision of English for Authors who are not native English effect: comparison between spray in closed eyes and eye speakers.

Received November 22, 2017 - Accepted March 2, 2018

- 53 -

Places ILove -Oloron-Sainte Marie, Aquitaine, France,October2009

© Icro Maremmani