Abstract
Rationale
Naltrexone is an opioid antagonist that is currently approved as a treatment for opioid and alcohol dependence. Although it is highly effective in completely antagonizing the effects of opioids, medication noncompliance is a difficult obstacle to treatment. Therefore, a sustained-release form of naltrexone may improve treatment outcome.
Objective
The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex®).
Materials and methods
Five heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, the effects of a range of heroin doses (0, 6.25, 12.5, and 25 mg, i.v.) were examined. Participants then received 384 mg naltrexone base. The effects of heroin were again evaluated for the next 6 weeks. One dose of heroin was tested per day and the entire dose range was tested each week. Doses were administered in non-systematic order. During a morning sample session, participants received a dose of heroin and $20 and subjective, performance, and physiological effects were measured both before and after drug administration. During an afternoon choice session, participants were given the opportunity to choose the sampled heroin dose and/or amount of money using a modified progressive ratio procedure.
Results
Depot naltrexone antagonized both the reinforcing and subjective effects of heroin for 4–5 weeks. Subjective ratings of withdrawal were reduced after week 2 and throughout the remainder of the study. The effects of heroin on mean trough pupil diameter began to emerge by week 5. There were no clinically significant effects on respiratory or cardiovascular function.
Conclusions
The present results extend our previous findings by showing that the reinforcing effects of heroin were reduced for 4–5 weeks after administration of 384 mg depot naltrexone.
Similar content being viewed by others
References
Alim TN, Tai B, Chiang CN, Green T, Rosse RB, Lindquist T, Deutsch SI (1995) Tolerability study of a depot form of naltrexone substance abusers. In: Harris LS (ed) Problems of drug dependence 1994, vol 2. NIDA Research Monograph No. 153 (NIH Publ. No. 95-3883). U.S. Government Printing Office, Washington, D.C., p 253
Callahan EJ, Rawson RA, McCleave B, Arias R, Glazer M, Liberman RP (1980) The treatment of heroin addiction: naltrexone alone and with behavior therapy. Int J Addict 15(6):795-807
Chiang CN, Hollister LE, Gillespie HK, Foltz RL (1985a) Clinical evaluation of a naltrexone sustained-release preparation. Drug Alcohol Depend 16:1–8
Chiang CN, Kishimoto A, Barnett G, Hollister LE (1985b) Implantable narcotic antagonists: a possible new treatment for narcotic addiction. Psychopharmacol Bull 21:672–675
Comer SD, Collins ED (2002) Self-administration of intravenous buprenorphine and buprenorphine/naloxone combination by recently detoxified heroin abusers. J Pharmacol Exp Ther 303(2):695–703
Comer SD, Collins ED, Fischman MW (1997) Choice between money and intranasal heroin in morphine-maintained humans. Behav Pharmacol 8:667–690
Comer SD, Collins ED, Wilson ST, Donovan MR, Foltin RW, Fischman MW (1998) Effect of an alternative reinforcer on i.v. heroin self-administration by humans. Eur J Pharmacol 345:13–26
Comer SD, Collins ED, Kleber HD, Nuwayser ES, Kerrigan JH, Fischman MW (2002) Depot naltrexone: long-lasting antagonism of the effects of heroin in humans. Psychopharmacology 159:351–360
Comer SD, Walker EA, Collins ED (2005) Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology 181(4):664–675
Crowley TJ, Wagner JE, Zerbe G, Macdonald M (1985) Naltrexone-induced dysphoria in former opioid addicts. Am J Psychiatry 142:1081–1084
Evans SM, Foltin RW, Levin FR, Fischman MW (1995) Behavioral and subjective effects of DN-2327 (pazinaclone) and alprazolam in normal volunteers. Behav Pharmacol 6:176–186
Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261:623–632
Foltin RW, Fischman MW (1995) Interaction of buprenorphine with cocaine–morphine combinations. Exp Clin Psychopharmacol 3(3):261–269
Fraser HF, Van Horn GD, Martin WR, Wolbach AB, Isbell H (1961) Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs, (B) A short-term “direct” addiction test. J Pharmacol Exp Ther 133:371–387
Gossop M, Green L, Phillips G, Bradley B (1989) Lapse, relapse, and survival among opiate addicts after treatment: a prospective follow-up study. Br J Psychiatry 154:348–353
Greenstein RA, Arndt IC, McLellan AT, O’Brien CP, Evans B (1984) Naltrexone: a clinical perspective. J Clin Psychiatry 45:25–28
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD (1987) Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 13:293–308
Heishman SJ, Francis-Wood A, Keenan RM, Chiang CN, Terrill JB, Tai B, Henningfield JE (1994) Safety and pharmacokinetics of a new formulation of naltrexone. In: Harris LS (ed) Problems of drug dependence 1993, vol 2. NIDA Research Monograph No. 141 (NIH Publ. No. 94-3749). U.S. Government Printing Office, Washington, D.C., p 82
Heishman SJ, Schuh KJ, Schuster CR, Henningfield JE, Goldberg SR (2000) Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer. Psychopharmacology 148:272–280
Hollister LE, Johnson K, Boukhabza D, Gillespie HK (1981) Aversive effects of naltrexone in subjects not dependent on opiates. Drug Alcohol Depend 8:37–41
Hollister LE, Schwin RL, Kapser P (1977) Naltrexone treatment of opiate-dependent persons. Drug Alcohol Depend 2:203–209
Judson BA, Carney TM, Goldstein A (1981) Naltrexone treatment of heroin addiction: efficacy and safety in a double-blind dosage comparison. Drug Alcohol Depend 7:325–346
Kelly TH, Foltin RW, Emurian CS, Fischman MW (1993) Performance-based testing for drugs of abuse: dose and time profiles of marijuana, amphetamine, alcohol, and diazepam. J Anal Toxicol 17:264–272
Kirchmayer U, Davoli M, Verster A, Amato L, Feri M, Perucci CA (2002) A systematic review on the efficacy of naltrexone maintenance treatment in opioid dependence. Addiction 97(10):1241–1249
Kosten TR, Kleber HD (1984) Strategies to improve compliance with narcotic antagonists. Am J Drug Alcohol Abuse 10:249–266
Kranzler HR, Modesto-Lowe V, Nuwayser ES (1998) Sustained-release naltrexone for alcoholism treatment: a preliminary study. Alcohol Clin Exp Res 22:1074–1079
Lamb RJ, Preston KL, Schindler CW, Meisch RA, Davis F, Katz JL, Henningfield JE, Goldberg SR (1991) The reinforcing and subjective effects of morphine in post-addicts: a dose-response study. J Pharmacol Exp Ther 259:1165–1173
Martin WR, Jasinski DR, Mansky PA (1973) Naltrexone, an antagonist for the treatment of heroin dependence. Arch Gen Psychiatry 28:784–791
Martin W, Sandquist VL (1974) A sustained release depot for narcotic antagonists. Arch Gen Psychiatry 30:31–33
McLeod DR, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the Digit Symbol Substitution Test (DSST). Behav Res Meth Instrum 14:463–466
Mirin SM, Meyer RE, McNamee HB (1976) Psychopathology, craving, and mood during heroin acquisition: an experimental study. Int J Addict 11:525–544
Oncken C, Kirk JV, Kranzler HR (2001) Adverse effects of oral naltrexone: analysis of data from two clinical trials. Psychopharmacology 154:397–402
Rothenberg JL, Sullivan MA, Church SH, Seracini A, Collins E, Kleber HD, Nunes EV (2002) Behavioral naltrexone therapy: an integrated therapy for opiate dependence. J Subst Abuse Treat 23(4):351–360
Sideroff SI, Charuvastra VS, Jarvik ME (1978) Craving in heroin addicts maintained on the opiate antagonist naltrexone. Am J Drug Alcohol Abuse 5:415–423
Wang RIH, Wiesen RL, Lamid S, Roh BL (1974) Rating the presence and severity of opiate dependence. Clin Pharmacol Ther 16:653–658
Washton AM, Gold MS, Pottash AC (1984) Successful use of naltrexone in addicted physicians and business executives. Adv Alcohol Subst Abuse 4(2):89–96
Wesnes K, Warburton DM (1983) Effects of smoking on rapid information processing performance. Neuropsychobiology 9:223–229
Acknowledgments
The authors would like to thank Michael R. Donovan, R.N.; Ronnie M. Shapiro, R.N.; Evaristo Akerele, M.D.; Adam Bisaga, M.D.; and Eric Rubin, M.D., Ph.D. for medical assistance; and Laura Andima, B.S., Kevin Walsh, B.S., and Christy Aberg, B.A. for technical assistance with this study. This research was supported by the National Institute on Drug Abuse (DA09236).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sullivan, M.A., Vosburg, S.K. & Comer, S.D. Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin. Psychopharmacology 189, 37–46 (2006). https://doi.org/10.1007/s00213-006-0509-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-006-0509-x