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Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers

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Abstract

Rationale

Although buprenorphine is effective in treating opioid dependence, optimal maintenance doses of buprenorphine or the buprenorphine/naloxone combination have not yet been established.

Objective

The present study was designed to evaluate the effects of buprenorphine/naloxone maintenance (2/0.5, 8/2, 32/8 mg sublingual) on the reinforcing and subjective effects of heroin (0, 12.5, 25, 50, and 100 mg intranasal) in heroin-dependent individuals.

Methods

During test weeks, participants (N=7) first sampled a dose of heroin and $20. During subsequent choice sessions, participants could choose to self-administer heroin and/or money. Participants responded under a modified progressive-ratio schedule (PR 50, ..., 2,800) during a ten-trial self-administration task.

Results

Heroin break point values and subjective responses were significantly lower under 8/2 and 32/8 mg buprenorphine/naloxone compared to 2/0.5 mg. The self-administration and subjective effects data for heroin in the presence of buprenorphine/naloxone were compared to a separate control group of recently detoxified participants (N=8) in order to obtain estimates for the apparent in vivo dissociation constant (K A), the efficacy estimate (τ), and the estimated fraction of receptors remaining after buprenorphine/naloxone treatment (q). The apparent in vivo dissociation constant for heroin ranged from 50 to 126 mg (K A) and the efficacy estimate ranged from 13 to 20 (τ). In addition, 2/0.5, 8/2, and 32/8 mg buprenorphine/naloxone dose-dependently reduced the receptor population by 74, 83, and 91%, respectively.

Conclusions

These data demonstrate that both 8/2 and 32/8 mg buprenorphine/naloxone were well tolerated and effective in reducing the reinforcing and subjective effects of heroin, relative to the 2/0.5-mg dose. The data also show for the first time in humans that it is possible to quantify the efficacy and affinity of heroin for mu opioid receptors, and that 80–90% of mu receptors need to be inactivated in order to obtain significant reductions in heroin-induced effects. These results have important implications for future studies in which it will be possible to obtain estimates of relative affinity and efficacy of different agonists at mu opioid receptors.

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References

  • Adams JU, Paronis CA, Holtzman SG (1990) Assessment of relative intrinsic activity of mu-opioid analgesics in vivo by using beta-funaltrexamine. J Pharmacol Exp Ther 255(3):1027–1032

    PubMed  CAS  Google Scholar 

  • Barrett AC, Smith ES, Picker MJ (2003) Use of irreversible antagonists to determine the relative efficacy of mu opioids in a pigeon drug discrimination procedure: comparison of beta-funaltrexamine and clocinnamox. J Pharmacol Exp Ther 1061–1070

  • Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988a) A clinical trial with buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther 43:72–78

    Article  PubMed  CAS  Google Scholar 

  • Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988b) Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247:47 53

    PubMed  CAS  Google Scholar 

  • Bickel WK, Amass L, Crean JP, Badger GJ (1999) Buprenorphine dosing every 1, 2, or 3 days in opioid-dependent patients. Psychopharmacology 146:111–118

    Article  PubMed  CAS  Google Scholar 

  • Black JW, Leff P (1983) Operational models of pharmacological agonism. Proc R Soc Lond B 220:141–162

    Article  PubMed  CAS  Google Scholar 

  • Black JW, Leff P, Shankley NP, Wood J (1985) An operational model of pharmacological agonism: the effects of E/[A] curve shape on agonist dissociation constant estimation. Br J Pharmacol 84:561–571

    PubMed  CAS  Google Scholar 

  • Chiang CN, Hawks RL (2003) Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend 70:S39–S47

    Article  PubMed  CAS  Google Scholar 

  • Comer SD, Burke TF, Lewis JW, Woods JH (1992) Clocinnamox: a novel, systemically-active, irreversible opioid antagonist. J Pharmacol Exp Ther 262:1051–1056

    PubMed  CAS  Google Scholar 

  • Comer SD, Collins ED, Fischman MW (1997) Choice between money and intranasal heroin in morphine-maintained humans. Behav Pharmacol 8:667–690

    Article  Google Scholar 

  • Comer SD, Collins ED, MacArthur RB, Fischman MW (1999) Comparison of intranasal and intravenous heroin self-administration by morphine-maintained humans. Psychopharmacology 143:327–338

    Article  PubMed  CAS  Google Scholar 

  • Comer SD, Collins ED, Fischman MW (2001) Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans. Psychopharmacology 154:28–37

    Article  PubMed  CAS  Google Scholar 

  • Drug Enforcement Administration Illegal Drug Price and Purity Drug Intelligence Report, April 2003. http://www.usdoj.gov:80/dea/pubs/intel/02058/02058.html

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261(2):623–632

    PubMed  CAS  Google Scholar 

  • 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 ldquo;direct” addiction test. J Pharmacol Exp Ther 133:371–387

    PubMed  CAS  Google Scholar 

  • Furchgott RF (1966) The use of β-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor–agonist complexes. Adv Drug Res 3:21–56

    Google Scholar 

  • Greenwald MK, Schuh KJ, Hopper JA, Schuster CR, Johanson C-E (2002) Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans. Psychopharmacology 160:344–352

    Article  PubMed  CAS  Google Scholar 

  • Greenwald MK, Johanson C-E, Moody DE, Woods JH, Kilbourn MR, Koeppe RA, Schuster CR, Zubieta J-K (2003) Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 28:2000–2009

    PubMed  CAS  Google Scholar 

  • Hambrook J, Rance M (1976) The interaction of buprenorphine with the opiate receptor: lipophylicity as a determining factor in drug-receptor kinetics. In: Kosterlitz H (ed) Opiates and endogenous peptides. North-Holland, Amsterdam, pp 295–301

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Harris DS, Mendelson JE, Lin ET, Upton RA, Jones RT (2004) Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality. Clin Pharmacokinet 43(5):329–40

    Article  PubMed  CAS  Google Scholar 

  • Johnson RE, Jaffe JH, Fudala PJ (1992) A controlled trial of buprenorphine treatment for opioid dependence. J Am Med Assoc 267(20):2750–2755

    Article  CAS  Google Scholar 

  • Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. New Engl J Med 343(18):1290–1297

    Article  PubMed  CAS  Google Scholar 

  • Johnson RE, Strain EC, Amass L (2003) Buprenorphine: how to use it right. Drug Alcohol Depend 70:S59–S77

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Ling W, Wesson DR, Charuvastra C, Klett CJ (1996) A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry 53:401–407

    PubMed  CAS  Google Scholar 

  • Martin TJ, Dworkin SI, Smith JE (1995) Alkylation of mu opioid receptors by beta-funaltrexamine in vivo: comparison of the effects on in situ binding and heroin self-administration in rats. J Pharmacol Ther Exp 272:1135–1140

    CAS  Google Scholar 

  • Martin TJ, DeMontis MG, Kim SA, Sizemore GM, Dworkin SI, Smith JE (1998) Effects of beta-funaltrexamine on dose–effect curves for heroin self-administration in rats: comparison with alteration of [3H]DAMGO binding to rat brain sections. Drug Alcohol Depend 52:135–147

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Mello NK, Mendelson JH (1980) Buprenorphine suppresses heroin use by heroin addicts. Science 207:657–659

    Article  PubMed  CAS  Google Scholar 

  • Mello NK, Mendelson JH, Kuehnle JC (1982) Buprenorphine effects on human heroin self-administration: an operant analysis. J Pharmacol Exp Ther 223:30–39

    PubMed  CAS  Google Scholar 

  • Mello NK, Bree MP, Mendelson JH (1983) Comparison of buprenorphine and methadone effects on opiate self-administration in primates. J Pharmacol Exp Ther 225:378–386

    PubMed  CAS  Google Scholar 

  • Miller TP, Taylor JL, Tinklenberg JR (1988) A comparison of assessment techniques measuring the effects of methylphenidate, secobarbital, diazepam and diphenhydramine in abstinent alcoholics. Neuropsychobiology 19:90–96

    PubMed  CAS  Google Scholar 

  • Nath RP, Upton RA, Everhart ET, Cheung P, Shwonek P, Jones RT, Mendelson JE (1999) Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 39:619–623

    Article  PubMed  CAS  Google Scholar 

  • Negus SS, Brandt MR, Gatch MB, Mello NK (2003) Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and beta-funaltrexamine. Drug Alcohol Depend 70(1):17–27

    Article  PubMed  CAS  Google Scholar 

  • Pitts RC, Allen RA, Walker EA, Dykstra LA (1998) Clocinnamox antagonism of the antinociceptive effects of mu opioids in squirrel monkeys. J Pharmacol Exp Ther 285:1197–1206

    PubMed  CAS  Google Scholar 

  • Raffa RB, Porreca F, Cowan A, Tallarida RJ (1982) Morphine–receptor dissociation constant and the stimulus effect relation for inhibition of gastrointestinal transit in the rat. Eur J Pharmacol 79:11–16

    Article  PubMed  CAS  Google Scholar 

  • Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1994) Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry 151:1025–1030

    PubMed  CAS  Google Scholar 

  • Tallarida RJ, Cowan A (1982) The affinity of morphine for its pharmacologic receptor in vivo. J Pharmacol Exp Ther 222:198–201

    PubMed  CAS  Google Scholar 

  • Walker EA, Zernig G, Woods JH (1995) Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure. J Pharmacol Exp Ther 273:1345–1352

    PubMed  CAS  Google Scholar 

  • Walker EA, Zernig G, Young AM (1998) In vivo apparent affinity and efficacy estimates for μ opiates in a rat tail-withdrawal assay. Psychopharmacology 136:15–23

    Article  PubMed  CAS  Google Scholar 

  • Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55:569–580

    Article  PubMed  CAS  Google Scholar 

  • Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 274:361–372

    PubMed  CAS  Google Scholar 

  • Ward SJ, Portoghese PS, Takemori AE (1982) Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine. J Pharmacol Exp Ther 220(3):494–498

    PubMed  CAS  Google Scholar 

  • Wesnes K, Warburton DM (1983) Effects of smoking on rapid information processing performance. Neuropsychobiology 9:223–229

    PubMed  CAS  Google Scholar 

  • Winger G, Woods JH (1996) Effects of buprenorphine on behaviour maintained by heroin and alfentanil in rhesus monkeys. Behav Pharmacol 7(2):155–159

    Article  PubMed  CAS  Google Scholar 

  • Wolfram S (2003) The Mathematica book, 2nd edn. Wolfram Media/Cambridge University Press, Champaign, IL

    Google Scholar 

  • Zacny JP, Conley K, Galinkin J (1997) Comparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers. J Pharmacol Exp Ther 282:1187–1197

    PubMed  CAS  Google Scholar 

  • Zacny JP, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C (2003) College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend 69:215–232

    Article  PubMed  Google Scholar 

  • Zernig G, Issaevitch T (1995) Software for the calculation of agonist efficacy and apparent in vivo affinity by simultaneous analysis of several dose–response curves. Wolfram Research, Champaign, IL

    Google Scholar 

  • Zernig G, Butelman ER, Lewis JW, Walker EA, Woods JH (1994) In vivo determination of mu opioid receptor turnover in rhesus monkeys after irreversible blockade with clocinnamox. J Pharmacol Exp Ther 269:57–65

    PubMed  CAS  Google Scholar 

  • Zernig G, Issaevitch T, Woods JH (1996) Calculation of agonist efficacy, apparent affinity, and receptor population changes after administration of insurmountable antagonists: comparison of different analytical approaches. J Pharmacol Toxicol Methods 35:223–237

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The assistance of Michael R. Donovan, Mabel Torres, and Drs. Evaristo Akerele, Adam Bisaga, and Maria Sullivan is gratefully acknowledged. This research was supported by grant DA09236.

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Authors and Affiliations

  1. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry , College of Physicians and Surgeons of Columbia University, 1051 Riverside Dr., Unit 120, New York, NY, 10032, USA

    Sandra D. Comer & Eric D. Collins

  2. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    Ellen A. Walker

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  1. Sandra D. Comer
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  2. Ellen A. Walker
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  3. Eric D. Collins
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Correspondence to Sandra D. Comer.

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Comer, S.D., Walker, E.A. & Collins, E.D. Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology 181, 664–675 (2005). https://doi.org/10.1007/s00213-005-0023-6

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