Abstract
The pharmacology of buprenorphine is unique because of its partial agonist profile at the mu-opioid receptor (ie, high affinity, low intrinsic activity and slow dissociation). This unique profile results in greater safety, less physical dependence, and greater flexibility in dose scheduling. Buprenorphine has been investigated in combination with the opioid antagonist, naloxone, with the goal of decreasing abuse, misuse, and diversion. When combined with naloxone in a sublingual tablet, buprenorphine has been shown to be effective 1) in retaining patients in treatment, 2) in reducing opioid use and craving, and 3) when dosed less-than-daily. The pharmacologic effects of buprenorphine are not altered by the addition of naloxone when administered to the population in an appropriate combination ratio. However, if taken intravenously by individuals dependent on short-or long-acting opioids a precipitated withdrawal syndrome is observed, which should reduce its abuse potential. This review discusses the rationale for development and evidence supporting the use of a buprenorphine/naloxone combination product. The buprenorphine/naloxone combination product should be considered for use in primary care office-based settings as a safe and effective treatment that is likely to increase the availability of agonist treatment for opioid dependence.
Similar content being viewed by others
References and Recommended Reading
Office of National Drug Control Policy: Policy Paper Opioid Agonist Treatment, March 1999. Washington, DC: Office of National Drug Control Policy; 1999.
Office of National Drug Control Policy: The National Drug Control Strategy, 2000. Washington, DC: Office of National Drug Control Policy; 2000.
Chiang CN, Hawks R: Development of a buprenorphinenaloxone combination drug for the treatment of drug addiction. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office.NIDA Research Monograph No. 141. 1993, 458.
O’Connor PG, Oliveto AH, Shi JM, et al.: A pilot study of primary-care-based buprenorphine maintenance for heroin dependence. Am J Drug Alcohol Abuse 1996, 22:523–531.
O’Connor PG, Oliveto AH, Shi JM, et al.: A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med 1998, 105:100–105. In a primary care setting retention was higher and continuous opioid abstinence and opioid use were lower compared with a traditional drug treatment setting. This study demonstrated that buprenorphine treatment is effective in a primary care setting.
Johnson RE, Jaffe JH, Fudala PJ: A controlled trial of buprenorphine treatment for opioid dependence. JAMA 1992, 267:2750–2755.
Strain EC, Stitzer ML, Liebson IA, Bigelow GE: Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry 1994, 151:1025–1030.
Kosten TR, Schottenfeld R, Ziedonis D, Falcioni J: Buprenorphine versus methadone maintenance for opiate dependence. J Nerv Ment Dis 1993, 181:358–364.
Ling W, Wesson DR, Charuvastra C, Klett CJ: A controlled trial comparing buprenorphine and methadone maintenance in opiate dependence. Arch Gen Psychiatry 1996, 54:401–407.
Ling W, Charuvastra C, Collins JC, et al.: Buprenorphine maintenance treatment for opiate dependence: a multicenter, randomized clinical trial. Addiction 1998, 93:475–486.
Ajir K, Chiang N, Ling W: Pharmacokinetics of liquid vs tablets. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office. NIDA Research Monograph No. 180, 1999, 160.
Mendelson J, Upton RA, Everhart T, et al.: Bioavailability of sublingual buprenorphine. J Clin Pharmacol 1997a, 37:31–37.
Nath RP, Upton RA, Everhart T, et al.: Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 1999, 39:619–623.
Schuh KJ, Johanson C.E: Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend 1999, 56:55–60.
Weinberg DS, Inturrisi CE, Reidenberg B, et al.: Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther 1988, 44:335–342.
Jasinski DR, Johnson RE, Henningfield JE: Abuse liability assessment in human subjects. Trends Pharmacol Sci 1984, 5:196–200.
Umbricht A, Huestis MA, Cone EJ, Preston KL: Safety of buprenorphine: ceiling for cardio-respiratory effects at high IV doses. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office. NIDA Research Monograph No. 179. 1998, 225.
Walsh SL, Preston KL, Stitzer ML, et al.: Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 1994, 55:569–580.
Walsh SL, Preston KL, Bigelow GE, Stitzer ML: Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 1995, 274:361–372.
Pickworth WB, Johnson RE, Holicky BA, Cone EJ: Subjective and physiologic effects of intravenous buprenorphine in humans. Clin Pharmacol Ther 1993, 53:570–576.
Jasinski DR, Pevnick JS, Griffith JD: Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry 1978, 35:501–516.
Strang J: Abuse of buprenorphine. Lancet 1985, 725.
O’Connor JJ, Moloney E, Travers R, Campbell A: Buprenorphine abuse among opiate addicts. Br J Addict 1988, 83:1085–1087.
Gray RF, Ferry A, Jauhar P: Emergence of buprenorphine dependence. Br J Addict 1989, 84:1373–1374.
Lavelle TL, Hammersley R, Forsyth A: The use of buprenorphine and temazepam by drug injectors. J Addic Dis 1991, 10:5–14.
Singh RA, Mattoo SK, Malhotra A, Varma VK: Cases of buprenorphine abuse in India. Acta Psychiatr Scand 1992, 86:46–48.
Robinson GM, Dukes PD, Robinson BJ, et al.: The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Depend 1993, 33:81–86.
Nigam AK, Srivastava RP, Saxena S, et al.: Naloxone-induced withdrawal in patients with buprenorphine dependence. Addiction 1994, 89:317–320.
Harper I: Temgesic abuse. N Z Med J 1983, 96:777.
Nutt JG, Jasinski DR: Methadone-naloxone mixtures for use in methadone maintenance programs. Clin Pharmacol Ther 1974, 15:156–166.
Loimer N, Presslich O, Grunberger J, Linzmayer L: Combined naloxone/methadone preparations for opiate substitution therapy. J Subst Abuse Treat 1991, 8:157–160.
Poklis A: Decline in abuse of pentazocine/tripelennamine (T’s and Blues) associated with the addition of naloxone to pentazocine tablets. Drug Alcohol Depend 1984, 2:135–140.
Ghodse AH: Analysis of epidemiological data on agonistantagonist analgesics. Drug Alcohol Depend 1987, 20:375–383.
Baum C, Hsu JP, Nelson RC: The impact of the addition of naloxone on the use and abuse of pentazocine. Public Health Rep 1987, 102:426–429.
Keup W: Abuse patterns in alcohol, therapeutic drug and non-therapeutic drug dependence. In Early warning system data for the Federal Republic of Germany 1976–1990. Freiburg im Breisgau: Lambertus 1993, 88.
O’Brien CP, Greenstein R, Ternes J, Woody GE: Clinical pharmacology of narcotic antagonists. Ann N Y Acad Sci 1978, 311:232–239.
Hardman JG, Limbird LE, Molinoff PB, et al.: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th edn. New York: McGraw-Hill, Health Professions Division; 1996, 550.
Preston KL, Bigelow GE, Liebson IA: Effects of sublingually given naloxone in opioid-dependent human volunteers. Drug Alcohol Depend 1990, 25:27–34.
Jasinski DR, Fudala PJ, Johnson RE: Sublingual versus subcutaneous buprenorphine in opiate abusers. Clin Pharmacol Ther 1989, 45:513–519.
Rolly G, Poelaert J, Mungroop H, Paelinck H: A combination of buprenorphine and naloxone compared with buprenorphine administered intramuscularly in postoperative patients. J Int Med Res 1986, 14:148–152.
Vanacker B, Vandermeersch E, Tomassen J: Comparison of intramuscular buprenorphine and a buprenorphine/ naloxone combination in the treatment of post operative pain. Curr Med Res Opin 1986, 10:139–144.
Weinhold LL, Preston KL, Farre M, et al.: Buprenorphine alone and in combination with naloxone in non-dependent humans. Drug Alcohol Depend 1992, 30:263–274.
Strain EC, Stoller KB, Walsh SL, Bigelow GE: Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology 2000, 148:374–383. The authors concluded that both buprenorphine and buprenorphine/ naloxone have the potential for abuse comparable with 4 mg of hydromorphone in nondependent opioid abusers and, therefore, could be expected to have abuse potential in opioid naïve individuals.
Preston KL, Bigelow GE, Liebson IA: Buprenorphine and naloxone alone and in combination in opioid-dependent humans. Psychopharmacology 1988, 94:484–490.
Mendelson J, Jones RT, Welm S, et al.: Buprenorphine and naloxone interactions in methadone maintenance patients. Biol Psychiatry 1997b, 41:1095–1101.
Mendelson J, Jones RT, Fernandez I, et al.: Buprenorphine and naloxone interactions in opiate-dependent volunteers. Clin Pharmacol Ther 1996, 60:105–114.
Fudala PJ, Yu E, Macfadden W, et al.: Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts. Drug Alcohol Depend 1998a, 50:1–8. This study compares the buprenorphine/naloxone combination in a ratios of 4:1 and provides additional evidence (see Mendelson et al. [48]) that the 4:1 ratio of buprenorphine to naloxone is the most appropriate for producing both therapeutic and adverse effects.
Mendelson J, Jones RT, Welm S, et al.: Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers. Psychopharmacology 1999, 141:37–46. This study compares the buprenorphine/naloxone combination in ratios of 2:1, 4:1, and 8:1. This study establishes the 4:1 ratio of buprenorphine to naloxone as the most appropriate for producing both therapeutic and adverse effects.
Stoller KB, Strain EC, Bigelow GE: Buprenorphine/naloxone combination tablet: effects in opiate-dependent volunteers. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office. NIDA Research Monograph No. 179, 1998, 230.
Fudala PJ, Bridge TP, Herbert S, et al.: Buprenorphine/Naloxone Collaborative Study Group. A multisite efficacy evaluation of a buprenorphine/naloxone product for opiate dependence treatment. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office. NIDA Research Monograph No. 179. 1998b, 105. This study represents the one single large-scale controlled outpatient clinical trial required by the Food and Drug Administration for the approval of the buprenorphine plus naloxone combination tablet.
L, Kamien JB, Branstetter SA, Mikulich SK: A controlled comparison of the buprenorphine-naloxone tablet and methadone for opioid maintenance treatment: interim results. In Problems of Drug Dependence. Edited by Harris LS. Washington, DC: Government Printing Office. NIDA Research Monograph No. 180. 1999, 161. This study represents the only large-scale controlled outpatient clinical trial comparing the buprenorphine plus naloxone c ombination tablet to methadone.
Amass L, Kamien JB, Mikulich SK: Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet. Drug Alcohol Depend 2000, 58:143–152.
Amass L, Bickel WK, Crean JP, et al.: Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans. Psychopharmacology 1998, 136:217–225. Results from this study with the buprenorphine plus naloxone combination tablet were similar to those from studies with buprenorphine alone and showed that multiples of the daily dose should be administered when less than daily dosing is used.
Bickel WK, Amass L, Crean JP, Badger GJ: Buprenorphine dosing every 1, 2, or 3 days in opioid-dependent patients. Psychopharmacology 1999, 146:111–118.
Fudala PJ, Jaffe JH, Dax EM, Johnson RE: Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal. Clin Pharmacol Ther 1990, 47:525–534.
Johnson RE, Eissenberg T, Stitzer ML, et al.: Buprenorphine treatment of opioid dependence: clinical trial of daily versus alternate-day dosing. Drug Alcohol Depend 1995, 40:27–35.
Perez de los Cobos J, Martin S, Etcheberrigaray A, et al.: A controlled trial of daily versus thrice-weekly buprenorphine administration for the treatment of opioid dependence. Drug Alcohol Depend. 2000, 59:223–233.
Lintzeris N: Guidelines for transferring from methadone to buprenorphine. In Schering-Plough Pharmaceutical and Reckitt Benckiser, Wells Healthcare Communications (ed.) Buprenorphine Highlights - Europad 2000. Highlights from the conference "Heroin Addiction in Europe"; p 4.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Johnson, R.E., McCagh, J.C. Buprenorphine and Naloxone for Heroin Dependence. Curr Psychiatry Rep 2, 519–526 (2000). https://doi.org/10.1007/s11920-000-0012-8
Issue Date:
DOI: https://doi.org/10.1007/s11920-000-0012-8