Abstract
Rationale
Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence.
Objectives
The present study investigated the effects of buprenorphine alone and in combination with naloxone administered intramuscularly and sublingually to non-dependent opioid abusers.
Methods
In a within-subject crossover design, non-dependent opioid-experienced volunteers (N = 8) were administered acute doses of buprenorphine (4, 8, and 16 mg) and buprenorphine/naloxone (4/1, 8/2, and 16/4 mg) via both intramuscular and sublingual routes, intramuscular hydromorphone (2 and 4 mg as an opioid agonist control), and placebo, for a total of 15 drug conditions. Laboratory sessions were conducted twice per week using a double-blind, double-dummy design.
Results
Buprenorphine and buprenorphine/naloxone engendered effects similar to hydromorphone. Intramuscular administration produced a greater magnitude of effects compared to the sublingual route at the intermediate dose of buprenorphine and at both the low and high doses of the buprenorphine/naloxone combination. The addition of naloxone did not significantly alter the effects of buprenorphine.
Conclusions
These results suggest that buprenorphine and buprenorphine/naloxone have similar abuse potential in non-dependent opioid abusers, and that the addition of naloxone at these doses and in this dose ratio confers no evident advantage for decreasing the abuse potential of intramuscular or sublingual buprenorphine in this population.
Similar content being viewed by others
References
Alho H, Sinclair D, Vuori E, Holopainen A (2007) Abuse liability of buprenorphine–naloxone tablets in untreated IV drug users. Drug Alcohol Depend 88:75–78
Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA (1981) Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol 12:117–122
Chiang CN, Hawks RL (2003) Pharmacokinetics of the combination tablet of buprenorphine and naloxone. Drug Alcohol Depend 70:S39–S47
Comer SD, Collins ED (2002) Self-administration of intravenous buprenorphine and the buprenorphine/naloxone combination by recently detoxified heroin abusers. J Pharmacol Exp Ther 303:695–703
Cowan A, Lewis JW, MacFarlane IR (1977) Agonist and antagonist properties of buprenorphine: a new antinociceptive agent. Br J Pharmacol 60:537–545
Dum JE, Herz A (1981) In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonist and antagonistic actions. Br J Pharmacol 74:627–633
Fraser HG, van Horn GD, Marin 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
Fudala PJ, Yu E, Macfadden W, Boardman C, Chiang CN (1998) Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts. Drug Alcohol Depend 50:1–8
Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J (2000) Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend 61:85–94
Jasinski DR (1977) Assessment of the abuse potentiality of morphinelike drugs (methods used in man). In: Martin WR (ed) Drug addiction I. Springer, Berlin, pp 197–258
Jasinski DR, Pevnick JS, Griffith JD (1978) Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry 35:501–516
Jasinski DR, Fudala PJ, Johnson RE (1989) Sublingual versus subcutaneous buprenorphine in opiate abusers. Clin Pharmacol Ther 45:513–519
Johnson RE, Jaffe JH, Fudala PJ (1992) A controlled trial of buprenorphine treatment for opioid dependence. Arch Gen Psychiatry 35:501–516
Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343:1290–1297
Johnson RE, Strain EC, Amass L (2003) Buprenorphine: how to use it right. Drug Alcohol Depend 70:S59–S77
Jones HE, Bigelow GE, Preston KL (1999) Assessment of opioid partial agonist activity with the three-choice hydromorphone dose-discrimination procedure. J Pharmacol Exp Ther 289:1350–1361
Lewis JW (1985) Buprenorphine. Drug Alcohol Depend 14:363–372
Ling W, Charuvastra C, Collins JF, Batki S, Brown LS Jr, Kintaudi P, Wesson DR, McNicholas L, Tusel DJ, Malkerneker U, Renner JA Jr, Santos E, Casandonte P, Fye C, Stine S, Wang RI, Segal D (1998) Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 93:475–486
Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll FI, Maidment NT, Evans CJ (2003) Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci 23:10331–10337
Mendelson J, Jones RT (2003) Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment? Drug Alcohol Depend 70:S29–S37
Mendelson J, Jones RT, Fernandez I, Welm S, Melby AK, Baggott MJ (1996) Buprenorphine and naloxone interactions in opiate-dependent volunteers. Clin Pharmacol Ther 60:105–114
Mendelson J, Jones RT, Welm S, Brown J, Batki SL (1997a) Buprenorphine and naloxone interactions in methadone maintenance patients. Biol Pshcyiatry 41:1095–1101
Mendelson J, Upton RA, Everhart ET, Jacob P, Jones RT (1997b) Bioavailability of sublingual buprenorphine. J Clin Pharmacol 37:31–37
Mendelson J, Jones RT, Welm S, Baggott M, Fernandez I, Melby AK, Nath RP (1999) Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers. Psychopharmacology 141:37–46
Preston KL, Bigelow GE (2000) Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 295:114–124
Preston KL, Bigelow GE, Liebson IA (1988) Buprenorphine and naloxone alone and in combination in opioid-dependent human volunteers. Psychopharmacology 94:484–490
Preston KL, Bigelow GE, Liebson IA (1990) Effects of sublingually given naloxone in opioid-dependent human volunteers. Drug Alcohol Depend 25:27–34
Rosado J, Walsh SL, Bigelow GE, Strain EC (2007) Sublingual buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of daily methadone. Drug Alcohol Depend 90:261–269
Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR (1997) Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psychiatry 54:713–720
Stoller KB, Bigelow GE, Walsh SL, Strain EC (2001) Effects of buprenorphine/naloxone in opioid dependent humans. Psychopharmacology 154:230–242
Strain EC, Preston KL, Liebson IA, Bigelow GE (1993) Precipitated withdrawal by pentazocine in methadone-maintained volunteers. J Pharmacol Exp Ther 267:624–634
Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1994) Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry 151(7):1025–1030
Strain EC, Stoller K, Walsh SL, Bigelow GE (2000) Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology 148:347–383
Strain EC, Moody DE, Stoller KB, Walsh SL, Bigelow GE (2004) Relative bioavailability of different buprenorphine formulations under chronic dosing conditions. Drug Alcohol Depend 74:37–43
Walsh SL, Strain EC, Abreu ME, Bigelow GE (2001) Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology 157:151–162
Weinberg DS, Inturrisi CE, Reidenberg B, Moulin DE, Nip TJ, Wallenstein S, Houde RW, Foley KM (1988) Sublingual absorption of select opioid analgesics. Clin Pharmacol Ther 44:335–342
Weinhold LL, Preston KL, Farre M, Liebson IA, Bigelow GE (1992) Buprenorphine alone and in combination with naloxone in non-dependent humans. Drug Alcohol Depend 30:263–274
Acknowledgements
This study is supported by R01 DA08045, K24 DA023186 and T32 DA07209. The authors thank the medical, nursing, and pharmacy staff for work on the protocol, as well as the research assistants for the aid in preparation of this manuscript.
Disclosure
Drugs used in the study described in this article are manufactured by Reckitt Benckiser Pharmaceuticals, Inc. Dr. Strain is a consultant to and a paid member of the Scientific Advisory Board of Reckitt Benckiser Pharmaceuticals. The terms of this arrangement are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Duke, A.N., Correia, C.J., Walsh, S.L. et al. Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers. Psychopharmacology 211, 303–312 (2010). https://doi.org/10.1007/s00213-010-1898-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-010-1898-4