Review
Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment?

https://doi.org/10.1016/S0376-8716(03)00057-7Get rights and content

Abstract

Although only a partial μ-opiate agonist, buprenorphine can be abused and diverted from medical therapy to the illicit drug market. A combination of buprenorphine and naloxone for sublingual administration may discourage diversion and abuse by precipitating opiate withdrawal when taken parenterally. Because opiate-abusing populations are not homogeneous and have varying levels of opiate dependence, the efficacy of buprenorphine and naloxone in precipitating opiate withdrawal or in attenuating the pleasurable effects of buprenorphine may vary. This chapter describes the effects of sublingual and parenteral buprenorphine and naloxone combinations in several populations of opiate-dependent people. We conclude that buprenorphine and naloxone combinations should not diminish the efficacy of sublingual buprenorphine, but should have lower abuse liability than buprenorphine alone.

Introduction

Initial reports suggested that buprenorphine would have a low abuse potential (Jasinski et al., 1978, Jasinski, 1979). However, like all potent μ-opiates, parenteral abuse and illicit diversion of buprenorphine has been reported worldwide (O'Connor et al., 1988, Singh et al., 1992, Robinson et al., 1993). The majority of the reported abuse occurs in heroin addicts who intravenously administer extracts of crushed tablets (Segui et al., 1991, Lavelle et al., 1991, San et al., 1993, Nigam et al., 1994). Injection drug abusers are at risk for serious bacterial and viral diseases, including HIV. Strategies which diminish the parenteral abuse liability of treatment medications will decrease transmission of infections between injection drug abusers; hence, the development of a formulation of buprenorphine less abusable by injection.

The efficacy of buprenorphine, alone or in combination with naloxone, for the treatment of opiate dependence is described in other chapters. Here we review the rationale for selecting a 4:1 ratio of buprenorphine to naloxone for marketed formulation and how the combination was assessed for safety and efficacy. We discuss the effects of both buprenorphine and naloxone in different populations of opiate abusers and nonabusers and use these findings to estimate abuse liability.

Section snippets

Requirements for a buprenorphine and naloxone combination

Buprenorphine and naloxone dose combinations should diminish the parenteral abuse liability of buprenorphine in opiate-dependent individuals by precipitating opiate withdrawal when taken parenterally but not sublingually. Naloxone in solution has a relatively low sublingual absorption of 8–10% (Weinberg et al., 1988, Preston et al., 1990, Harris et al., 2000), whereas buprenorphine in solution is better absorbed (≈30–50%) and has significant pharmacologic activity when given sublingually (Olley

Efficacy of buprenorphine and naloxone in precipitating opiate withdrawal

Some buprenorphine likely will be diverted from therapeutic to illicit use. Effective deterrence will depend to some extent on the magnitude and likelihood of adverse events. Because people already dependent on opiates are most likely to abuse an opiate drug, several studies have evaluated the efficacy of buprenorphine and naloxone combinations in precipitating opiate withdrawal. Complicating matters, opiate-abusing and dependent populations are not homogeneous. The varying levels of tolerance

Buprenorphine and naloxone effects in opiate-dependent people

Quantification of the degree of opiate dependence can be difficult. No agreed upon definition exists distinguishing low, moderate, and high levels of opiate dependence. Substitution trials have used daily doses as large as 240 mg morphine (Fraser and Isbell, 1960) given in equal doses (60 mg s.c. doses every 6 h) to suppress withdrawal in highly dependent subjects. More recent substitution and challenge studies of partial agonists of morphine were conducted with volunteers dependent on 60 mg

Comparisons of three different buprenorphine and naloxone dose ratios

Empirical evaluation of a range of dose combinations guided optimal formulation of a s.l. medication with low abuse liability for the treatment of opiate dependence. We tested the effects of three buprenorphine and naloxone combinations in opiate-dependent subjects where controlled doses of morphine were substituted for illicit heroin (Mendelson et al., 1999). The primary goals of this study were to determine the dose range over which i.v. naloxone, in combination with i.v. buprenorphine, would

What about buprenorphine and naloxone in less dependent populations?

A substantial percentage of individuals abusing heroin or other opiates do not experience precipitated withdrawal after naloxone challenge (Kanof et al., 1991). Combination formulations might not be aversive in these individuals because naloxone-precipitated withdrawal would not occur. Therefore, in nondependent abusers an important additional feature of a combination would be attenuation of pleasurable and reinforcing effects of buprenorphine if the combination dose is taken parenterally. In

Buprenorphine and naloxone effects in buprenorphine-stabilized opiate addicts

Would the combination dose present a problem for patients taking buprenorphine regularly? In opiate-dependent subjects stabilized for 7 days on 8 mg/day of s.l. buprenorphine solution (Harris et al., 2000), s.l. 8 mg buprenorphine with 4 or 8 mg naloxone (2:1 and 1:1 ratios) did not precipitate opiate withdrawal. Buprenorphine abuse in patients treated with s.l. buprenorphine may also be limited by the partial agonist properties of buprenorphine with ceiling effects at higher doses (Walsh et

Safety of buprenorphine and naloxone combinations

Buprenorphine and naloxone combinations appeared safe in our opiate-dependent subjects. Naloxone produced an expected dose-dependent sympathetic activation with statistically significant (but clinically and functionally insignificant) increases in heart rate, blood pressure, and respiratory rate. No subject developed unstable cardiovascular changes despite substantial subjective withdrawal. Therefore, although unpleasant, combination formulations are probably safe in otherwise healthy

Effects of buprenorphine on opiate withdrawal

Because buprenorphine is a partial μ-agonist and could displace full μ-agonists from receptor sites, in theory μ-opiate-dependent people could experience precipitated withdrawal after buprenorphine. Precipitated withdrawal was evident in morphine-dependent laboratory animals (Martin et al., 1976) and in methadone-maintained volunteers challenged with i.m. injections of 1 and 2 mg buprenorphine (but not 0.5, 4 or 8 mg) 20 h after the last methadone dose (Strain et al., 1995). In our studies,

Conclusions

The abuse liability of buprenorphine in μ-opiate-dependent individuals can safely and effectively be diminished by the use of buprenorphine and naloxone combination formulations. Intravenous administration of buprenorphine and naloxone combinations containing more than 0.5 mg naloxone in a 2:1 or 4:1 ratio of buprenorphine to naloxone reliably precipitates opiate withdrawal. The combination dose is judged to have low illicit street value by parenteral opiate abusers. In addition to

Acknowledgements

The authors thank Nora Chiang Ph.D., our project officer at the NIDA Medication Development Division, for constructive advice regarding all of our buprenorphine experiments and the staff of the Drug Dependence Research Center at University of California, San Francisco. Supported by US Public Health Service grants DA12393 and DA00053 and contract No. N01DA–4–8306 from the National Institute on Drug Abuse, National Institutes of Health, and the General Clinical Research Center at University of

References (54)

  • K.L. Preston et al.

    Effects of sublingually given naloxone in opioid-dependent human volunteers

    Drug Alcohol Depend.

    (1990)
  • G.M. Robinson et al.

    The misuse of buprenorphine and a buprenorphine–naloxone combination in Wellington, New Zealand

    Drug Alcohol Depend.

    (1993)
  • L.L. Weinhold et al.

    Buprenorphine alone and in combination with naloxone in nondependent humans

    Drug Alcohol Depend.

    (1992)
  • S.D. Comer et al.

    Self-administration of intravenous buprenorphine and the buprenorphine/naloxone combination by recently detoxified heroin abusers

    J. Pharmacol. Exp. Ther.

    (2002)
  • J.L. Cracowski et al.

    Myocardial infarction associated with buprenorphine (Ltr)

    Ann. Inter. Med.

    (1999)
  • H. Eder et al.

    Comparison of buprenorphine and methadone maintenance in opiate addicts

    Eur. Addict. Res.

    (1998)
  • T. Eissenberg et al.

    Buprenorphine's physical dependence potential: antagonist-precipitated withdrawal in humans

    J. Pharmacol. Exp. Ther.

    (1996)
  • G. Fischer et al.

    Treatment of opioid-dependent pregnant women with buprenorphine

    Addiction

    (2000)
  • H.F. Fraser et al.

    Human pharmacology and addiction liabilities of phenazocine and levophenacylmorphan

    Bull. Narcot.

    (1960)
  • A.G. Gilman et al.

    Goodman and Gilman's The Pharmacological Basis of Therapeutics

    (1990)
  • D.R. Jasinski

    Assessment of the abuse potentiality of morphine-like drugs (Methods used in man)

  • D.R. Jasinski

    Human pharmacology of narcotic antagonists

    Br. J. Clin. Pharmacol.

    (1979)
  • D.R. Jasinski et al.

    Sublingual versus subcutaneous buprenorphine in opiate abusers

    Clin. Pharmacol. Ther.

    (1989)
  • D.R. Jasinski et al.

    Human pharmacology and abuse potential of the analgesic buprenorphine

    Arch. Gen. Psychiatry

    (1978)
  • R.E. Johnson et al.

    A controlled trial of buprenorphine treatment for opioid addiction

    J. Am. Med. Assn.

    (1992)
  • T.L. Lavelle et al.

    The use of buprenorphine and temazepam by drug injectors

    J. Addict. Dis.

    (1991)
  • W. Ling et al.

    Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial

    Addiction

    (1998)
  • Cited by (0)

    View full text