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