Review Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4:1 ratio for treatment? John Mendelson *, Reese T. Jones Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of California, 401 Parnassus Avenue, San Francisco, CA 94143-0984, USA Received 19 December 2002; accepted 4 February 2003 Abstract Although only a partial m-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. # 2003 Published by Elsevier Science Ireland Ltd. Keywords: Opiate; Dependence; Treatment; Buprenorphine; Naloxone 1. Introduction Initial reports suggested that buprenorphine would have a low abuse potential (Jasinski et al., 1978; Jasinski, 1979). However, like all potent m-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 transmis- sion 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 combina- tion with naloxone, for the treatment of opiate depen- dence 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 com- bination 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. 2. Requirements for a buprenorphine and naloxone combination Buprenorphine and naloxone dose combinations should diminish the parenteral abuse liability of bupre- norphine in opiate-dependent individuals by precipitat- ing 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 * Corresponding author. Tel.:  /1-415-476-7472; fax:  /1-415-476- 7690. E-mail address: jemmd@itsa.ucsf.edu (J. Mendelson). Drug and Alcohol Dependence 70 (2003) S29 /S37 www.elsevier.com/locate/drugalcdep 03765-8716/03/$ - see front matter # 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0376-8716(03)00057-7