Medications for the treatment of substance abuse may be developed for a variety of purposes (e.g., ameliorate toxicity, treat overdoses) but a primary goal is to attenuate the subjective, behavioral, or physiological effects of the drug of abuse. Buprenorphine is a high affinity, mu opioid partial agonist, with kappa antagonist action (Cowan et al. 1977;Heel et al. 1979;Lewis et al. 1983). This compound is being evaluated as an alternative to methadone maintenance and detoxification in the treatment of opioid dependence (Bickel and Amass 1995). Buprenorphine's mu receptor ( OR) agonist actions could reduce opiate craving and prevent withdrawal, thus improving compliance with treatment compared to conventional opiate receptor antagonists (e.g., naltrexone). At the same time, its partial efficacy and high affinity at OR's provide long lasting functional antagonism, making it an effective means of blocking the effects of abused opiates. This unique combination of NO . 3 Buprenorphine and Mu Receptor 327 pharmacological properties confers potential advantages, including enhanced safety over existing medications for treating opioid abuse (Lange et al. 1990).Buprenorphine sublingual (SL) liquid has been shown to decrease heroin self-administration in singledose human laboratory studies (Mello and Mendelson 1980;Mello et al. 1981Mello et al. , 1982; the dose-dependency of its effects on reinforcement has been less well characterized. In a clinical study, Johnson et al. (1995) compared the short-term efficacy of placebo, 2 and 8 mg/day buprenorphine in a parallel group, randomized design during a two-week initial maintenance period. In this study, active doses were more effective than placebo in decreasing heroin use, however, there were no differences in therapeutic efficacy between 2 and 8 mg. Schottenfeld et al. (1993) used a within-subject study design in which heroin-dependent outpatients received ascending/descending maintenance doses of buprenorphine ranging from 2 to 16 mg/day. Sixteen milligrams produced significant decreases in opioid-positive urine samples, relative to lower doses. Thus, available data suggest that, relative to placebo, buprenorphine doses ranging from 2 to 8 mg are equally capable of decreasing opioid use, whereas doses of 16 mg have greater efficacy. This may suggest that the effect of buprenorphine in decreasing opiate self-administration may not be dose-dependent, at least in lower dose ranges. In fact, in a recently completed laboratory study in heroindependent volunteers, maintenance doses of 2, 4, and 8 mg buprenorphine showed equal efficacy in decreasing the reinforcing effects of hydromorphone (Greenwald et al. 1999).On the other hand, laboratory studies have demonstrated that SL buprenorphine blocks many of the subjective effects of hydromorphone, a full mu opioid agonist, in a dose-dependent manner. For instance, Bickel et al. (1988) showed that maintenance on buprenorphine (2, 4, 8, 16 mg) produced dose-related decreases in subjective effects to cumulative hydromorphone (0, 6,...
