John Drieze

Naltrexone–Buprenorphine Interactions: Effects on Cocaine Self-Administration

An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphines agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphines effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphines suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphines reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphines effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.

The Effects of Nalbuphine and Butorphanol Treatment on Cocaine and Food Self-Administration by Rhesus Monkeys

This study was designed to determine whether opioid mixed agonist-antagonist analgesics other than buprenorphine also selectively reduce cocaine self-administration by rhesus monkeys. The effects of daily treatment with nalbuphine (0.1 to 3 mg/kg/day) or (0.254 to 7.62 µmol/kg/day), butorphanol (0.01 to 0.3 mg/kg/day) or (0.0209 to 0.628 µmol/kg/day), and saline on cocaine and food self-administration were each studied for 40 sessions over 10 consecutive days. Cocaine (0.05 or 0.10 mg/kg/inj) and food (1-gm banana pellets) self-administration were maintained on a fixed ratio 4 (variable ratio 16:S) schedule of reinforcement. Both nalbuphine and butorphanol reduced cocaine self-administration (p < 0.0001) but this effect was not selective since food self-administration also decreased in a dose-dependent manner (p < 0.0001). Nalbuphine administration (1 to 3 mg/kg/day) decreased cocaine injections to 40% to 60% below baseline (p < 0.01) and food pellets 30% to 68% below baseline (p < 0.01). Lower doses of nalbuphine (0.10 and 0.30 mg/kg) did not change cocaine- or food-maintained responding significantly. All doses of butorphanol (0.01 to 0.3 mg/kg/day) reduced cocaine injections to 16% to 58% below baseline (p < 0.01). Food self-administration decreased to 21% to 70% below baseline (p < 0.01) at butorphanol doses of 0.03 to 0.3 mg/kg/day). These data suggest that these opioid mixed agonist-antagonist analgesics may not be useful as pharmacotherapies for the treatment of cocaine abuse.

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphines effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.