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 buprenorphine's 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 buprenorphine's 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 buprenorphine's 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 buprenorphine's 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 buprenorphine's 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.
Mello
N K
NK
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts 02178.
Lukas
S E
SE
Mendelson
J H
JH
Drieze
J
J
D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D012055:Reinforcement Schedule; D012646:Self Administration / Q000523:psychology
D004338:Drug Combinations; D002047:Buprenorphine; D009271:Naltrexone; D003042:Cocaine