The discriminative stimulus effects of naloxone and naltrexone in morphine-treated rhesus monkeys: comparison of oral and subcutaneous administration

Rationale: Opioid antagonists are used to reverse the toxic effects of opio ids, to diagnose opioid dependence and to treat opioid and other (alcohol) drug abuse. Objectives: This study compared the discriminative stimulus eff ects of two opioid antagonists (naloxone and naltrexone), after parenteral and oral administration. Methods: The discriminative stimulus effects of na loxone and naltrexone were evaluated every 15 min over a 2-h period in four morphine-treated (3.2 mg/kg per day) rhesus monkeys discriminating between subcutaneous (SC) injections of naltrexone (0.01 or 0.032 mg/kg) and salin e, while responding under a fixed-ratio 5 schedule of stimulus shock termin ation. Results: Within 15 min of SC administration, naloxone and naltrexone produced greater than 90% drug-appropriate responding at doses of 0.032 an d 0.01 mg/kg, respectively. The largest dose of naloxone (3.2 mg/kg) admini stered orally produced 82% drug-appropriate responding within 90 min; the s ame dose of naltrexone administered orally produced greater than 90% drug-a ppropriate responding within 30 min. Although both drugs were at least 100- fold more potent when administered SC, as compared to orally, there was lit tle difference (3-fold) between the potency of naloxone and naltrexone by e ither route. Conclusions: These results fail to support the view that nalox one has reduced bioavailability after oral administration, as compared to n altrexone, or that its pharmacokinetic profile is particularly advantageous for some therapeutic settings (e.g. Talwin Nx).