Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers
Rationale: Conducting complete dose-response evaluations of multiple drugs in a single within-subjects experiment is very time-consuming when a complete session is required for evaluation of each dose. Objective: To evaluate a within-session cumulative-dosing procedure as a potentially efficient method for conducting dose-response evaluations of mixed-action opioids. Methods: Fifteen healthy volunteers received intravenous injections of saline, butorphanol, nalbuphine, pentazocine, or morphine in a randomized, double-blind, crossover design. Subjects received one injection per hour for the first 4 h, and a 3-h recovery period followed. Saline was injected first, then saline or increasing doses of each drug (except pentazocine, see below) were administered every hour for the next 3 h. The absolute doses per injection were morphine and nalbuphine 2.5, 5, and 10 mg/70 kg, butorphanol 0.5, 1, and 2 mg/70 kg, and pentazocine 7.5, 15, and 0 mg/70 kg. (The highest dose of pentazocine was omitted because of the risk of dysphoria and psychotomimesis.) These injections resulted in cumulative doses of morphine or nalbuphine 2.5, 7.5, and 17.5 mg/70 kg, butorphanol 0.5, 1.5, and 3.5 mg/70 kg, and pentazocine 7.5 and 22.5 mg/70 kg. Mood, psychomotor performance, and vital signs were assessed. Results: Effects of all opioids were similar, with some exceptions. Butorphanol had the strongest effects on psychomotor performance and some subjective effects. Morphine was associated with delayed or prolonged side effects. Conclusions: Orderly dose-response functions and replication of results of single-dosing studies confirmed that the cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects.