Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers

The subjective, psychomotor, and physiological effects of three opioid mu-r eceptor agonists were studied in healthy volunteers using a cumulative-dosi ng procedure. Sixteen volunteers with no history of drug abuse received i.v . injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperi dine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL w as injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumul ative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomot or tests, and physiological measures were recorded at various times after e ach injection and during recovery, MEP tended to produce the most intense e ffects immediately after drug injection, which dissipated rapidly. MOR prod uced the mildest effects but was associated with unpleasant side effects du ring recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids pro duced consistent effects that are typically associated with abuse liability . Orderly dose-response functions suggested that our cumulative-dosing proc edure is an efficient way of determining dose-response functions for multip le opioids within the same subjects within the same study.