Modest opioid withdrawal suppression efficacy of oral tramadol in humans

Rationale: Tramadol is in an unscheduled atypical analgesic with low rates of diversion and abuse and mixed pharmacologic actions, including modest opioid agonist activity. Objectives: The purpose of the current study was to characterize the opioid withdrawal suppression efficacy of oral tramadol. Materials and methods: Residential, opioid-dependent adults (n=10) were maintained on morphine (15 mg subcutaneously, quad in diem) for approximately 6 weeks. Spontaneous opioid withdrawal was produced by substituting placebo for scheduled morphine doses 17.5 h before experimental sessions that occurred twice weekly. The acute effects of placebo, tramadol (50, 100, 200, and 400 mg orally), naloxone (0.1 and 0.2 mg intramuscularly [IM]), and morphine (15 and 30 mg IM) were tested under double-blind, double-dummy, randomized conditions. Outcomes included observer- and subject-rated measures, physiologic indices, and psychomotor/cognitive task performance. Results: Naloxone and morphine produced prototypic opioid antagonist and agonist effects, respectively. Tramadol 50 and 100 mg produced effects most similar to placebo. Tramadol 200 and 400 mg initially produced significant dose-related increases in ratings of "bad effects" and "feel sick," followed by evidence of opioid withdrawal suppression. Tramadol did not produce significant increases on measures of positive drug effects nor any clinically significant physiologic changes. Conclusions: Tramadol 200 and 400 mg show evidence of opioid withdrawal suppression without significant observer- and subject-rated opioid agonist effects. The profile of action did not suggest a high risk for tramadol abuse in opioid dependent individuals. Tramadol may be a useful medication for treating opioid withdrawal.