Pharmacodynamic profile of tramadol in humans: Influence of naltrexone pretreatment

Rationale Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. Objectives This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. Methods This inpatient, double-blind, randomized, withinsubject study examined the effects of oral placebo, tramadol (87.5, 175, and 350 mg), and hydromorphone (4 and 16 mg; positive control) after 1 h pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 h after initial drug administration. Results Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of "Good Effects" and "Liking" but also increased ratings of "Bad Effects." Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol's positive subjective effects and actually enhanced several unpleasant subjective ratings. Conclusions Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. Highdose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol's subjective profile of action.