Discriminative stimulus effects of tramadol in humans

Abstract

Tramadol is an unscheduled atypical analgesic that acts as an agonist at μ-opioid receptors and inhibits monoamine reuptake. Tramadol can suppress opioid withdrawal, and chronic administration can produce opioid physical dependence; however, diversion and abuse of tramadol is low. The present study further characterized tramadol in a three-choice discrimination procedure. Nondependent volunteers with active stimulant and opioid use (n = 8) participated in this residential laboratory study. Subjects were trained to discriminate between placebo, hydromorphone (8 mg), and methylphenidate (60 mg), and tests of acquisition confirmed that all volunteers could discriminate between the training drugs. The following drug conditions were then tested during discrimination test sessions: placebo, hydromorphone (4 and 8 mg), methylphenidate (30 and 60 mg), and tramadol (50, 100, 200, and 400 mg). In addition to discrimination measures, which included discrete choice, point distribution, and operant responding, subjective and physiological effects were measured for each test condition. Both doses of hydromorphone and methylphenidate were identified as hydromorphone- and methylphenidate-like, respectively. Lower doses of tramadol were generally identified as placebo, with higher doses (200 and 400 mg) identified as hydromorphone, or opioid-like. The highest dose of tramadol increased ratings on the stimulant scale, but was not significantly identified as methylphenidate-like. Tramadol did not significantly increase subjective ratings associated with reinforcement. Taken together, these results extend previous work with tramadol as a potential medication for the treatment of opioid dependence and withdrawal, showing acute doses of tramadol exhibit a profile of effects similar to opioid agonists and may have abuse liability in certain populations.

Fig. 1.

Reinforced operant responses for placebo (circles), hydromorphone (squares), and methylphenidate (triangles) during discrimination test sessions. Data points are means (+S.E.M.) for eight volunteers based on one administration of each test condition for each volunteer. For clarity, the placebo data points have been shifted rightward to avoid overlapping symbols. Closed symbols indicate a significant difference compared with placebo. *, p < 0.05 versus tramadol (50 and 100 mg); #, p < 0.05 versus tramadol (50, 100, 200, and 400 mg); φ, p < 0.05 versus methylphenidate (30 and 60 mg).

Fig. 2.

Volunteers were asked to rate how similar each test drug condition was to each drug, as identified by letter code. Data represent mean peak change from baseline (+S.E.M.) for visual analog scale scores for similar to placebo (top), similar to HM (middle), and similar to MPH (bottom). Closed symbols indicate a significant difference from placebo. *, p < 0.05 versus hydromorphone (4 and 8 mg); #, p < 0.05 versus methylphenidate (30 and 60 mg).

Fig. 3.

VAS ratings of like and bad effects (left) and subject-rated scores on the opioid agonist scale and stimulant scale (right) during discrimination test sessions. Data represent mean peak (+S.E.M.) scores from eight volunteers; each test drug condition is represented once for each volunteer. A closed symbol indicates a significant difference from placebo. *, p < 0.05 versus tramadol (50 mg); **, p < 0.05 versus tramadol (50 and 100 mg); ***, p < 0.05 versus tramadol (50, 100, and 200 mg).