Mu opioid mediated discriminative-stimulus effects of tramadol: an individual subjects analysis

Abstract

Drug discrimination procedures use dose-dependent generalization, substitution, and pretreatment with selective agonists and antagonists to evaluate receptor systems mediating interoceptive effects of drugs. Despite the extensive use of these techniques in the nonhuman animal literature, few studies have used human participants. Specifically, human studies have not routinely used antagonist administration as a pharmacological tool to elucidate the mechanisms mediating the discriminative stimulus effects of drugs. This study evaluated the discriminative-stimulus effects of tramadol, an atypical analgesic with monoamine and mu opioid activity. Three human participants first learned to discriminate 100 mg tramadol from placebo. A range of tramadol doses (25 to 150 mg) and hydromorphone (4 mg) with and without naltrexone pretreatment (50 mg) were then administered to participants after they acquired the discrimination. Tramadol produced dose-dependent increases in drug-appropriate responding and hydromorphone partially or fully substituted for tramadol in all participants. These effects were attenuated by naltrexone. Individual participant records indicated a relationship between mu opioid activity (i.e., miosis) and drug discrimination performance. Our findings indicate that mu opioid activity may mediate the discriminative-stimulus effects of tramadol in humans. The correspondence of generalization, substitution, and pretreatment findings with the animal literature supports the neuropharmacological specificity of the drug discrimination procedure.

Keywords: drug discrimination; humans; miosis; naltrexone; opioids; point-distribution; tramadol.

Figure 1

Percent correct responses during tramadol discrimination training. Circles represent sessions with oral 100 mg tramadol. Triangles represent sessions with oral placebo. Filled shapes are sessions with ≥ 80% session-appropriate responding (noted by the dotted line). Subjects acquired the tramadol discrimination when ≥ 80% session-appropriate responding occurred in four consecutive sessions. Left panels are from the 3 subjects who successfully acquired the tramadol discrimination, whereas right panels are from the 2 subjects who failed to acquire the discrimination.

Figure 2

Percent drug-appropriate responses (left panels) and nadir pupil diameter (right panels). Values over PL (placebo) and 100 on the left side of each panel represent average value observed during the four acquisition sessions (two placebo, two 100 mg tramadol) during which the discrimination was acquired. Values over HY represent data obtained during 4 mg hydromorphone testing. The dotted line in right panel is the nadir pupil diameter observed during the 100 mg tramadol training dose sessions. Circles are data during placebo pretreatment, whereas squares are data during 50 mg naltrexone pretreatment. Filled shapes are sessions where full substitution (≥ 80% drug-appropriate responding) was observed. Half-filled shapes are sessions where partial substitution (21% to 79% drug-appropriate responding) was observed.

Figure 3

Peak subject-rated effects for Any Effect (left panels), Good Effect (middle panels), and Bad Effect (right panels). Dotted lines represents peak effect observed during the 100 mg tramadol training session. See Figure 2 legend for additional details on axes and legend.

Figure 4

Physiological effects for systolic blood pressure (left panels), diastolic blood pressure (left-middle panels), heart rate (right-middle panels), and oxygen saturation (right panels). Dotted lines represents peak (nadir for oxygen saturation) effect observed during the 100 mg tramadol training session. See Figure 2 legend for additional details on axes and legend.