A Placebo-Controlled Study of Paroxetine and Imipramine in Human Experimental Pain Models

Background: Clinical trials in painful diabetic neuropathy indicate that the ability of antidepressants to inhibit reuptake of serotonin and noradrenaline may be of major importance.

Purpose: This study aimed to obtain experimental evidence of the analgesic effect of a selective serotonin reuptake inhibitor (paroxetine) with a tricyclic antidepressant (imipramine) as a control.

Methods: The hypoalgesic effects of single oral doses of 40 mg paroxetine and 100 mg imipramine were evaluated in two randomized, placebo-controlled, double-blind, three-way, crossover experiments, each including 18 healthy volunteers. In Experiment I, pain tests included determination of pain detection/tolerance thresholds to pressure and pain rating during the cold pressor test. In Experiment II, pain detection/tolerance thresholds to single electric stimulation and pain summation threshold to repetitive electrical stimulation of the sural nerve were determined.

Results: Compared with placebo, imipramine significantly increased pressure pain tolerance thresholds (p = 0.03) and marginally increased thresholds for pressure pain detection (p = 0.06) and pain summation on repetitive electrical stimulation (p = 0.07). Imipramine did not cause any significant changes in pain perception during the cold pressor test or thresholds for single electrical sural nerve stimulation. Paroxetine did not alter pain perception in any of the models. Peak concentrations of paroxetine were low (30–160 nM) compared with the analgesic effective steady-state concentrations reported in clinical trials. In contrast, imipramine peak concentrations were comparable with levels found effective in clinical trials (139–441 nM).

Conclusion: The lack of effect of paroxetine in this study can be explained by low single dose drug levels but pharmacodynamic differences between paroxetine and imipramine cannot be excluded.