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Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P < 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria:changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min;changes in pain scores estimated by patients using the visual analogue pain scale (VAPS);changes in patients' estimates of pain intensity associated with various daily activities.Significant pain relief was apparent within 2–3 days in those patients who had a beneficial effect, which contrasts with the documented 3–4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.