¹Department of Neurology, Odense University Hospital, and Clinical Pharmacology, University of Southern Denmark, Odense, Denmark and the Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

Correspondence: Søren H. Sindrup, MD, Department of Neurology, Odense University Hospital, DK-5000 Odense C, Denmark.

^*Supported by a grant from Grünenthal GmbH, Stolberg, Germany. Grünenthal also provided study medication.

Received 7 June 1999; Accepted 22 September 1999.

Abstract

Background and Objective: Tramadol is a racemic drug that may act through a monoaminergic effect of (+)- and (-)-tramadol and through an opioid effect of its metabolite (+)-M1. The objective of this study was to investigate the relationship between relief of pain and serum concentrations of tramadol and M1 in tramadol treatment of painful polyneuropathy.

Methods: In a randomized, double-blind, placebo-controlled trial of 200 to 400 mg/day tramadol, serum concentrations of (+)- and (-)-tramadol and (+)- and (-)-M1 were determined in 28 of 34 patients. On-going and touch-evoked pain was rated daily by the patients by use of 0- to 10-point numeric rating scales during two 4-week treatment periods.

Results: Tramadol significantly reduced both on-going (P = .002) and touch-evoked pain (P < .001). There was no relation between relief of on-going and touch-evoked pain and serum concentrations of (+)-tramadol, (-)-tramadol, (+)-M1, or (-)-M1 (P = .11 to P = .89). Seventeen of the patients were categorized as responders for on-going pain and 16 for touch-evoked pain. Responders for on-going pain tended to have higher serum concentrations of (+)-M1 than nonresponders (median, 27 nmol/L versus 16 nmol/L; P = .08). Isobolograms showed that the fraction of nonresponders was higher among patients with low concentrations of both tramadol and (+)-M1 both for on-going (P = .009) and touch-evoked (P = .02) pain.

Conclusion: The opioid effect of (+)-M1 may be of importance for tramadol relief of on-going neuropathic pain but, in general, relief of neuropathic pain seems to depend on both the monoaminergic effect of (+)- and (-)-tramadol and the opioid effect of (+)-M1.