• S H Sindrup, C Madsen, K Brøsen, and T S Jensen.
• Department of Neurology, Odense University Hospital, Denmark.
• Clin. Pharmacol. Ther. 1999 Dec 1;66(6):636-41.

Background And ObjectiveTramadol is a racemic drug that may act through a monoaminergic effect of (+)- and (-)-tramadol and through an opioid effect of its metabolite (+)-Ml. The objective of this study was to investigate the relationship between relief of pain and serum concentrations of tramadol and Ml in tramadol treatment of painful polyneuropathy.MethodsIn a randomized, double-blind, placebo-controlled trial of 200 to 400 mg/day tramadol, serum concentrations of (+)- and (-)-tramadol and (+)- and (-)-Ml were determined in 28 of 34 patients. Ongoing 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.ResultsTramadol 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 (+)-Ml 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 (+)-Ml both for on-going (P = .009) and touch-evoked (P = .02) pain.ConclusionThe opioid effect of (+)-Ml 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 (+)-Ml.

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