The effect of tramadol in painful polyneuropathy in relation to serum drugand metabolite levels

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 (+)-MI, The objective of this study was to investigate t he 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. Ongoing and touch-evoked p ain was rated daily by the patients by use of 0- to 10-point numeric rating scales during two C-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 an d touch-evoked pain and serum concentrations of (c)-tramadol, (-)-tramadol, (+)-M1, or (-)-MI (P = .11 to P = .89). Seventeen of the patients were cat egorized as responders for on-going pain and 16 for touch-evoked pain. Resp onders for on-going pain tended to have higher serum concentrations of(+)-M I than nonresponders (median, 27 nmol/L versus 16 nmol/L; P = .08). Isobolo grams showed that the fraction of nonresponders was higher among patients w ith 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 r elief of on-going neuropathic pain but, in general, relief of neuropathic p ain seems to depend on both the monoaminergic effect of ()- and (-)-tramado l and the opioid effect of (+)-M1.