The effect of tramadol in painful polyneuropathy in relation to serum drug and 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 (+)-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. Clinical Pharmacology & Therapeutics (1999) 66, 636–641; doi: 10.1053/cp.1999.v66.103171001