title: The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels.
abstract: OBJECTIVE
  Tramadol 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.
  
  
  METHODS
  In 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.
  
  
  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 (+)-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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Neurology, Odense University Hospital, Denmark.
authors.forename: S H
authors.initials: SH
authors.lastname: Sindrup
authors.forename: C
authors.initials: C
authors.lastname: Madsen
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.forename: T S
authors.initials: TS
authors.lastname: Jensen
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D011115:Polyneuropathies / Q000097:blood / Q000188:drug therapy*; D014110:Touch; D014147:Tramadol / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol