title: The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin, and their Combination in Painful Polyneuropathy.
abstract: The aim of this study was to explore the serum concentration-effect relation for first-line drugs in neuropathic pain and to determine if efficacy could be increased.
  
  
  
  Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin, and their combination in painful polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0 to 10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography.
  
  
  
  In 47 patients, pain was reduced -1.0 (95% confidence interval [CI], -1.5 to -0.6) by imipramine, -0.4 (95% CI, -0.9 to 0.1) by pregabalin, and -1.6 (95% CI, -2.1 to -1.1) by combination therapy. On monotherapy, there was no difference between responders and nonresponders with respect to concentrations of imipramine (mean, 161 vs. 229 nmol/L, P=0.129) and pregabalin (mean, 9.8 vs. 11.7 μmol/L, P=0.178). There was no correlation between drug concentration and pain reduction for imipramine (r=0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine < or ≥100 nmol/L, pregabalin < or ≥10 μmol/L) either for monotherapy or for combination therapy (P=0.161 to 0.797). Isobolographic presentations of reponders with imipramine and pregabalin concentrations during combination therapy did not indicate synergistic interaction.
  
  
  
  There were no important relations between drug concentrations and efficacy, or indication of synergistic interaction between the drugs. It was not concluded that treatment can be improved by measurement of drug concentration of pregabalin.
authors.affiliation: *Department of Neurology, Odense University Hospital §Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense Departments of †Neurology ‡Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren H
authors.initials: SH
authors.lastname: Sindrup
authors.forename: Jakob V
authors.initials: JV
authors.lastname: Holbech
authors.forename: Flemming W
authors.initials: FW
authors.lastname: Bach
authors.forename: Nanna B
authors.initials: NB
authors.lastname: Finnerup
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
authors.forename: Troels S
authors.initials: TS
authors.lastname: Jensen
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000097:blood* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007099:Imipramine / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000097:blood* / Q000188:drug therapy; D010147:Pain Measurement; D018373:Peripheral Nervous System Agents / Q000097:blood* / Q000627:therapeutic use; D011115:Polyneuropathies / Q000097:blood* / Q000188:drug therapy; D000069583:Pregabalin / Q000097:blood* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000700:Analgesics; D018373:Peripheral Nervous System Agents; D000069583:Pregabalin; D007099:Imipramine