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The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin, and their Combination in Painful Polyneuropathy

Sindrup, Søren H. MD, Dr Med Sci*; Holbech, Jakob V. MD, PhD*; Bach, Flemming W. MD, Dr Med Sci; Finnerup, Nanna B. MD, Dr Med Sci; Brøsen, Kim MD, Dr Med Sci§; Jensen, Troels S. MD, Dr Med Sci

doi: 10.1097/AJP.0000000000000497
Original Articles

Objective: 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.

Methods: 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.

Results: 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.

Discussion: 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.

*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

J.V.H. reports grants from Pfizer in relation to the present work. F.W.B. reports to have been compensated as an investigator in clinical trials on neuropathic pain sponsored by Pfizer and Grünenthal. N.B.F. reports personal fees from Grünenthal, Teva Pharmaceuticals, and Novartis Pharma, and grants from EU/EFPIA outside the submitted work. K.B. reports no disclosures relevant to the manuscript. T.S.J. reports to be on the Advisory Board for Pfizer, Grünenthal, and Orion. S.H.S. reports grants from Pfizer in relation to the present work and grants from EU/EFPIA outside the submitted work.

Supported by a grant from Odense University Hospital, Odense, Denmark. Pregabalin, imipramine, and matching placebo were provided by Pfizer and Nycomed. The authors declare no conflict of interest.

Reprints: Søren H. Sindrup, MD, Dr Med Sci, Department of Neurology, Odense University Hospital, Odense C 5000, Denmark (e-mail:

Received December 13, 2016

Received in revised form February 19, 2017

Accepted February 27, 2017

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