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Neurology supplements are not peer-reviewed. Information contained in Neurology supplements represent the opinions of the authors and are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology.

Advances and limitations in the evaluation of analgesic combination therapy

From the Division of Translational Pain Research, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Address correspondence and reprint requests to Dr. Christine N. Sang, Translational Pain Research, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, PBB AB 275, Boston, MA 02115; e-mail: csang{at}partners.org

Combination therapy using multiple drugs or modalities that target multiple mechanisms is common practice in the treatment of chronic pain. The benefit of combination therapy is purported to lie in its ability to provide improved efficacy with reduced toxicity. However, there are few published trials evaluating combination analgesics. Therefore, clinical choices regarding treatments, doses, and schedules tend to be determined empirically from innumerable drug combinations and permutations. Synergism is in part dependent on the pain condition, drug-drug interactions, and dose responses of the individual treatment components (among known and unknown factors), and a quantification of synergistic interactions would enable a rational approach to the use of combination analgesic therapy. Traditionally, drug interactions were evaluated by first establishing dose-response relationships of the individual component drugs and the combination in fixed dose ratios, followed by constructing isobolograms that would then allow a detailed statistical analysis. This strategy is at best challenging to perform in chronic analgesic trials. This article discusses the gold standard analytic approach to evaluating combination therapies (isobolograms), various permutations of this approach in human subjects, and the challenges of designing randomized controlled clinical trials that assess synergism between two therapies.

Supported by grants (to CNS) from the National Institutes of Health (NS R0141503) and by the Christopher Reeve Paralysis Foundation.

Publication of this supplement was supported in part by an educational grant from Pfizer Inc to the Office of Professional Education, University of Rochester School of Medicine and Dentistry.

Disclosure: The sponsor has provided CNS with grant support and other honoraria during her professional career. DRB has disclosed no financial relationship with the sponsor.