Advances and limitations in the evaluation of analgesic combination therapy.
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.
Black
Delbert R
DR
Division of Translational Pain Research, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sang
Christine N
CN
D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002908:Chronic Disease / Q000188:drug therapy; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation / Q000379:methods / Q000592:standards; D004347:Drug Interactions / Q000502:physiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D010148:Intractable Pain / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards
D000700:Analgesics