Advances in research on combination therapy for the management of pain

Pharmacotherapy remains an important component of multidisciplinary, multimodal pain treatment. Based on a well-established understanding of multiple concurrent mechanisms of nociceptive transmission and modulation, the demonstrated potential for synergistic interactions of drug combinations seen in preclinical studies supports the hypothesis of superior analgesia, and possibly also, fewer side-effects as compared with monotherapy. Likely related to this hypothesis and rationale, real-world evidence shows that approximately half of all patients with chronic pain, and even more with acute pain, concurrently receive 2 or more drugs from different mechanistic classes. To date, many dozens of randomized controlled trials have evaluated various analgesic combinations for the treatment of postoperative, neuropathic, back, arthritis, fibromyalgia, pelvic, and cancer-related pain conditions. Despite this growing area of research, most analgesic drug combinations are currently administered without rigorous evidence, thus exposing patients to the added cost or risk of some combinations that are not necessarily superior to monotherapy. As such, we propose future efforts to more efficiently exploit the potential benefits of combination therapy including: (1) expansion and coordination of translational collaborations to prioritize the most beneficial and clinically relevant combinations; (2) ensuring that preclinical combination studies evaluate multiple drug dosages and multiple relevant adverse effects; (3) ensuring that clinical trials include comparisons with each and every monotherapy component of the combination; (4) conducting further real-world studies of clinically beneficial combinations to ensure safety and efficacy in broader clinical settings; and (5) the application of these principles also to the evaluation of nonpharmacological treatment combinations.