Challenges for pain management in the twenty-first century

Abstract

Pain occurs in 20 % of the population, 50 % of patients who present with cancer have pain and 70 % of patients with advanced cancer will have acute and chronic pain. Opioids are the standard treatment of choice, but half of patients experience side effects which can reduce quality of life. Chronic pain is the result of central neuroplasticity and hypersensitivity. Within disease entities, there are different pain phenotypes which are generated by distinct mechanisms, and each phenotype in turn has different responses to analgesics. Analgesics such as opioids selectively bias signalling from mu, kappa, and delta receptors. Receptor responses are modulated by homotropic and heterotropic tolerance mechanisms. Combinations of opioids may modulate responses through single receptors or dimers and reestablish nociception in animal models. This is particularly seen with methadone and morphine. Bivalent opioids are reported to reduce psychologic dependence (as measured by reduced conditioned place preference in animal models), improve analgesia, and reduce side effects presumably through interactions on opioid dimers. Multivalent opioid/non-opioid receptor drugs and opioid-monoamine transporter inhibitor bivalent analgesics are available and have advantages compared to opioid monomers, as demonstrated in certain animal models and clinical situations. The key to analgesic development is to target pain phenotypes with selective analgesics initially in animal models then validate results through enrichment designed trials.