Abstract
Several preclinical and clinical studies suggested that tramadol has a multi-mechanistic analgesic action. Upon in vitro evaluation, tramadol parent drug was determined to have only very weak affinity for opioid receptors. Metabolism via CYP2D6, though, yields the O-desmethyl metabolite (M1), which has much greater opioid receptor affinity. In tests in animals and human volunteers, tramadol’s analgesic effect is only partially blocked by the opioid antagonist naloxone. Yet the contribution of parent drug to analgesia is still debated. Observance of good analgesic response to tramadol in Japanese and other Asian populations that express the CYP2D6*10 genotype suggests that parent drug accounts for the majority of tramadol’s analgesic effect in most clinical settings. Understanding of tramadol’s multi-mechanistic action continues to form the basis for understanding its clinical attributes.
Highlights
Japan was one of the first countries to approve the centrally-acting analgesic tramadol hydrochloride
Observance of good analgesic response to tramadol in Japanese and other Asian populations that express the CYP2D6*10 genotype suggests that parent drug accounts for the majority of tramadol’s analgesic effect in most clinical settings
An extensive a comprehensive early pharmacologic evaluation, which predated the discovery of opioid receptors, revealed that tramadol has significant antinociceptive activity in animal models that are predictive of analgesic activity in humans and CNS effects suggestive of opioid activity [1]
Summary
Japan was one of the first countries to approve the centrally-acting analgesic tramadol hydrochloride (in 1978). Tramadol is available throughout the world and it is used extensively alone or in combination with other analgesics for the management of a wide variety of acute and chronic pain conditions. Tramadol was originally believed to act only through a -opioid receptor mechanism of analgesic action, but extensive subsequent study in animal models and in humans has established a second, and important, contribution related to a non-opioid mechanism of analgesic action [1]. The clinical analgesic and safety profile of tramadol is consistent with these dual mechanisms contributing individually, and sometimes synergistically, to its overall clinical profile [1]. The extent to which M1 is required for the analgesic efficacy of tramadol has remained a matter of discussion
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