• Robert B Raffa, Christian Elling, and Thomas M Tzschentke.
• College of Pharmacy, University of Arizona, Tucson, AZ, USA. robert.raffa@gmail.com.
• Adv Ther. 2018 Oct 1; 35 (10): 1471-1484.

IntroductionThe distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component's relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol's analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects.Areas CoveredSeveral approaches to in vitro and in vivo data to estimate the contribution of tapentadol's opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data.Expert OpinionTraditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism-the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug-receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the μ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the μ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%).FundingGrünenthal GmbH.

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