Members of the same pharmacological family are not alike: Different opioids, different consequences, hope for the opioid crisis?

Pain management is the specialized medical practice of modulating pain perception and thus easing the suffering and improving the life quality of individuals suffering from painful conditions. Since this requires the modulation of the activity of endogenous systems involved in pain perception, and given the large role that the opioidergic system plays in pain perception, opioids are currently the most effective pain treatment available and are likely to remain relevant for the foreseeable future. This contributes to the rise in opioid use, misuse, and overdose death, which is currently characterized by public health officials in the United States as an epidemic. Historically, the majority of preclinical rodent studies were focused on morphine. This has resulted in our understanding of opioids in general being highly biased by our knowledge of morphine specifically. However, recent in vitro studies suggest that direct extrapolation of research findings from morphine to other opioids is likely to be flawed. Notably, these studies suggest that different opioid analgesics (opioid agonists) engage different downstream signaling effects within the cell, despite binding to and activating the same receptors. This recognition implies that, in contrast to the historical status quo, different opioids cannot be made equivalent by merely dose adjustment. Notably, even at equianalgesic doses, different opioids could result in different beneficial and risk outcomes. In order to foster further translational research regarding drug-specific differences among opioids, here we review basic research elucidating differences among opioids in pharmacokinetics, pharmacodynamics, their capacity for second messenger pathway activation, and their interactions with the immune system and the dopamine D2 receptors.