Nature's first “atypical opioids”: Kratom and mitragynines

Summary What is known and objective Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are “multimechanistic”) and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more‐modern analgesics combine opioid and non‐opioid mechanisms, and have become known as “atypical opioids.” Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. Comment Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non‐opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. What is new and conclusion As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non‐opioid properties. Fascinatingly, just as the poppy plant ( Papaver ) evolved the typical opioids, Mitragyna evolved the mitragynines—Nature's “atypical opioids.”