Since the seminal paper by Laura Bohn 20 years ago, expectations have built up that biased mu-opioid receptor agonists will deliver what we all hoped to see since Friedrich Sertürner isolated morphine from opium. With several hundreds of publications, many of which in top journals, a Nobel Prize and a very closely watched development as well as clinical testing of the biased mu-opioid agonists, one can hardly think of a more exciting field. But we also know that, after a period of initial (even if decade-long) excitement, there comes a time to gather the stones together (Ecclesiastes 3:5).
On October 30, 2020, it was announced that the most advanced mu-opioid receptor agonist, oliceridine, has been classified as a Schedule II controlled substance by the U.S. Drug Enforcement Administration (DEA). Schedule II includes controlled substances with a high potential for abuse similar to other opioids including fentanyl, methadone, morphine, oxycodone, etc.
The DEA decision has caused some of our colleagues to revisit the preclinical evidence that supported the claims of better safety and tolerability profile of biased mu-opioid agonists. Whether this is by coincidence or not, several critical reviews have appeared recently and the most recent manuscript (still a preprint) challenges even the conclusions based on the original results by Bohn et al. in 2000. This preprint suggests that opioid-induced antinociceptive tolerance may develop even in the absence of β-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.
It has been repeatedly discussed that both, positive and negative data are important and there may be many reasons why initial findings cannot be confirmed or are confirmed only partially. This recent discussion of biased opioid agonists only serves to illustrate that, no matter how exciting the science is behind a certain hypothesis or theory, robust evidence supporting both internal and external validity of the therapeutic efficacy claims are essential for scientific excitement to translate into clinical benefit.