A new approach to ensuring safe opioid pain management
While opioids are the most effective treatment for pain management, particularly chronic pain, their prolonged use has many drawbacks, including tolerance, which requires increasing doses to maintain the analgesic effect, and hyperalgesia, an increased sensitivity to pain induced by opioids. Researchers from the University of Montpellier, Inserm, and CNRS, in collaboration with Biodol Therapeutics, have studied these two phenomena in an attempt to find solutions. Their study, published on November 7, 2024, in Nature Communications, opens up promising avenues for eliminating tolerance and hyperalgesia while increasing the analgesic effect of opioids.
In the fight against pain, particularly chronic pain, the most effective weapons in the therapeutic arsenal are opioids, which have unmatched analgesic efficacy. The problem is that prolonged use of opioids can lead to tolerance, forcing patients to increase the dose to maintain the analgesic effect, with serious consequences in terms of side effects and the risk of addiction. Furthermore, opioids can paradoxically induce abnormal sensitivity to pain, known as "hyperalgesia."
Although the mechanisms underlying these phenomena remain poorly understood, we know that these contradictory effects are mediated in particular by the peripheral mu-opioid receptor MOR. This is an important pathway, but it is not the only one involved. In this study, Cyril Rivat, a researcher at the Montpellier Institute of Neuroscience (INM), and his colleagues at the University of Montpellier, Inserm, CNRS, and Biodol Therapeutics, have demonstrated co-expression of the MOR receptor and the FLT3 tyrosine kinase receptor, which may be involved in the development of opioid tolerance and paradoxical hyperalgesia.
To disrupt the effect of this newly identified FLT3 receptor, the researchers tested the effects of a particular molecule, an inhibitor called BDT001. When administered to rodents at the same time as morphine, this inhibitor not only prevented the onset of tolerance and hyperalgesia, but also significantly increased the analgesic potential of morphine without exacerbating the other adverse effects induced by opioids.
Treatment with the inhibitor BDT001 has also been shown to suppress tolerance and hyperalgesia already established in rodents previously exposed to opioids, thereby restoring the efficacy of morphine.
"Our results suggest that combining morphine and FLT3 inhibitors could become a promising avenue for managing chronic pain, safely harnessing the power of opioids without the risk of increasing doses or even reducing them to minimize side effects," emphasizes Cyril Rivat. This is a major breakthrough at a time when these drugs are at the center of a huge health issue, particularly in the United States, where the "opioid crisis" has caused the deaths of 800,000 people in 25 years.
Jouvenel, A., Tassou, A., Thouaye, M. et al. FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia. Nat Commun 15, 9633 (2024). https://doi.org/10.1038/s41467-024-54054-y
Listen to Cyril Rivat's interview on the program A l’UM la science: securing pain treatment