A New Approach to Ensuring Safe Opioid Pain Management
While opioids are the most effective treatment for pain management, particularly chronic pain, their long-term use has many drawbacks, including tolerance—which requires increasing doses to maintain the analgesic effect—and hyperalgesia, an opioid-induced increased sensitivity to pain. Researchers from the University of Montpellier, Inserm, and the CNRS, in collaboration with Biodol Therapeutics, have investigated these two phenomena in an effort to find solutions. Their study, published on November 7, 2024, in Nature Communications, opens up promising avenues for eliminating tolerance and hyperalgesia while enhancing the analgesic effect of opioids.
In the fight against pain, particularly chronic pain, the most effective weapons in the therapeutic arsenal are opioids, which offer unmatched analgesic efficacy. The problem is that prolonged use of opioids can lead to tolerance, forcing the patient 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 an abnormal sensitivity to pain, known as “hyperalgesia.”
While 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 Neurosciences (INM), and his colleagues from the University of Montpellier, Inserm, the CNRS, and Biodol Therapeutics, have demonstrated the co-expression of the MOR receptor and the FLT3 tyrosine kinase receptor, which appears to contribute to the development of opioid-induced tolerance and paradoxical hyperalgesia.
To disrupt the action of this newly identified FLT3 receptor, the researchers tested the effects of a specific molecule, an inhibitor called BDT001. When administered to rodents at the same time as morphine, this inhibitor not only prevented the development of tolerance and hyperalgesia but also significantly increased morphine’s analgesic potential without exacerbating other opioid-induced adverse effects.
Treatment with the inhibitor BDT001 has also demonstrated its ability to reverse tolerance and hyperalgesia that had already developed in rodents previously exposed to opioids, thereby restoring the efficacy of morphine.
“Our findings suggest that combining morphine with FLT3 inhibitors could become a promising approach to managing chronic pain, allowing us to safely harness the potency of opioids without the risk of increasing doses—or even reducing them—to minimize side effects,” notes Cyril Rivat. This is a major breakthrough at a time when these drugs are at the center of a massive public health crisis, particularly in the United States, where the “opioid crisis” has claimed the lives of 800,000 people over the past 25 years.
Jouvenel, A., Tassou, A., Thouaye, M., et al. Inhibition of FLT3 signaling 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 show Science at UM: Ensuring Safe Pain Management