A new way to secure pain management with opioids

A new way to secure pain management with opioids

[Press release] - Published on November 28, 2024 in Press Corner, Science-Society

While opioids are the most effective treatment for the management of pain, and in particular chronic pain, their prolonged use has a number of drawbacks, including tolerance, which requires higher doses to maintain the analgesic effect, and hyperalgesia, a heightened sensitivity to pain induced by opioids. Researchers from the University of Montpellier, Inserm and CNRS, in collaboration with the company Biodol Therapeutics, have investigated these two phenomena in an attempt to find solutions. Their study, published on November 7, 2024 in Nature Communications, opens up promising avenues for suppressing tolerance and hyperalgesia, while enhancing the analgesic effect of opioids.

In the fight against pain, particularly chronic pain, the best weapons in the therapeutic arsenal are opioids, which have demonstrated unequalled 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. Moreover, opioids can paradoxically induce abnormal sensitivity to pain, known as "hyperalgesia".

While the mechanisms behind these phenomena remain imperfectly understood, we do know that these contradictory effects are mediated in particular by the peripheral mu-opioid receptor MOR. An important pathway, but not the only one involved. In this study, Cyril Rivat, a researcher at the Institut des Neurosciences de Montpellier (INM), and his colleagues from the Université de Montpellier, Inserm, CNRS and Biodol Therapeutics, have identified co-expression of the MOR receptor and the FLT3 receptor tyrosine kinase, which is thought to 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. Administered to rodents at the same time as morphine, it not only prevented the onset of tolerance and hyperalgesia, but also significantly increased morphine's analgesic potential without aggravating other opioid-induced side effects.

Treatment with the BDT001 inhibitor also demonstrated its ability to suppress tolerance and hyperalgesia already present in rodents previously exposed to opioids, thus restoring morphine efficacy.

" Our results suggest that the combination of morphine and FLT3 inhibitors could become a promising avenue for the management of chronic pain, enabling us to safely harness the power of opioids, without the risk of increasing doses or even reducing them in order to reduce overall side effects ", emphasizes Cyril Rivat. This is a major advance at a time when these drugs are at the heart of an enormous health issue, particularly in the United States, where the "opioid crisis" has led to 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 show A l'UM la science: making pain management safer