With the number of opioid overdose deaths reaching epidemic levels in the US over recent years, there are already more than enough reasons to exercise caution when taking prescription painkillers. Now, a new study has added yet more cause for concern, by indicating that taking drugs like morphine or oxycodone can actually increase sensitivity to pain in mice.

Opioid drugs work by binding to certain receptors in the brain and central nervous system in order to dampen the neural response to painful stimuli. For this reason, they are commonly used as painkillers, and are extremely effective at relieving acute discomfort.

However, the new study – which appears in the Proceedings of the National Academy of Sciences – suggests that, while these drugs may alleviate acute pain, they can actually contribute to the development of chronic pain.

To test this, the researchers inflicted a nerve injury upon mice, after which some were given a five-day course of morphine treatment, while others were not. Following this, the study authors tested the rodents’ pain thresholds by repeatedly prodding them with nylon fibers, and found that those that had received painkillers took twice as long to return to their normal pain tolerance levels as those that did not get any morphine.

They then gave the drug to another group of mice that had not suffered any injuries, and found that, while this caused a short-term drop in their pain tolerance, this effect did not last long. As such, the study authors propose a “two-hit hypothesis,” as only those mice that had received both an injury and painkillers seemed to experience a long-term increase in their pain sensitivity.

Such a conclusion resonates with previous research that suggests that a single painful episode “primes” a type of cell called microglia to release messengers called inflammasomes, which increase the sensitivity of pain-receptive nerve cells. Once in this primed state, these microglia are then sent over the edge by a second stimulus, causing them to unload high concentrations of these inflammasomes, resulting in chronic pain.

The study authors therefore suggest that the administration of morphine somehow acts as this second “hit,” triggering the release of microglial inflammasomes. To confirm this, they repeated the experiment using mice that had been genetically engineered so that their microglia could be inhibited, and found that this prevented them from suffering an increased sensitivity to pain.

Commenting on this discovery, study co-author Linda Watkins explained that the research highlights “a very ugly side to opioids that had not been recognized before,” adding that taking such drugs “can have devastating consequences of making pain worse and longer lasting.”