There’s an unfortunate irony for people who rely on morphine, oxycodone, and other opioid painkillers: The drug that’s supposed to offer you relief can actually make you more sensitive to pain over time. That effect, known as hyperalgesia, could render these medications gradually less effective for chronic pain, leading people to rely on higher and higher doses. A new study in rats—the first to look at the interaction between opioids and nerve injury for months after the painkilling treatment was stopped—paints an especially grim picture. An opioid sets off a chain of immune signals in the spinal cord that amplifies pain rather than dulling it, even after the drug leaves the body, the researchers found. Yet drugs already under development might be able to reverse the effect.

It’s no secret that powerful painkillers have a dark side. Overdose deaths from prescription opioids have roughly quadrupled over 2 decades, in near lockstep with increased prescribing. And many researchers see hyperalgesia as a part of that equation—a force that compels people to take more and more medication, while prolonging exposure to sometimes addictive drugs known to dangerously slow breathing at high doses. Separate from their pain-blocking interaction with receptors in the brain, opioids seem to reshape the nervous system to amplify pain signals, even after the original illness or injury subsides. Animals given opioids become more sensitive to pain, and people already taking opioids before a surgery tend to report more pain afterward.

But how opioids actually interact with pre-existing pain has been poorly studied, says Peter Grace, a neuroscientist at the University of Colorado (CU), Boulder. His team has been trying to trace hyperalgesia to the way opioids affect the immune system. In the new study, he and his collaborators used a rat model meant to mimic chronic nerve pain in people—the kind many might feel from traumatic nerve injury, stroke, or nerve damage caused by diabetes. They sliced into the rats’ thighs and tied a fine thread around a major nerve. The thread swelled over time, causing the nerve to painfully constrict, and then dissolved after about 6 weeks.

Ten days after that injury, half the rats received a 5-day treatment of morphine. Then over about 3 months, the researchers periodically measured the rodents’ threshold of pain by poking their hind paws with stiff nylon hairs of varying thicknesses. (The finer the hair that causes the rat to withdraw its paw, the logic goes, the more sensitive it is to pain.) After 6 weeks, injured rats that had received no morphine withdrew from the same kind of pokes as uninjured control rats. But morphine-treated rats remained sensitive to pokes with much finer hairs. It took them 12 weeks to return to the same pain sensitivity as the control rats, the team reports today in the Proceedings of the National Academy of Sciences. Even after the physical injury had presumably healed, they were in pain.

“Just the primary observation itself, I think, is amazing,” says Vania Apkarian, a neuroscientist at Northwestern University, Chicago, in Illinois, who was not involved in the study. The result “should have a wake-up impact on the field.”

Control rats with no injury also saw their pain tolerance dip if they got morphine, but they returned to their original threshold after about a week. So what made pain sensitivity jump so much more dramatically in the rats with an injury?

The authors propose that the nerve damage and the morphine delivered a kind of one-two punch to cells in the spinal cord called microglia—sentinels of the nervous system that scout for infection. Microglia release inflammatory signaling molecules into the spinal cord, which activate neurons that shoot pain signals up to the brain. Previous studies have shown that opioids make microglia more sensitive to activation. In the new study, the authors found that morphine activates a specific group of signaling proteins in microglia, collectively known as an inflammasome.

That’s not likely to be the only mechanism behind hyperalgesia, Apkarian notes. But in the study, inhibiting microglia—by inserting a gene for a receptor that makes them susceptible to a deactivating drug—reversed the pain-prolonging effect in morphine treated-rats, as did blocking certain proteins in the inflammasome.

Researchers are already exploring drugs that interrupt this pathway to treat pain or improve the performance of opioids. A clinical trial recently launched at Yale University, for example, will test whether an antibiotic that inhibits glial cells prevents the inflammatory effects of opioids. And Linda Watkins, a CU Boulder neuroscientist and senior author on the new study, co-founded a company to develop a chronic pain treatment that blocks one of the signaling proteins in the inflammasome, called toll-like receptor 4.

In the meantime, the finding certainly shouldn’t be the basis for withholding opioids from people in pain, says Catherine Cahill, a neuroscientist at the University of California, Irvine. These drugs also work to block the emotional component of pain in the brain, she notes—a form of relief this study doesn’t account for. And opioids might not prolong pain in humans the way they did in these rats, she says, because the dosing of morphine and its quick cessation likely caused repeated withdrawal that can increase stress and inflammation. Humans usually don’t experience the same withdrawal because they take sustained-release formulations and taper off opioids gradually.

Grace says the field badly needs a human study that systematically tests pain thresholds over time in opioid users. His team is working to confirm the animal findings with pain from other kinds of injury, and in female rats, which weren’t included in this study. In the meantime, he says, “I hope that it’ll get people to really question what the benefit of long-term opioid therapy might be.”