Anti-inflammatory drugs like ibuprofen are used to treat chronic pain. What if they cause it?

In treating a sprained ankle, a strained muscle, or various other injuries, doctors regularly prescribe, and patients often reach for, anti-inflammatory painkillers like ibuprofen, aspirin, or dexamethasone. But a provocative new paper published to Science Translational Medicine suggests that reducing inflammation in the short-term could actually stifle healing, resulting in chronic pain over the long-term.

“What we’re saying here is pretty radical,” Jeffrey Mogil, a neuroscientist at McGill University and a senior author on the paper, told Stat. Mogil and his nineteen co-authors, hailing from institutions around the world, backed their assertion with three fairly convincing lines of evidence.

The case against anti-inflammatory drugs

They first collected blood samples from 98 patients in Italy seeking treatment for acute lower back pain, tracking any changes in gene expression over three months. Some of the patients went on to develop chronic lower back pain, while others did not. The researchers found that patients whose pain resolved showed increased activation in genes involved in inflammation. Their immune cells ratcheted up the fundamental immune process then quickly pared it down. Those same inflammatory genes remained relatively inert in patients who went on to develop chronic pain. To the researchers, this suggested that a vigorous, short-term inflammatory response speeds healing and resolves pain.

Mogil and his co-authors subsequently tested this hypothesis in injured mice, giving one group an over-the-counter anti-inflammatory drug, one group the anti-inflammatory steroid dexamethasone, and another group saline (salt water) as a placebo over the course of a few days. While the mice that received the anti-inflammatory and the steroid experienced greater pain relief in the short term, their pain took far longer to resolve overall compared to the mice that received saline — on the order of months instead of weeks.

Lastly, the researchers pored through the UK Biobank, a large-scale biomedical database containing in-depth genetic and health information from half a million UK participants, searching for records of patients with acute lower back pain who treated their symptoms with various painkillers. They found that patients who used non-steroidal anti-inflammatory drugs like ibuprofen or aspirin were 76% more likely to develop chronic back pain compared to patients who used other painkillers that didn’t reduce inflammation.

Taken together, these lines of evidence present a strong case against fighting early inflammation.

However, the researchers only looked at lower back pain. Moreover, findings in mice studies regularly fail to replicate in humans. And finally, the UK Biobank study is subject to confounding variables. Perhaps patients who took NSAIDs had far worse back pain and inflammation than patients who didn’t take NSAIDs, and it was because their back injuries were more troublesome that they went on to develop chronic pain.

A clinical trial is coming

While the researchers’ finding would be paradigm-changing if confirmed — suggesting that clinicians should be more willing to allow early inflammation to run its course, and that pain sufferers at home might want to consider reaching for acetaminophen rather than ibuprofen — the study did not come out of nowhere. In the past few years, scientists have been starting to realize that acute inflammation (perhaps from an injury) and chronic inflammation (say, from obesity) are quite different. The former is good and the latter bad.

The redness, swelling, and pain from acute inflammation are signs that blood is flowing to the area, bringing along rampaging immune cells (that clear the area of contaminants and damaged cells) as well as chemicals that stimulate healing. You don’t want the immune cells to stick around too long, risking “friendly fire,” but you also don’t want to force the healing compounds out too early. Right now, medicine may be doing the latter when it comes to treating pain and inflammation. It’s only when inflammation is too debilitating that clinicians might want to prescribe anti-inflammatory medications.

We’ll know more in the near future, as the researchers are planning to conduct a “straightforward” randomized clinical trial in humans, comparing rates of chronic pain in people given either anti-inflammatory pain medicines or pain medicines that don’t tamp down inflammation.