For two decades, Luda Diatchenko investigated the underlying biology of pain like a detective chasing clue after clue: What role does this gene play? How about that protein?
She always wondered, though, what she would find if she could look at how every gene inside a cell behaves as pain evolves in the body. It’d be like Sherlock Holmes trading his magnifying glass for video of the crime as it was being committed.
But when such technology finally became cheaply available in 2018 — thanks to advances in RNA sequencing — the footage shocked her.
“This was very, very unexpected,” said Diatchenko, a professor in McGill University’s Division of Experimental Medicine.
The results, reported Wednesday in Science Translational Medicine, repudiated much of what she and other pain researchers believed about how an initial bout of acute pain can develop into a chronic and debilitating condition. A large body of research suggests that chronic inflammation is a key driver of chronic pain, so many pain specialists focused on hosing down inflammation from the earliest sign of injury, extinguishing the immunological fire before it got out of control.
Diatchenko’s results, however, suggest that initial inflammation is necessary for the body to recover. If true, it could mean that decades-old protocols for treating pain with IV steroids in the hospital or aspirin and ibuprofen at home were actually counterproductive, increasing patients’ risk of developing chronic pain.
In other words, the “standard medical management for this type of pain turns out to be probably making matters worse, not better,” said Jeffrey Mogil, a neuroscientist at McGill and another senior author on the paper. “What we’re saying here is pretty radical.”
Like many radical claims, it is likely to divide outside researchers. Mogil said the paper was rejected from the New England Journal of Medicine, despite largely positive reviews, after one reviewer wrote that he would not “overturn decades of medical practice” until the group presented more convincing evidence: a randomized, controlled trial testing whether acute patients who receive anti-inflammatories are more likely to develop chronic pain than those who received placebo.
And even if the findings hold up, they may only do so for a subset of patients. Michael Kent, a professor of anesthesiology at Duke University, noted Diatchenko’s study focused on patients with lower-back pain.
Many of his patients have post-surgical pain. Their inflammatory systems, he said, are so out of whack that they need steroids or non-steroidal anti-inflammatories, a class of drugs that includes aspirin and ibuprofen.
“People are just so inflamed and not moving, and so in pain,” he said. “And by them not moving, they put themselves at way bigger risk of blood clots and pneumonia.”
For the handful of researchers who have long pushed the pain field to recognize a more nimble role for inflammation in the body, though, the results are a major breakthrough.
And they suggest a surprisingly simple fix could make a (small) dent in the growing number of people — now 1 in 5 Americans — who have chronic pain: switching from aspirin to Tylenol, which alleviates pain without affecting inflammation.
“I mean, in short, this is a paradigm-changing paper,” said Thomas Buchheit, director of the Regenerative Pain Therapies Program at Duke, who was not involved in the work. “We have been treating everything that hurts with a steroid injection or an anti-inflammatory for years.”
Precisely why some patients see pain resolve after an initial injury and others see it persist for upward of three months — the clinical definition of chronic pain — has long remained a mystery. Most researchers assumed that there was some kind of active dysfunction unfolding in the chronic pain patients, said Mogil.
When Diatchenko started the study, she expected her molecular footage would catch the genes driving that dysfunction in the act. In theory, you would then be able to develop some kind of drug to shut down or modulate them.
Alongside Italian collaborators, she collected blood from 98 lower-back pain patients in Italy and followed them for three months. With the help of Marc Parisien, a computational biologist at McGill, they then used a technology called RNAseq, in which researchers sequence all the RNA inside a cell, on immune cells from both patients who had their pain resolve by the last visit and on patients who didn’t.
RNAseq reveals which of a cell’s genes are active, the best proxy for what’s happening inside the cell at a given moment. Diatchenko expected the cells in patients who developed chronic pain to be buzzing with activity, the sign of a disease process underway.
Instead, the chronic patients’ cells were silent. “Completely, like, dead,” said Diatchenko.
Meanwhile, the immune cells of patients whose pain resolved were abuzz. More than half of their genome changed expression. “They have this massive immunological process going on,” she said.
That was the first surprise: Instead of something going wrong in patients who develop chronic pain, something was going right in patients who didn’t. But what?
Further analysis showed the genes activated in patients who didn’t develop chronic pain were involved in inflammation. The cells first upregulated inflammation and then quickly downregulated it.
That suggested inflammation was protective. But when Diatchenko called Mogil, who specializes in mice studies, about the results, he told her it was impossible: Everyone knows that when you give mice with chronic pain anti-inflammatories, it reduces their pain.
They realized, however, that no one ever followed the mice for very long. Mogil proceeded to run studies where he injured mice and gave one group an over-the-counter anti-inflammatory, one group the commonly used IV steroid dexamethasone, and another group saline.
The mice who received an over-the-counter anti-inflammatory or dexamethasone initially showed fewer pain symptoms than saline mice. But within weeks, most of the saline mice saw their pain entirely subside. By contrast, the mice who received anti-inflammatories still flinched when you touched their paw.
“It took them 150 days to resolve their pain instead of two weeks,” said Daitchenko.
To confirm that anti-inflammatories can actually have this debilitating impact, the researchers then went to the UK Biobank, a massive database of diverse patient data, and looked at patients who reported acute pain.
Indeed, they found those who had taken an anti-inflammatory were around 75% more likely to develop chronic pain as controls. No other type of painkiller, including Tylenol, that they looked at showed a similar correlation.
It’s still not clear exactly why inflammation might be having this protective effect, although some experts said it shouldn’t be shocking. While long-term inflammation is known to be debilitating, doctors will sometimes intentionally induce inflammation in a concentrated region to promote tissue repair.
And researchers have long known exercise can have regenerative effects, even though it is highly inflammatory.
“Basically, inflammation is a double-edged sword,” said Ru-Rong Ji, a professor of neurobiology at Duke who was not involved in the work.
Kent, the pain specialist, said that although he imagined anti-inflammatories would always be needed for post-operative pain, the work now suggests that there may be a Goldilocks zone of inflammation doctors should reach for with such drugs. He imagined running titration studies to find a new optimal level of anti-inflammatory use.
Mogil and Diatchenko are also now working on launching the randomized clinical trial the NEJM reviewer requested. Although randomized trials are notoriously expensive, he said this one should be fairly straightforward.
“I don’t expect people to change immediately,” said Mogil. “But yeah, I think the writing is on the wall.”
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