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Why acute pain sometimes resolves after a few weeks or months, but becomes chronic in other people, is not entirely understood, particularly at the molecular level. A study published yesterday (May 11) in Science Translational Medicine suggests that the initial inflammatory response may be key to avoiding lasting pain.
The study authors report that pain in the lower backs of patients with elevated inflammation was more likely to resolve after three months than that of patients with a more discreet reaction. Thousands of genes, many of them related to the inflammatory response and immune cell activation, changed expression in the blood samples of those who recovered, while none seem to be altered when pain persisted. Based on mouse experiments and a database analysis of drug use and medical conditions, the team found preliminary evidence that blocking the inflammatory response with medication can prolong musculoskeletal pain.
The results challenge two decades of research indicating “that actually a proinflammatory state is accelerating the transition from acute to chronic pain,” says Bart Morlion, a pain specialist at KU Leuven in Belgium who was not involved in the work; he consults for pharmaceutical companies and works with them on clinical trials.
One of the leaders of the study, pain researcher Luda Diatchenko of McGill University in Montreal, who is a paid consultant for companies developing treatments for pain, tells The Scientist that her team was initially interested in finding molecular markers that appear after an injury or similar trauma and that might predict which patients will end up with chronic pain. For this, the team first analyzed RNA transcripts—an indicator that genes are in use—present in blood samples from 98 patients with low back pain that were collected at their initial visits and then did the same analysis again, three months later. At that point, the pain had resolved for about half of the patients, but the other half experienced chronic pain.
Diatchenko says she expected to find an “active pathological process” leading to chronic pain, but instead uncovered the opposite. That is, for the patients still experiencing pain after three months, no genes had changed their expression significantly between the two visits. In contrast, those who recovered had alterations in the expression levels of more than 5,000 genes, suggesting that “the resolution of pain is an active biological process,” she says.
By tracking the type of cells present in the blood samples, the team also found that those with a positive outcome had a more intense inflammatory response at their initial visit, led by neutrophils—white blood cells that are among the first to migrate to a site of injury.
If this is true, it will have major implications . . . that in the whole world, daily clinical practice needs to be changed.
—Bart Morlion, KU Leuven
Puzzled by her findings, Diatchenko says she shared her results with Jeffrey Mogil, also at McGill, who tested the connection between inflammation and pain resolution in mice. His team performed a series of experiments in which they measured the animals’ sensitivity to pain induced through one of three techniques—for example, an injury in the sciatic nerve, which connects the spinal cord to the feet—and assessed how their pain evolved over time while they received different treatments. Blocking inflammation with the steroid dexamethasone or the nonsteroidal anti-inflammatory drug diclofenac notably alleviated pain during the first week, but both medications prolonged pain in the long run. In contrast, mice receiving a saline solution as a control and those receiving other pain medications that do not alter inflammation resolved pain in a significantly shorter period of time.
Whether blocking inflammation in humans has similar effects has yet to be tested. However, when the authors performed a retrospective analysis of drug use and back pain evolution using a UK database, they found that patients who had reported the use of nonsteroidal anti-inflammatory drugs were more likely to develop chronic pain. The use of pain medications that do not block inflammation, such as acetaminophen (also known as paracetamol or Tylenol), was not associated with long-lasting pain. The effects of steroids were not assessed, as there was no data available to do so, explains Diatchenko.
“This is a very nice study,” concludes Morlion, adding that the results need to be replicated and checked for different types of pain, such as postoperative pain. He notes that follow-up studies will also require a better design: researchers will need to control for risk factors associated with chronic pain, such as psychological distress and high initial pain intensities, that the retrospective human studies in the current work only assessed using surrogate markers.
But “if this is true, it will have major implications,” he remarks—namely, “that in the whole world, daily clinical practice needs to be changed.”
Editor’s note (May 14): This article has been edited to include mention of the consulting relationships of one of the study authors.