Researchers have long believed that inflammation, a key part of the body's healing process, is somehow involved in the transition from acute to chronic pain when the inflammation is excessive or prolonged. But a new study turns that thinking on its head, finding that inflammation doesn't seem to contribute to chronic pain, but instead helps curb it.
A study supported by the U.S. National Institute of Dental and Craniofacial Research (NIDCR) suggests that painkillers that suppress inflammation may be counterproductive in the long term for pain relief. The results also provide new insights into healing, potentially explaining how activities that stimulate the immune system to cause inflammation, such as exercise, massage and heat therapy, can often help relieve pain.
“It turns out that acute pain is a very active biological process, and the development of chronic pain is the absence of this process,” says senior study author Dr. Luda Dyachenko, Ph.D., a human geneticist from McGill State Research University (Canada). “We have to be careful about suppressing our immune response in the acute stage, understand the implications and pay more attention to pain management.”
Temporomandibular joint pain relief, low back pain
Dyachenko wondered why in some patients the pain simply goes away, while in others the pain stubbornly persists. Her team first focused on low back pain, one of the world's leading causes of disability.
The researchers took blood samples from 98 study participants when they first developed low back pain. And repeated the analysis after three months. Later, half of the volunteers developed chronic low back pain, while the other half recovered.
By comparing biological markers in blood cells between the two groups, Dyachenko expected to find that chronic pain sufferers would have greater upregulation of genes that cause inflammation and are thought to fuel chronic pain. But the results took her by surprise. In patients who developed chronic pain, nothing much happened.
“Their gene activity was sort of frozen,” says Dyachenko. “But in patients who were recovering, we saw tremendous activity. More than half of their genes changed expression.”
The cells of the recovered volunteers were initially full of inflammation-related gene activity, and this activity gradually declined over the three months of the study. In contrast, the chronic pain group started out with less inflammatory gene activity that did not change over time.
The researchers observed similar results in a cohort of 64 study participants with another musculoskeletal disorder: temporomandibular disorder (TMJ). In the TMJ group, people who eventually recovered initially had intense inflammatory gene activity that decreased over time, suggesting that inflammation in the acute phase may protect against chronic pain.
Can anti-inflammatory drugs cause pain?
When Dyachenko shared the results with her co-author and colleague, pain researcher Jeffrey Mogil, Ph.D., he was at a loss. For decades, scientists have known that suppressing inflammation relieves pain. There is an explanation – people and animals treated with anti-inflammatory treatment in previous studies were not observed for long enough to know what happens after immediate pain suppression.
Mogil decided to investigate Dyachenko's results on mice with human-like pain conditions. For six days, the animals received saline as a control or dexamethasone, an anti-inflammatory steroid commonly prescribed for low back pain.
Although dexamethasone initially blunted the animals' pain responses by blocking the inflammatory immune response, the pain eventually returned and became chronic, lasting up to 120 days in some cases. In mice treated with saline, pain responses typically subsided in about half that time.
The team also observed prolonged pain in mice treated with diclofenac, a non-steroidal anti-inflammatory drug (NSAID) in the same class as the over-the-counter pain reliever ibuprofen. But the mice did not develop persistent pain when they were given drugs that suppressed pain without altering inflammation.
To better understand whether the results could be applied to humans, the researchers turned to the British Biobank, the largest open-access repository of biologically important information that contains genetic and phenotypic data from nearly 500,000 people across the United Kingdom. An analysis of 2624 people with acute back pain found that those who reported taking NSAIDs were 1.7 times more likely to develop chronic back pain than those who did not, confirming the importance of inflammatory responses in pain recovery.
Taken together, the findings suggest that rather than causing long-term pain, sustained inflammatory responses that dissipate quickly may be the key to preventing chronic pain. The results of the study also imply that drugs that reduce inflammation may be detrimental to pain regeneration.
“For me, this study is interesting because it gives us a new direction in how we can choose the prescription of drugs,” – said Dyachenko. “We're always thinking about what we can suppress, but our data suggests that we should boost immune responses in patients.”
Dyachenko notes that the study may explain why exercise and physical therapy are very effective for people with musculoskeletal pain, such as lower back pain and TMJ. These treatments stimulate mild inflammatory responses throughout the body.
“Many people immediately reacted to our study: 'Oh my god, we shouldn't be using these anti-inflammatory drugs,' but I'm not suggesting people stop them right now,” Dyachenko says. While evidence suggests that inflammation may protect against chronic pain, “our human studies have only been correlation, not causation, and we really need clinical trials to know for sure.”