Inflammation has often been cast as a villain in medicine — and has long been tied to the sensation of pain and to painful diseases like arthritis. However, a new study of patients with low back pain or facial pain surprisingly shows that the body may need inflammation to prevent acute, short-term pain from turning into chronic pain.
The new study involved 98 patients with low back pain, experiments with mice, and an analysis of data from a patient database in the U.K. Overall, patients who took anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) had a higher risk of ending up with persistent, chronic pain.
Definitions of acute pain and chronic pain can differ, with the Cleveland Clinic defining chronic pain as lasting at least six months. In this study, the authors defined acute pain as pain that resolved in less than three months, while they defined chronic pain as lasting longer than three months.
The results, published in the May 10 issue of Science Translational Medicine, address a fundamental question in pain research — what underlies the transition from acute pain to chronic pain — and turn the conventional perception of pain and inflammation on its head. The findings could also inform future efforts to manage and prevent chronic pain in patients in the clinic.
"The biggest clinical implication is a complete reconsideration of both prevention strategies and treatments," said Massimo Allegri, a doctor at Policlinico of Monza Hospital in Monza, Italy, and a senior author of the new study.
"NSAIDs and steroids should be reconsidered in the treatment of acute pain, at least in the timeline of the treatment, as in the initial phase [of a few months] it seems really important to not reduce [immune] response."
A Pernicious Health Burden
Chronic pain continues to be one of society's most pernicious medical issues, responsible for enormous healthcare costs and widespread suffering. One recent study estimated that chronic pain affects more than 50 million Americans, or 20% of the population, and leads to almost $300 billion in annual healthcare costs.
Low back pain is the most frequently reported form of chronic pain, and any of the millions of affected patients can recount how painful and debilitating it can be in daily life. Clinicians usually treat low back pain with NSAIDs such as ibuprofen and corticosteroids, which target inflammatory responses produced by the immune system.
However, these drugs only temporarily relieve symptoms and don't always bring permanent relief. Although many patients with short-term, acute back pain don't end up developing chronic pain, those who do face a lack of therapies that can eliminate or cure their pain.
More than 15% of patients with an acute episode of pain end up developing chronic pain, according to Allegri. However, scientists still don't completely understand why acute pain resolves in some patients but persists as chronic pain in others. Understanding who is at risk and why could allow clinicians to better tailor rehab and therapeutic programs and develop new drugs for acute pain.
"All people have acute pain; acute pain is protective against injuries, as it signals us and promotes withdrawal from the stimuli like hot stoves," said Luda Diatchenko, a professor at McGill University in Montreal, Canada, and a senior author of the new study. "The majority of people resolve acute pain. But what is happening with those who don't?"
Common Pain Medications Delay Recovery
To understand this mysterious transition, Marc Parisien, a research associate at McGill and lead author of the study, Diatchenko, Allegri, and colleagues recruited 98 patients with acute low back pain and followed them for three months.
As the study progressed, the research team gathered data on the patients' transcriptional activity — the first step in how genes are expressed. They compared these data between patients whose acute pain resolved after the three months and patients whose pain persisted at the end of the study.
Counterintuitively, the patients whose pain resolved showed a spike in the activity of inflammatory genes during their acute pain stages, which the scientists tied to immune cells called neutrophils. In the chronic pain group, the immune system didn't show these reactions and remained largely static.
A similar phenomenon occurred in a second group of patients with temporomandibular disorders, which can cause long-lasting pain in the face and jaw. As with the low back pain patients, patients whose pain resolved showed many transcriptional changes and more activity of neutrophils and inflammatory genes.
To corroborate and build on their findings, Parisien's team treated mice with mild pain with various pain medications or depleted their neutrophils with an antibody.
Mice that received the anti-inflammatory steroid dexamethasone or the NSAID diclofenac showed some initial signs of pain relief, but eventually developed persistent pain in the long term. Meanwhile, other pain-relieving drugs such as lidocaine, which isn't anti-inflammatory, relieved pain without this prolonging effect.
Depleting the animals' neutrophils had a similar delaying effect and extended pain, but injecting neutrophils had the opposite result. The mice that received neutrophil injections showed no chronic pain even after receiving dexamethasone, suggesting the body depends on these immune cells to resolve acute pain.
Finally, the team examined data from people with low back pain in the UK Biobank, a large-scale medical database. They compared the trajectory of pain in people who received different pain-relieving drugs, such as NSAIDs, acetaminophen, and antidepressants.
The database study revealed that people who took NSAIDs had a 1.76-fold higher risk of chronic pain than those taking acetaminophen and other drugs that relieve pain but don't suppress inflammation. Furthermore, subjects who showed a higher percentage of neutrophils in their white blood cells during the acute stage of pain had a lower risk of chronic back pain later in life.
"We have clearly demonstrated that if the immune response is not strong enough chronic pain is quite common after an acute episode, independently from other factors," Allegri said.
A Counterintuitive Discovery for Pain Therapy
When discussing their study's results, Diatchenko and Allegri both highlighted the surprising and counterintuitive nature of their findings.
"The highest revelation to me was that we always think of pain as some active pathological process happening to us," Diatchenko said in a related podcast where she discussed the study's results.
"But looking now at the data, it's the opposite," she added. "It's an active adaptational process that's happening in people who resolve pain, and having chronic pain is the absence of it."
Similarly, Allegri said that researchers had long thought of chronic pain as the body's overreaction to a problem that was causing acute pain. However, he believes his team's study has unveiled the opposite: a strong inflammatory response may actually help the body resolve pain by quashing the root cause.
"These results open a completely new future in treatment of acute pain and in prevention of chronic pain not only for acute low back pain but for all those acute pain syndromes," he said. Regenerative medicine and other types of treatments that enhance the immune response could one day bring relief to patients, he added.
The paper still carries limitations that need to be addressed with further research, the authors cautioned. For example, the study of the patients with low back pain lacked control subjects for comparison, and the team didn't track chronic pain in the patients after the end of the three-month study.
"I think our data shall make us think about our approaches to treating acute and chronic pain," Diatchenko concluded. "Clinical trials on long-term effects of anti-inflammatory treatment in acute pain settings, like trauma and surgery, should be conducted."