Pain is often prolonged by anti-inflammatory drugs

Medications such as NSAIDs (non-steroidal anti-inflammatory drugs) and steroids, while offering immediate temporary pain relief, can promote the transition from a an acute to a chronic pain state.

Research recently published in the journal Science Translational Medicine reveals an additional mechanism by which treatment using steroids and anti-inflammatory drugs like ibuprofen to treat low back pain can increase the risk of developing tenacious chronic pain.

We have long known that NSAIDs such as ibuprofen are “resolution toxic”, meaning that their extended use prevents inflammation from resolving (winding down) because they block the action of PGE2 (Prostaglandin E2), an agent in acute inflammation which is also necessary for resolution phase chemistry. The authors if this new research have confirmed a cellular mechanism by which this occurs. They state:

“Chronic pain can develop from an acute pain state…clinical data showed that the use of anti-inflammatory drugs was associated with increased risk of persistent pain, suggesting that anti-inflammatory treatments might have negative effects on pain duration.”

They used transcriptome-wide genetic response data to investigate the molecular pathophysiological mechanisms in peripheral blood immune cells that underlie the transition of acute to chronic low back pain, identified a specific protective effect of the acute inflammatory response against the development of chronic pain.

Low back pain

The authors chose to study low back pain because it is has such a huge impact on quality of life and is the most frequently reported chronic pain problem.

“LBP ranks the highest of all chronic conditions in terms of years lived with disability, with its prevalence and burden increasing with age (4). Current treatments for LBP often target the immune system and include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and corticosteroids, although all of these drug classes are minimally effective at best (5).”

Complex physiology of the inflammatory pain response

Chronic pain is driven by a complex interplay of the immune and nervous systems that activate a variety of genes in diverse biological pathways. Circulating immune cells are recruited to sites of damage or inflammation and also penetrate the brain, contributing to “central sensitization”, a lower threshold of response to pain signaling.

“Circulating immune cells such as neutrophils, monocytes, and T cells are recruited to sites of tissue damage and/or inflammation and often also infiltrate the peripheral and central nervous systems (13, 14). Activation of these cells results in the expression of various inflammatory mediators, including cytokines/chemokines, lipids, and proteases, that act both directly on peripheral sensory or central second order neurons and indirectly on other immune or local cells to regulate pain. Microglia and astrocytes in the central nervous system act in a similar fashion, contributing to central sensitization and pain (15–18). The presence of these activated immune cells and glia, peripherally or centrally, is thought to contribute to the transition from acute to chronic pain (19–21).”

Impairing the inflammatory response prolongs resolution

Suppressing inflammation with drugs that impair key components of the immune response clearly prolongs pain. Pain resolution is a very active process that recruits a wide range of genes that are suppressed by common medications.

“Our initial bioinformatics results indicated that there was a substantial difference in the time courses of transcriptomic changes in subjects with resolved pain compared to those with persistent pain. The trajectories show substantial differences: In the resolved pain group, several thousand genes were found to be differentially expressed over time, whereas there were no differences in the persistent pain group. Thus, our data suggest that active biological processes protect from transitioning to chronic pain after an acute pain episode.”

The special role of neutrophils

Neutrophils, a type of white blood cell, play key roles in both inflammation and the resolution of inflammation.

“We found neutrophil activation–dependent elevation of the inflammatory response at the acute stage of pain in subjects with resolved pain, which was decreased by the time of the second visit. Conversely, subjects with persistent pain did not show any changes in their inflammatory response...The replication of our findings in the TMD cohort also suggests that our findings are likely to be applicable to other chronic pain conditions.”

“…our findings are in line with the observation that the beginning of the inflammatory process programs its resolution (34), and it is thus the failure to initiate an appropriate inflammatory response that may lead to chronic pain…Last, consistent with our bioinformatics and animal model results, higher percentages of neutrophils at the acute pain state protected against chronic pain development.”

“…acute treatment of inflammation with either the steroid, dexamethasone, or the NSAID, diclofenac—although both effectively reducing pain behavior during their administration—greatly prolonged the resolution of neuropathic, myofascial, and especially inflammatory pain states…We further showed the neutrophil dependence of these effects, with steroid-like pain prolongation being produced by neutrophil depletion and a complete blockade of allodynia produced by peripheral injection of neutrophils themselves…higher percentages of neutrophils at the acute pain state protected against chronic pain development.”

Rethinking the use of common pain medications

The authors’ findings have tremendous implications for treatment of the most common problem that presents to doctors. They conclude:

“Together, our results suggest that active immune processes confer adaptation at the acute pain stage, and impairment of such inflammatory responses in subjects with acute LBP (or TMD) increases the risk of developing chronic pain. These adaptive inflammatory responses are intrinsically transcriptionally driven, probably modified by both genetics and environmental factors, and can be inhibited by steroids and NSAIDs…Our conclusions may have a substantial impact on medical treatment of the most common presenting complaints to health care professionals. Specifically, our data suggest that the long-term effects of anti-inflammatory drugs should be further investigated in the treatment of acute LBP and likely other pain conditions..”

This draws our attention to the use of “natural” medicines that promote, rather than block, inflammation’s resolution phase chemistry.