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This is the Hot Topic article from May 2022. Hot topics highlight recent medical research findings and appear in IFM’s monthly Connections newsletter, exclusively for IFM members. Learn more about becoming an IFM member.

Inflammation may be the original example of a physiological double-edged sword: it is critical for repair and immunity but can also be incredibly destructive. Too much of it leads to the bulk of the chronic diseases that beset the modern world. But too little of it results in wounds that fail to heal and infections that cannot be kept at bay. While many of our healthcare efforts today focus on dampening inappropriate or prolonged inflammation, there are certainly cases in which we want to allow inflammation to occur. One notable example is following a vaccination, when inflammation provides the milieu for a robust immune response. Indeed, it has been suggested that anti-inflammatory medications taken before or just following a vaccination against COVID-19, flu, or pediatric diseases may decrease the resulting antibody response,^1-4 although the data on that are mixed.⁵ But what about the role of inflammation in healing acute injuries? A new study suggests that inflammation is critical in the healing process of acute issues that cause pain and that suppressing it may be a key trigger in the development of chronic pain.⁶

In the study, researchers approached the problem from multiple angles, starting by searching for molecular markers in the blood that would predict which patients would have pain that subsided and which would have pain that persisted. They took blood samples from 98 people at the time that they first reported developing low back pain (LBP) and again three months later. Using genome-wide transcriptomics, they found that patients whose pain resolved quickly showed high levels of neutrophil-driven inflammation, common in the early stages of an acute immune response, while those whose pain became chronic lacked this inflammatory response. The inflammation was not present in either group three months after the onset of pain. When the researchers repeated the study in another group of patients first reporting temporomandibular joint (TMJ) pain, they found again that those who recovered quickly had high levels of neutrophil-driven inflammation compared to those whose pain persisted. The authors suggested that this acute inflammatory response may be a protective mechanism against the development of chronic pain.⁶

The researchers then moved into an animal model and found that mice with sciatic nerve compression injuries or sciatic nerve irritation that were also treated with the anti-inflammatory steroid dexamethasone went on to develop chronic pain while control mice did not. The researchers repeated the experiment but this time gave one group of mice the nonsteroidal anti-inflammatory drug (NSAID) diclofenac and treated others with pain relievers that do not block inflammation (gabapentin, morphine, or lidocaine); only the diclofenac-treated mice developed chronic pain.⁶

Finally, the group then turned to data from the UK Biobank, examining 2,163 people with acute back pain, 461 of whom went on to have chronic pain. They found that patients who had taken an NSAID had nearly double the chance of developing chronic back pain as those taking drugs that did not block inflammation or no drugs (OR = 1.78, p = 3.9 × 10^-5).⁶

Taken together, these findings suggest that taking NSAIDs or steroids during acute pain may prevent the natural inflammatory process from hastening the resolution of pain and lead to chronic pain states, which could have huge implications for how we treat conditions like LBP. Well-known to be one of the most common reasons for a doctor visit, up to 80% of people report at least one episode of LBP during their lifetime.⁷ Most people experiencing acute LBP recover within one month,⁸ perhaps double that if there is radiculopathy. However, some 10-40% of all LBP patients go on to develop chronic symptoms and suffer some form of disability. The reasons that one person’s pain abates while another’s becomes chronic are not currently understood. If blocking inflammation in the acute phase can trigger this shift, we may want to consider prioritizing methods of analgesia that don’t block acute inflammation.

This study suggests that active immune processes mediated by neutrophils early in the response to acute pain may adaptively prevent the transition to chronic pain. While it should be noted that this was not a randomized controlled trial and further prospective trials are needed to confirm the result, these findings call into question the benign reputation of NSAIDs, which, despite some significant side effects, are often seen as low risk and first line treatments for analgesia and inflammatory pain. Further research should explore if these findings extend to other anti-inflammatory treatments such as botanicals, although we know that plant-derived compounds tend to be pleiotropic and so may have other health-promoting effects, and perhaps even ice, which is often suggested as an acute treatment for injuries, although the extent to which icing aids healing has itself been recently questioned. As we await further data, it may be worth considering the potential risk of anti-inflammatory treatments for acute analgesia.

References

1. Chen JS, Alfajaro MM, Chow RD, et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection. J Virol. 2021;95(7):e00014-21. doi:1128/JVI.00014-21
2. Saleh E, Moody MA, Walter EB. Effect of antipyretic analgesics on immune responses to vaccination. Hum Vaccine Immunother. 2016;12(9):2391-2402. doi:1080/21645515.2016.1183077
3. Das RR, Panigrahi I, Naik SS. The effect of prophylactic antipyretic administration on post-vaccination adverse reactions and antibody response in children: a systematic review. PLoS One. 2014;9(9):e106629. doi:1371/journal.pone.0106629
4. Scheifele D, Ward B. Fever prophylaxis can reduce vaccine responses: a caution. Paediatr Child Health. 2018;23(4):245-246. doi:1093/pch/pxy011
5. Ooi EE, Dhar A, Petruschke R, Locht C, Buchy P, Low JGH. Use of analgesics/antipyretics in the management of symptoms associated with COVID-19 vaccination. NPJ Vaccines. 2022;7(1):31. doi:1038/s41541-022-00453-5
6. Parisien M, Lima LV, Dagostino C, et al. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med. 2022;14(644):eabj9954. doi:1126/scitranslmed.abj9954
7. Leboeuf-Yde C, Lauritsen JM, Lauritzen T. Why has the search for causes of low back pain largely been nonconclusive?Spine. 1997;22(8):877-881. doi:1097/00007632-199704150-00010
8. Jarvik JG, Deyo RA. Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med. 2002;137(7):586-597. doi:7326/0003-4819-137-7-200210010-00010