Do Anti-Inflammatories Increase the Risk of Chronic Pain?

A new study provides some interesting evidence

Inflammation is a major contributor to acute and chronic pain, and therefore we want to get rid of it. But inflammation is often there for a good reason. It's a basic physiological function that protects the health of the body and it’s been evolving for billions of years. We might therefore expect that interfering with the inflammatory process might have some unwanted side effects.

This consideration explains the recent controversy over whether it’s a good idea to ice a damaged body part after an injury. The logic of icing is to reduce the inflammation that is causing pain. But there is a countervailing logic: inflammation initiates the healing process, so interfering with inflammation might delay healing. This concern has been validated in research showing, for example, that icing delays muscle healing after eccentric exercise. This has led numerous experts to question the value of the “I” in the familiar RICE acronym, including the guy who invented it.

We should keep this background in mind when considering a new study on the effects of anti-inflammatory drugs on recovery from acute pain. It finds that anti-inflammatories may prevent the proliferation of neutrophils, and that this might be a bad thing because neutrophils somehow help initiate processes that resolve pain. Here are some details and quotes from the paper.

The study is based on three lines of evidence (1) analysis of immune system activity over time in people with acute low back pain: (2) an intervention on rodents with musculoskeletal injury; and (3) analysis of data from the UK Biobank tracking back pain and NSAID usage over time.

In the first part of the study, researchers assessed the immune system activity of 98 people with a low back pain in the acute stage, and then again three months later. Some of these people recovered from pain, and others did not. One notable difference between the groups was that the recovery group had high levels of neutrophil activation in the acute phase:

These results indicate the importance of the upregulation of inflammatory response at the acute stage of musculoskeletal pain as a protective mechanism against the development of chronic pain. … active inflammatory responses, particularly those regulated by neutrophils, contribute to pain resolution.

In the next part of the study, researchers tested the effects of anti-inflammatory drugs on neutrophil activation and chronic pain risk in rodents. Their guess was that the anti-inflammatories would inhibit neutrophil activation and this would prolong musculoskeletal pain. And that’s what they found. Further, injection of neutrophils prevented this effect, and similar effects were not seen with analgesics that didn’t impact inflammation.

we confirmed that the acute treatment of inflammation with [anti-inflammatory drugs] effectively reduced pain behavior during their administration, [but] greatly prolonged the resolution of neuropathic, myofascial, and especially inflammatory pain states. Three analgesics without anti-inflammatory properties (gabapentin, morphine, and lidocaine) produced short-term analgesic effects without affecting the overall duration of the painful (allodynic) episode.

The third stage of the study was an analysis of data on back pain provided by the UK Biobank project. This found that people who used NSAIDs for back pain were at an elevated risk for developing chronic pain:

We found that individuals with acute back pain were at 1.76-fold greater risk of developing chronic back pain if they reported NSAID usage (P = 2.0 × 10−5) than if they were not taking NSAIDs.

Elevated risk for developing chronic back pain was not found in people who took analgesics without anti-inflammatory properties.

Here are some quotes summarizing the overall meaning of the findings from the perspective of the authors:

Our data suggest that active biological processes protect from transitioning to chronic pain after an acute pain episode. …

Our findings are in line with the observation that the beginning of the inflammatory process programs its resolution, and it is thus the failure to initiate an appropriate inflammatory response that may lead to chronic pain. …

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.

The evidence from this study sounded persuasive to me, but I am not an expert in this area, can't provide a solid assessment of the quality of the paper, and haven't read any criticisms of the paper. But here's a few caveats about the study (which by the way apply to almost any study).

First, it's just one study, and needs to be replicated. Second, studies with interesting results tend to not get replicated, or if they do, they have smaller effect sizes. Third, the immune system is very complex with many different players involved, and therefore: (a) anti-inflammatory drugs are probably just one of many factors that affect neutrophil activation, and (b) neutrophil activation is probably only one of many factors that affect the transition from acute chronic pain.

That being said, this seems like an interesting result and I will look forward to reading future research. And next time I get injured and need pain relief, I might be more likely to reach for a bottle of Tylenol than Advil.

[Picture courtesy of Wikimedia Commons.]