The double edge of anti-inflammatories: they could increase the risk of chronic pain

Chronic pain is a major global health problem, especially in older societies. This disease has a profound impact on the quality of life and autonomy of patients and entails a high cost for States. In Spain alone, the Ministry of Health estimates that eight million people suffer from some type of persistent pain (17% of the country’s population). Among all the types of chronic pain, low back pain is the one that stands out the most due to the high number of years with disability that it causes and because its frequency and impact increase with age.

Despite the great relevance of this disease in the world, the molecular mechanisms involved in the transformation of acute pain into chronic pain are practically unknown. Knowing better what happens in this process could help prevent its appearance or develop more effective painkillers to treat it. The most recent studies suggest that both the nervous system and the immune system are involved in the appearance of this type of pain. In this way, chronic pain would be a neuroinflammatory condition. Various cells of the immune system participate in the regulation of pain by releasing molecules that act directly or indirectly on peripheral sensory neurons or the central nervous system.

Now, recent research, the results of which are published in the journal Science Translational Medicine, provides valuable data on how the immune system participates in the resolution of acute low back pain, thus protecting the body from the onset of chronic pain. To carry out the study, an international team of researchers has evaluated the immune system of samples from both patients (98 participants with acute low back pain, who were followed up for 3 months) and mice with low back pain.

One of the steps the scientists took was to study the array of RNA molecules present in cells of the immune system, a process called transcriptomic analysis. From this analysis, the authors discovered that when people with low back pain showed an activation of their neutrophils (cells involved in the early response of the immune system), mediated by the increased activity of inflammatory genes, the pain disappeared in them within three months. However, these changes in the inflammatory activity of these cells did not occur in those individuals who continued to suffer from low back pain.

Experiments conducted in animal models complement and reinforce the findings in humans. When the researchers administered analgesics with anti-inflammatory effects (such as dexamethasone or diclofenac) to mice with pain, this symptom persisted for longer than in those that did not receive these drugs, even though the pain disappeared at the beginning of their use. This phenomenon also occurred if the function of the neutrophils was blocked by the continued use of specific antibodies against these cells (pain resolution time was up to ten times higher than normal).

The previous negative effect could be reversed: it was only necessary to administer neutrophils or proteins normally released by these cells (S100A8/A9) so that the pain resolution time would return to normal. In addition, the greater persistence of pain did not appear if analgesics without anti-inflammatory effect were used.

Clinical data obtained from epidemiological studies from the UK Biobank also support the above results. This biobank is a huge biomedical database containing extensive health and genetic information on around half a million participants.

The researchers found, from this source, that people with low back pain who were taking non-steroidal anti-inflammatory drugs (NSAIDs), which include drugs such as ibuprofen, aspirin or diclofenac, had a higher risk of persistent pain. (two to ten years after the start of its consumption). This effect was not detected in those taking other drugs such as paracetamol or antidepressants.

Taken together, these data suggest that analgesics with an anti-inflammatory effect, which are widely used to relieve acute pain, could be counterproductive in the long term in patients with low back pain, by increasing the risk of chronic pain. Thus, the use of analgesics with no effect on inflammation may have a more favorable long-term result (to prevent the onset of chronic pain) than those with an anti-inflammatory effect.

However, clinical trials will be necessary to confirm these findings and demonstrate the cause and effect relationship between the use of these drugs and greater persistence of pain. In the event that these results are validated, it would be necessary to rethink the treatment of acute pain that millions of people currently receive in order to interfere as little as possible with the inflammatory process.

Esther Samper

Reference: “Acute inflammatory response via neutrophil activation protects against the development of chronic pain”, Marc Parisien et al. in Science Translational Medicine, vol. 14, no. 644, eabj9954, May 11, 2022.

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