NSAIDs and the Anti-inflammatory Myth

In the context of the opioid crisis and seeking alternatives to their use, we are perhaps relying on nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen more than ever. Coupled with the belief that we should provide “prescription-strength” pain relief (>400 mg per dose of ibuprofen), we may be increasing risk to our patients with no additional benefit. In recent years, the therapeutic ceiling of NSAIDs has been recognized and discussed. Thus, ibuprofen 400 mg per dose and 1,200 mg per day, regarded as over-the-counter doses with an excellent side effect profile, provide maximal analgesic effect.¹ At higher doses (eg, 2,400 mg per day), the risk of gastrointestinal, cardiovascular, renal, and hepatic complications is greater.²

So why prescribe higher doses? Many justify higher dosing by claiming the need to tap into the anti-inflammatory dosage range. Although this hypothetical benefit may be useful in chronic inflammatory conditions (eg, spondyloarthritis), most of the patients we are prescribing NSAIDs for do not have such conditions. For instance, we often presume there is an inflammatory component to most acute injuries (eg, muscle strain or joint sprain). Has anyone actually tested “inflammation” of a sprained joint? No such literature seems to be available. Furthermore, such injuries are self-limited, which begs the question, Is it the anti-inflammatory property of the NSAID that improved the patient’s symptoms, or simply the analgesic effect and time?

The Research

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A Cochrane database review from 2015 compared NSAIDs to other analgesics for acute soft-tissue injuries. It concluded, “There is generally low- or very low-quality but consistent evidence of no clinically important difference in analgesic efficacy between NSAIDs and other oral analgesics.”³ This review implies that if acute inflammation does exist with such injuries, either NSAIDs do not provide a clinically significant benefit in reducing inflammation or inflammation is not a significant contributor to symptoms of those injured.

Continuing with this theme are two additional Cochrane reviews. The first evaluated NSAIDs for the treatment of acute gout. One would suspect clear benefit from NSAIDs in a condition widely accepted as inflammatory in nature. After reviewing 23 trials, the authors concluded that limited evidence existed to support NSAID use for the treatment of acute gout.⁴ The second reviewed the same but for spondyloarthritis. NSAIDs were efficacious based on several functional scoring tools, and there was a trend toward reduced radiographic spinal progression.⁵ Thus, NSAIDs most likely provide benefit in chronic inflammatory conditions.

The concept of the anti-inflammatory effect of NSAIDs is largely a physiologic argument. If we believe NSAIDs reduce inflammation and other mechanisms of bone healing, we are forced to subscribe to the belief of some of our orthopedic colleagues that NSAIDs impede fracture healing. Many articles have been published citing these hypothetical concerns about inhibited fracture healing and studying animal models suggesting the same.

“Prostaglandins (PGs) are autocrine and paracrine lipid mediators produced by several cell types capable of mediating either a stimulatory or resorptive role depending on the physiological or pathological conditions. Administration of prostaglandins in animal models has shown to increase cortical and trabecular mass and cause hyperostosis in infants.”⁶ 

“The activity of prostaglandins in bone tissue is defined by maintaining bone turnover balance and its reactions to humoral mediators and mechanical stress. A balanced osteoblast and osteoclast activity guarantees bone turnover equilibrium. PGE2 takes part in all processes of trauma response, including homeostasis, inflammation and healing, and plays a key role in bone physiology.”⁷

However, at the end of the day, many articles have noted the lack of evidence confirming such an effect, particularly with short-term NSAID use.⁸

“What’s in a name? That which we call a rose by any other name would smell as sweet.” —William Shakespeare

Names do not define the subject. However, they can shape our thinking. Nonsteroidal anti-inflammatory drugs have claimed their anti-inflammatory properties merely by their name. However, the outcome benefit achieved for acutely injured patients is just as likely from their analgesic effects alone. Higher doses seem to add more risk without additional benefit.