NSAIDs: Quick History

Aspirin, the first nonsteroidal anti-inflammatory drug or NSAID, was developed in 1897. It was not until the 1950s that non-aspirin NSAIDs became available and forever changed the treatment of pain.

Nonetheless, NSAIDs, available over the counter and by prescription, are among the most commonly used medications in the world. Their high level of use is, in part, because they are especially useful as alternatives to opioids as treatments for chronic pain, particularly pain with underlying inflammation. However, using them in clinical practice requires a thoughtful and cautious approach. Balancing the benefit versus the risk of treatment is always a consideration.

NSAID Risks and Benefits

“Every therapeutic decision we make in medicine has benefits and risks,” said Kevin Byram, MD, assistant professor of medicine in the division of rheumatology and immunology and associate director of the rheumatology training program at the Vanderbilt University Medical Center. “The decision not to use an NSAID has risks and benefits, too,” he said. Among the risks of eschewing NSAIDs is, of course, the need for opioids in their place. However, Dr. Byram points out other risks as well. For example, the patient might not be as mobile, and that could cause them to lose the cardio-protective effects of exercise. All of this makes the use of NSAIDs complex and, at times, confusing.

Drawing on decades of research on NSAIDs, a team of researchers from the University of Michigan and the Cleveland Clinic examined the history of this class of drugs, their risks and benefits, and offered suggestions to clinicians for prescribing these drugs to treat pain and inflammation. Their recommendations were published this February in Rheumatic Disease Clinics

The research team’s findings suggest that all NSAIDs pose an increased risk of adverse cardiovascular events, a fact many clinicians are not aware of, said Deeba Minhas, MD, a rheumatologist and assistant professor of medicine at the Institute for Healthcare Policy and Innovation at the University of Michigan and first author on the study. She added that nuances in side effects based on COX profiles remain widely understood.

“Because we do not know ahead of time how patients may respond to NSAIDs,” the reviewers wrote, “it may be important to monitor patients closely after initiating an NSAID.” For example, they suggested monitoring blood pressure and asking about symptoms after 1 week of use. At 2 to 4 weeks, they recommended checking blood work for potential side effects and adjusting the dose if necessary. They also pointed out that emerging factors, such as biomarkers of COX inhibition, could aid clinicians in selecting the appropriate NSAID and its proper dose for a given patient.

  • using the lowest possible dose for the shortest possible time
  • considering topical NSAIDs when appropriate
  • engaging in shared decision-making with patients when making the risk-benefit calculation
  • creating a pain toolkit for patients that includes non-pharmacologic therapies such as TENS, physical therapy, occupational therapy, myofascial release, and mindfulness.

They also suggested asking the patient to keep a pain- and side-effect diary, or the equivalent app, and reviewing this at routine follow-up visits.

Regarding specific drug choices, Minhas et al suggested starting with ibuprofen plus a proton pump inhibitor (PPI) or naproxen plus PPI. Celecoxib might be a good alternative, although they advised against doses higher than 200 mg or twice daily regimens. In individuals taking aspirin, they recommended either naproxen plus PPI, taken two hours after the aspirin, or 200 mg of celecoxib plus PPI.

Additionally, they recommended that diclofenac be avoided in patients with cardiovascular risk factors. “Overall, it does not seem that there is a benefit to using diclofenac, though I think it is still highly prescribed,” said Dr. Minhas.

  1. Minhas D, Nidhaan A, Husni ME. Recommendations for the use of nonsteroidal anti-inflammatory drugs and cardiovascular disease risk: Decades later, any new lessons learned? Rheum Dis Clin North Am. 2023;49(1):179-191. doi:10.1016/j.rdc.2022.08.006