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March 03, 2021 05:00pm
By Jill Murphy, Associate Editor
Clinicians must understand the distinct differences between each NSAID in order to help guide their recommendations for pain relief.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescription and OTC medications commonly used to relieve pain in the United States.
Pain can present in a number of different ways that are unique to each individual patient. Depending on its level of severity, pain may require pharmacologic therapy.
Whether it’s caused by a headache, menstrual cramps, muscle strain, backache, or cancer, pain is something that practically everyone has experienced and used some class of medication to alleviate. NSAIDs are a popular choice of pharmacologic treatment for pain because of their proven effectiveness.
How Do NSAIDs Work?
NSAIDs provide an anti-inflammatory effect and decrease pain sensation, also known as analgesia. The benefits of NSAID analgesia and its anti-inflammatory effects stem from its inhibition of prostanoid biosynthesis.
Prostanoids are synthesized from arachidonic acid. Cyclooxygenase (COX) isozymes convert arachidonic acid to prostanoids, which are then converted through a series of reactions to prostaglandins.
Prostaglandins are responsible for a number of different physiological and pathological pathways that involve the inflammatory response, gastrointestinal (GI) mucosa, blood clotting, and renal control of blood pressure.1
There are 2 different forms of COX: COX-1 and COX-2. COX-1 is responsible for the protection of the GI tract and platelet homeostasis, while COX-2 is responsible for the inflammatory response among other things.2
Traditional NSAIDs inhibit both of these mechanisms, leading to their efficacy in providing pain relief. Drugs in this NSAID class include ibuprofen, naproxen, meloxicam, diclofenac, and aspirin.
Ibuprofen is available OTC in a 200-mg strength, while 400-mg and 800-mg doses are available by prescription. Naproxen is also available OTC in 220-mg oral tablets, as well as a 500-mg prescription strength. Meloxicam and diclofenac are both prescription-only medications, while all aspirin strengths are available OTC.
These 5 traditional NSAIDs account for nearly 86 million prescriptions dispensed for 44 million patients.2Despite their high proven efficacy, they are also associated with serious side effects and complications.
What Side Effects and Complications Can Result From NSAID Use?
Because of the drugs’ dual effect on COX-1 and COX-2 receptors, there is an increased risk of cardiovascular (CV) events and GI complications. COX-1 has protective factors that are responsible for promoting mucus and bicarbonate secretion, so the inhibition of COX-1 leads to less mucus and a more acidic environment in the GI tract, which can lead to serious bleeds.1
NSAIDs’ CV side effects result from excessive COX-2 inhibition. COX-2 is responsible for the conversion of prostaglandin (PGI2), which promotes vasodilation and prevents platelet activation and cell adhesion, leading to a cardioprotective role in the circulatory system. Therefore, its inhibition can lead to an increased risk of hypertension, myocardial infarction (MI), stroke, and heart failure.1,2
The risk for all of these side effects increases when higher doses of NSAIDs are taken for a longer period of time.
How Can Clinicians Curb NSAID Complications?
The discovery of these life-threatening complications spurred a closer look at the COX mechanism in the 1990s.
With the seemingly protective qualities of COX-1, there was a hypothesis that if COX-2 could be selectively inhibited without COX-1 inhibition, then anti-inflammatory effects could be achieved with less GI damage.
This led to a new selective COX-2 inhibition drug class called “coxibs.” One study reviewed the safety of rofecoxib, the first drug in this class, and found a significantly higher MI rate in patients taking rofecoxib compared with those taking naproxen (0.4% vs 0.1%, respectively).3
However, as the dose of rofecoxib was increased, an independent thrombotic risk was noted, and the drug was voluntarily removed from the market in 2004 after another trial showed double the number of CV events in patients taking rofecoxib than placebo.3
In 2005, at an advisory committee meeting that looked at data addressing these issues, the FDA mandated that all prescription NSAID labels have:
(1) a ‘black box’ warning highlighting the potential for increased risk for CV events and serious life-threatening GI bleeding, ulceration, and perforation; (2) statements indicating patients with, or at risk for, CV disease and the elderly may be at greater risk, and that these reactions may increase with duration of use; (3) a contraindication for use after coronary artery bypass graft surgery on the basis of reports with valdecoxib/parecoxib; (4) language that the lowest dose should be used for the shortest duration possible; and (5) wording in the warning section that there is no evidence that the concomitant use of aspirin with NSAIDs mitigates the CV risk, but that it does increase the GI risk.2
This led Pfizer to look at these issues more closely, comparing the different risk factors between specific NSAIDs in the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) Trial in 2006.
PRECISION was designed to compare celecoxib—the only coxib still available on the US market—with naproxen and ibuprofen. The primary endpoint was first occurrence of a composite CV event defined as CV mortality, non-fatal MI, or non-fatal stroke in patients with rheumatoid arthritis (RA) or osteoarthritis (OA) who generally require chronic high doses of NSAIDs.
The trial was intended to compare the side effect profiles of these drugs in the hopes of using the data to distinguish the commonly used NSAIDs in a way that might guide clinical practice more definitively.
Although there is an increasing amount of data on the CV and GI risks associated with NSAIDs, the American Heart Association (AHA) still leaves medication choice up to the discretion of the physician. The AHA recommends that clinicians keep patient risk factors, treatment factors, and COX selectivity in mind when deciding which NSAID may be appropriate.
There are almost no data comparing the nonselective NSAID drugs to each other, making it more difficult for prescribers to make a selection. PRECISION, which is ongoing, is the first trial to examine comparative risk factors, which could change guideline recommendations.4
What Are the Current Recommendations for NSAIDs?
In February 2014, the FDA held another advisory meeting looking at recently published analyses assessing the NSAID labeling assumptions. The agency looked at the committee’s opinions and decided to further restrict NSAID label guidelines.
The panel had considered studies that concluded:
The panel discussed whether there was a clinically significant difference in CV thrombotic events between NSAIDs. Despite the fact that there was differential risk, especially for naproxen, it decided that the data were not strong enough to support a label claim.
The panel also looked at whether there was a relationship between length of time on NSAIDs and increased CV risk. It found that there is a risk of CV thrombotic event from the start of NSAID therapy independent of dose, and the label should reflect this.
Another aspect that the panel addressed was whether the warnings and restrictions for individuals at higher risk for CV thrombotic events are appropriate or should be stricter. Although it could not identify specific population recommendations (except post-MI and RA patients), it determined that labeling specifying higher risk was indeed appropriate.
The last aspect the panel addressed was whether the PRECISION trial should be altered or stopped. It decided that the trial should continue because it may provide the best opportunity to answer the question about differential CV risk between NSAIDs, and suggested that if the trial was causing harm, it would have been stopped.
After reviewing the advisory committee results, the FDA recently decided that it will require stricter labels on both prescription and OTC NSAID medications.
There are already warnings in place for the GI, heart attack, and stroke risks, but the FDA is now requiring these drugs to provide more specific information regarding heart attack and stroke risks. It will also require manufacturers to provide heart attack and stroke risk information on the drug facts label.
How Should Clinicians Approach NSAID Prescribing?
With the PRECISION trial still under way, the specific differences between NSAIDs remain unclear, which may not change clinical practice just yet. Clinicians should continue to follow current guidelines when it comes to prescribing these medications.
The FDA is not yet willing, without proper data, to claim that certain NSAIDs may be safer than others for specific patient populations. With the data that have been released, although controversial, it does seem as though coxibs may have lower risk for GI complications but increased CV risk, while naproxen may have lower CV risk but higher risk for GI complications.
This type of information should be kept in mind when looking at a specific patient’s medical history before recommending one NSAID over another.
For the patient population, it is still acceptable to use OTC NSAIDs for minor pain, but patients need to be aware of the risks and complications. Patients should always read labels closely and follow the directions on the label when it comes to specific doses, so that they do not inadvertently increase their risk for side effects and complications.
Clinicians need to make sure that they assess and discuss with patients what OTC medications they might be taking in order to avoid drug interactions, duplicity in treatment, and to answer any questions patients may have that aren’t answered on the drug labels.
Despite the potential risks, NSAIDs are still very effective in reducing pain and inflammation without the same addictive potential that the stronger prescription opiate medications have. They will always have a place in treatment for minor and moderate pain, but it is important to continue research to ensure patient safety and tolerability.
Clinicians must understand the distinct differences between each NSAID in order to help guide their recommendations for pain relief. Until new data are released, careful administration and understanding of NSAID risk is extremely important for avoiding CV and GI side effects.
1. Brune K and Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs.J Pain Res. 2015:8:105-118.
2. Bello AE and Holt RJ. Cardiovacular risk with non-steroidal anti-inflammatory drugs: clinical implications.Drug Saf. 2014;37(11):897-902.
3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.NEJM. 2000;343:1520-1528.
4. Antman EM, Bennett JS, Daugherty A, Furburg C, Roberts H, Taubert KA; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association.Circ. 2007;115(12):1634-1642.