Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the first-line treatment options for managing many types of chronic musculoskeletal pain. NSAIDs exert their analgesic and anti-inflammatory effects by inhibiting the cyclooxygenase (COX) enzymes COX-1 and COX-2 that convert arachidonic acid to prostaglandin, prostacyclin, and thromboxane. COX-1 is continually expressed and regulates many cell functions, such as providing cytoprotection to the gastric mucosa, regulating platelet activity, and playing a role in kidney function.1 COX-2, on the other hand, is not constitutively expressed in most tissues (with the exception of the brain, bone, and kidney) and is only expressed during states of inflammation, demonstrating that its inhibition can lead to anti-inflammatory effects.1
NSAIDs differ from each other in the extent to which they block COX-1 and/or COX-2. The main classes of NSAIDs used for musculoskeletal pain are the nonselective COX inhibitors (such as ibuprofen and naproxen) and selective COX-2 inhibitors (such as celecoxib). When choosing whether or not to prescribe an NSAID and which NSAID should be chosen for an individual patient, it is important to consider the patient’s comorbidities and understand the specific mechanisms and side effects of the options being considered.
NSAIDs have been proven to be useful for relieving pain due to chronic inflammatory processes such as osteoarthritis.2 Their utility in targeting underlying pain that may not be directly due to an inflammatory process (such as low back pain) has not been as striking. There has been evidence, however, that compared to placebo, NSAIDs do have a small benefit for chronic low back pain, and they are recommended as first-line agents.3 A Cochrane review looked at the treatment of low back pain with NSAIDs versus placebo and found low-quality evidence that NSAIDs were more effective than placebo.4 Furthermore, NSAIDs have been shown to be more effective when there is a definite inflammatory process contributing to the pain. However, the cardiovascular, gastrointestinal, and renal side effects of NSAIDs must be considered before prescribing these agents.
Cardiovascular Side Effects
It has been demonstrated that most NSAIDs put patients at an increased risk of cardiovascular events such as myocardial infarction and stroke. The APPROVe trial inadvertently addressed these concerns with an investigation that was primarily intended to evaluate the effect of three years of treatment with rofecoxib (a selective COX-2 inhibitor) on the incidence of recurrent adenomatous polyps among patients with a history of colorectal adenomas.5 The study found that the use of rofecoxib in these patients was associated with an increased relative risk of thrombotic events compared to placebo (RR=1.92, P=0.008).5 This study led to Merck’s recall of rofecoxib (Vioxx) in 2004 because of the excess risk of myocardial infarction and stroke.6
Selective COX-2 inhibitors then had a negative reputation until the PRECISION trial (2016) revisited this topic and attempted to address cardiovascular concerns with selective COX-2 inhibitors.7 Patients with arthritis pain were randomized to receive treatment with either a nonselective NSAID (ibuprofen or naproxen), a selective COX-2 inhibitor (celecoxib), or placebo.7 This study demonstrated no significant difference in the cardiovascular events precipitated by celecoxib compared to naproxen or ibuprofen.7 However, due to the increased risk of cardiovascular events with any NSAID, it is generally advised to proceed with caution if a patient is at baseline increased risk. It has been demonstrated that naproxen may induce less vascular risk than other NSAIDs, but this result is not apparent across all studies.8
Gastrointestinal Side Effects
NSAIDs are known to produce gastrointestinal side effects due to the inhibition of gastric mucosal prostaglandin production by cyclooxygenases. These side effects–gastric ulcers, gastrointestinal bleeding, and perforation–are time-dependent, so reducing the time of NSAID usage is one way to prevent them.9 Additionally, proton pump inhibitors can be given along with the NSAID as prophylaxis for these potential gastrointestinal complications, especially in patients at increased risk.10 According to the American College of Gastroenterology, patients who are at high risk of gastrointestinal toxicity (recent bleeding ulcer or multiple gastrointestinal risk factors such as age >65, high-dose NSAID therapy, previous ulcer, or concurrent use of low-dose aspirin) should receive therapy other than NSAIDs.11 However, if NSAIDs are absolutely necessary, it is recommended that a COX-2 inhibitor should be used along with misoprostol or a high-dose proton-pump inhibitor.11 There has been growing evidence that the selective COX-2 inhibitor celecoxib may produce less adverse gastrointestinal effects compared to nonselective NSAIDs because COX-2 inhibitors do not completely interfere with the COX-1 function of providing gastric mucosal cytoprotection.7
Renal Side Effects
The renal side effects of NSAIDs are also significant, affecting 1-5% of patients taking NSAIDs.12,13 These include volume overload, hyperkalemia, acute kidney injury, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and elevations in blood pressure.13 Populations that are especially prone to NSAID-mediated acute kidney injury include people with heart failure, hypertension, chronic kidney disease, or taking diuretics with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker.14,15,16 NSAIDs should therefore be avoided in these high-risk patients.
In addition to the side effects and contraindications to NSAIDs, there are special considerations when prescribing NSAIDs to the elderly population (which is a large proportion of the patients who have chronic musculoskeletal pain requiring NSAIDs). According to the American Geriatrics Society, it is recommended that patients >75 should avoid chronic NSAID use unless alternatives to NSAIDs are not effective and the patient can take a proton-pump inhibitor or misoprostol.17
Overall, NSAIDs are a reasonable medication option for managing chronic musculoskeletal pain in patients without comorbidities. Physicians and patients must be fully cognizant of the risks associated with their chronic use. Furthermore, despite NSAIDs’ pain-relieving and anti-inflammatory properties, they have not been demonstrated to substantially alter the long-term course of a pain syndrome. NSAIDs should be thought of as a relieving but not a disease-modifying medication class.
Samantha Rettig is a 3rd year medical student at NYU Grossman School of Medicine
Peer reviewed by Michael Tanner, MD, associate editor, Clinical Correlations
Image courtesy of Wikimedia Commons
- Solomon DH. NSAIDs: Pharmacology and mechanism of action. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com/contents/nsaids-pharmacology-and-mechanism-of-action#H6. Accessed October 19, 2020.
- Pelletier JP, Martel-Pelletier J, Rannou F, Cooper C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys.Semin Arthritis Rheum. 2016;45(4 Suppl):S22-S27. doi:10.1016/j.semarthrit.2015.11.009
- Chou R, Deyo R, Friedly J, et al. Systemic pharmacologic therapies for low back pain: A systematic review for an American College of Physicians Clinical Practice Guideline.Ann Intern Med. 2017;166(7):480-492. doi:10.7326/M16-2458 https://pubmed.ncbi.nlm.nih.gov/28192790/
- Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW. Non-steroidal anti-inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev. 2016;2(2):CD012087. Published 2016 Feb 10. doi:10.1002/14651858.CD012087
- Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial [published correction appears in N Engl J Med. 2006 Jul 13;355(2):221]. N Engl J Med. 2005;352(11):1092-1102. doi:10.1056/NEJMoa050493
- Topol EJ. Failing the public health–rofecoxib, Merck, and the FDA. N Engl J Med. 2004;351(17):1707-1709. doi:10.1056/NEJMp048286 https://www.nejm.org/doi/full/10.1056/nejmp048286
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.N Engl J Med. 2016;375(26):2519-2529. doi:10.1056/NEJMoa1611593
- Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.Lancet. 2013;382(9894):769-779. doi:10.1016/S0140-6736(13)60900-9
- Richy F, Bruyere O, Ethgen O, et al. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach.Ann Rheum Dis. 2004;63(7):759-766. doi:10.1136/ard.2003.015925
- Chou R, McDonagh MS, Nakamoto E, Griffin J. Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review. Agency for Healthcare Research and Quality (US); 2011. https://pubmed.ncbi.nlm.nih.gov/22091473/
- Lanza FL, Chan FKL, Quigley EMM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications.Am J Gastroenterol. 2009;104(3):728-738. doi:10.1038/ajg.2009.115
- Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function.J Clin Pharmacol. 1991;31(7):588-598. doi:10.1002/j.1552-4604.1991.tb03743.x
- Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999;106(5B):13S-24S. doi:10.1016/s0002-9343(99)00113-8
- Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.Am J Kidney Dis. 2005;45(3):531-539. doi:10.1053/j.ajkd.2004.12.005
- Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.BMJ. 2013;346:e8525. doi:10.1136/bmj.e8525
- Luciano R, Perazella MA. NSAIDs: Acute kidney injury (acute renal failure). In: Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com/contents/nsaids-acute-kidney-injury-acute-renal-failure. Accessed October 19, 2020.
- By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.J Am Geriatr Soc. 2015;63(11):2227-2246. doi:10.1111/jgs.13702