Author(s): Chaitanya Konda, DO, Chiamaka Ukoha, MD, MEd, Samuel Moshofsky, MD, MEd, Mashal Ali, MD, Med
Originally published: November 5, 2012 Last updated: May 25, 2023
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Disease/ Disorder

Definition

Non-steroidal anti-inflammatory drugs (NSAIDs) are medications used to reduce inflammation and to relieve pain. They are one of the most commonly used medications in adults. NSAIDs are frequently used for their analgesic, anti-inflammatory, and antipyretic properties.1 For many acute pain conditions, NSAIDs have similar or better efficacy compared to opioids.2 CDC clinical practice guidelines for prescribing opioids for pain recommend focusing on non-pharmacological approaches to decrease pain and increase function, followed by non-opioid medications, including NSAIDs, prior to considering opioid prescription.3 Although there are many uses and advantages to using NSAIDs, they are not without risk of serious adverse effects. Risks, benefits, route of administration, dose, and duration should be considered and discussed with patients prior to recommending or prescribing NSAIDs to patients.

Etiology

NSAIDs are predominantly used for the treatment of nociceptive pain or acute inflammation. NSAIDs are generally not first line in the treatment of neuropathic pain, but sometimes can be used as an adjunct medication for multimodal pain control.  

NSAIDs are generally indicated for the symptomatic relief of multiple medical conditions, including:

  • rheumatoid arthritis
  • osteoarthritis (OA)
  • acute gout, inflammatory arthropathies
  • dysmenorrhea
  • headache and migraine
  • postoperative pain
  • mild to moderate pain because of inflammation and tissue injury
  • back/neck pain and radiculopathy
  • sprains
  • strains
  • kidney stones
  • fever

Epidemiology including risk factors and primary prevention

According to data analyzed from the National Health Interview Survey (NHIS) in 2019 by the CDC, an estimated 20.5% of US adults (approximately 50 million individuals) suffer from chronic pain,4 and some studies suggest worldwide up to 30% of the population live with chronic pain.5 Following initial nonpharmacologic recommendations for pain, NSAIDs are considered to be one of several medications to consider as next line treatment for many conditions that induce pain.3 Despite widespread use and effectiveness, NSAIDs are associated with multiple adverse effects, commonly affecting gastrointestinal (GI), cardiovascular, and renal systems. The risk of adverse events varies between individual drugs patients, and is related to multiple factors such as administration route, duration and dose of NSAID usage. This variability in response can be ascribed to the individual differences in pharmacodynamic, pharmacokinetic & drug metabolism properties.

In order to prevent adverse events, general consensus for most conditions is to start at the lowest effective dose and prescribe for the shortest period possible.

Patho-anatomy/physiology

NSAIDs work by inhibiting prostaglandin synthase or cyclooxygenase (COX). They impair the transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes.6 NSAIDs are classified according to their relative selectivity of inhibiting COX-1 or COX-2. However, studies have shown NSAID dosing results in variable levels of inhibition due to differences in pharmacokinetics, pharmacogenetics, and pharmacodynamics.7

Multiple randomized clinical trials show there is no evidence that a specific NSAID is superior to another.8

COX enzymes: Two related isoforms of the COX enzyme have been described: COX-1 (prostaglandin-H-synthase-1) and COX-2 (prostaglandin-H-synthase-2).9

  • COX-1 is variably expressed in most tissues. It regulates normal cellular processes (e.g., gastric mucosal integrity, vascular homeostasis, platelet function, and renal blood flow) and is stimulated by hormones or growth factors.
  • COX-2 expression is minimal under basal conditions. It is induced by pro-inflammatory stimuli (i.e., cytokines) in endothelial cells, monocytes/macrophages, tumor cells & plaque-associated cells.10 It is expressed in the brain, kidney, bones, and probably in the female reproductive system.

Thus, differences in the effectiveness with which a particular NSAID inhibits an isoform of COX may affect both its activity and toxicity. It has been proposed that an NSAID inhibiting only COX-2 should decrease inflammation without having any effect on the constitutive COX-1 isoform (thereby minimizing toxicity). Such an agent would maximize effectiveness without inducing toxicity, particularly GI erosions.

The selective COX-2 inhibitors demonstrate at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1 at therapeutic doses. They provide comparable analgesia with the nonspecific NSAIDs with a reduction in GI side effects. An additional possible benefit is protection against the development of colon cancer for older adults, but given its increased risk of cardiovascular and GI side effects, it is not recommended to be prescribed solely for the purpose of cancer prevention.11 Unfortunately, there is a possible increase in risk of heart attack, thrombosis, and stroke by a relative increase in thromboxane in these medications, which caused rofecoxib to be pulled from the market in 2004, and valdecoxib in 2005.

Specific secondary or associated conditions and complications

Common adverse effects of NSAID use:

NSAIDs-Table-1Download

COX-2 selective NSAIDs have lower risk of GI side effects.16 In patients with increased GI risk, a COX-2 selective agent can be used to decrease risk, or a proton pump inhibitor can be added as a first line agent in the prevention of NSAID induced gastrointestinal injuries.17 However, all NSAIDs, both non-selective and COX-2 selective agents, should be used with caution in patients with cardiovascular risk factors.14 The risks increase with higher doses and longer dosing periods. A black box warning currently exists on all NSAIDs for cardiovascular events & GI ulcers/bleeding.18

In order to minimize adverse effects of NSAIDs while maximizing analgesic and anti-inflammatory benefits, optimal dosing guidelines are needed. Studies have compared effectiveness of NSAIDs in the emergency department and found that lower doses (400 mg oral ibuprofen) produced similar analgesic effect (compared to 800 mg oral ibuprofen), and theoretically have lower risk of adverse effects at a lower dose. This study was related to acute pain without long term NSAID use but promotes the concept of “start low and go slow” for prescribing pain medications.19

Toxicity

  • Adverse effects including GI symptoms and renal dysfunction can occur at any dose, but risk increases with higher doses and prolonged duration of use
  • Ingestions of less than 100 mg/kg of most NSAIDs are unlikely to cause significant harm, and most patients respond well to symptomatic management.20
    • Ingestions greater than approximately 400 mg/kg can cause severe multisystem affects including GI, renal, CNS depression, and anion gap metabolic acidosis.
    • Multi-organ failure can occur with extreme ingestions
  • Renal failure and renal papillary necrosis are rare and occur most often in patients with decreased effective arterial volume, underlying renal dysfunction, or excessive overdose.
  • Acute central nervous system toxicity related to NSAIDs might range from drowsiness to seizure to coma.
  • NSAIDs might affect patients who suffer from asthma and chronic urticaria by causing anaphylactic and anaphylactoid reactions.
  • In the event of an overdose,
    •  For an ingested dose of less than 100 mg/kg treatment is primarily supportive and can be managed outpatient with a responsible caretaker.
    • Ingestions more than 400 mg/kg necessitates inpatient monitoring, activated charcoal can be administered for gastric decontamination if given within 2 hours of ingestion, and management of secondary toxic effects may be necessary.  No antidote exists.

Essentials of Assessment

Functional assessment

Patients who are taking NSAIDs should be asked to report the effectiveness of analgesia, functional improvement with activities of daily living, as well as potential side effects of the medications. It is not uncommon to see patients who fail to get relief with one family of NSAIDs, but find relief after switching to another family. Finally, doses of NSAIDs should be optimized according to patient symptoms and side effects.

Laboratory studies

  • Patients should be screened for risk factors associated with adverse effects such as gastric ulcer history, renal dysfunction, and cardiac disease. If not obtained previously, a basic metabolic panel can be useful to check baseline renal function, but is not required especially if the planned duration of NSAID use is short). Prescription should be based on an individualized assessment of the risk of adverse effects versus the therapeutic benefits of treatment.
  • If there is a known cardiac history (coronary artery disease, heart failure) NSAIDs should be used with caution and cardiac function should be monitored closely.
  • If patient is on anticoagulation, NSAIDs should be used in caution due to increased risk of bleeding, and appropriate labs should be monitored (i.e. PT/INR)
  • For patients chronically treated with daily NSAIDs, a complete blood count, blood urea nitrogen and creatinine, and aspartate aminotransferase should be obtained at least once yearly. More frequent testing should be considered for patients at increased risk of adverse events.

Professional issues

As more is understood regarding pain and pain management practices, the Institute of Medicine reports cultural change is needed regarding pain management to gain a better understanding of pain of all types and improving efforts to prevent, assess and treat pain.21 Pain management continues to be a public health issue due to the many barriers limiting the availability of pain care including educational, financial, geographical, and research challenges.

Specifically, with NSAIDs challenges faced are variability in response to dosing frequency, NSAID class switching effectiveness, and duration of use.22

Rehabilitation Management and Treatments

Pain is one of the most common reasons for seeking medical attention whether it be acute or chronic. A number of pharmacologic and non-pharmacologic therapies are available for these patients.

Treatment options for pain generally fall into six major categories:23

  • Lifestyle modifications (exercising, weight loss, dieting)
  • Exercise prescription or physical therapy
  • Pharmacologic (NSAIDS, topical medications, antidepressants, antiepileptics, etc.)
  • Interventional procedures
  • Cognitive behavioral therapy
  • Other therapies (acupuncture, massage, etc.)

NSAIDs can be delivered orally or topically. Intramuscular formulation is also available, although this is more frequently used in acute settings (i.e., emergency department, urgent care).

Neuropathic pain – NSAIDs are widely used as adjuvant medications in the treatment of neuropathic pain, however there is a lack of evidence of how effective oral NSAIDs are in treating neuropathic conditions.24

Nociceptive pain – When pharmacotherapy for nociceptive pain is required, acetaminophen is typically used in the clinical setting for mild to moderate inflammatory pain related to sprains and contusions.

The American college of Physicians (ACP)25 and American Academy of Family Physicians (AAFP)26 created a guideline of recommendations for non-pharmacological and pharmacological management of acute pain from non-low-back, musculoskeletal injuries in adults. Below is a summary of the recommendations given to reduce or relieve symptoms of pain, improve physical function, and improve patients’ treatment satisfaction

  • Strongly recommend using topical NSAIDS with or without menthol gel as first-line therapy given their effective pain relief and minimal safety concerns
  • Suggest oral NSAIDs, acetaminophen or transcutaneous electrical nerve stimulation as second line.
  • Suggest against opioids, including tramadol

Additionally, a systematic Cochrane Review of topical NSAIDs for acute musculoskeletal pain in adults revealed gel formulations of diclofenac, ibuprofen, and ketoprofen, and some diclofenac patches provide the best effects.27 In two trials that directly compared diclofenac 1.5% topical solution to oral diclofenac, incidence of dry skin at the application site was significantly greater for topical diclofenac, whereas incidence of GI adverse events was significantly greater for oral diclofenac; however, withdrawals because of adverse events were similar in the topical and oral diclofenac treatment groups.28,29

One algorithm from Ong, CKS et al. suggests the following:

If pain is mild to moderate, start with acetaminophen. If insufficient for pain relief or if pain is moderate to severe, consider switching/starting with ibuprofen +/- PPI for patients with a risk of GI bleed. If pain remains persistent, first switch from ibuprofen to naproxen and if there is still insufficient analgesia, a combination of NSAID + acetaminophen or opioid can be trialed. Special consideration must be made for those allergic to traditional NSAIDs or in whom there is significant cardiac, renal or hepatic impairment.30

Coordination of care

Optimal patient outcomes employ a multidisciplinary approach. NSAIDs should not be the sole focus of treatment, but should be used when needed, in conjunction with other treatment modalities. Health care providers should aim to tailor a patient’s pain management to their personal experiences and collaborate with other disciples such as physical therapist, occupational therapist, psychological counselors, and social workers to assist in improving quality of life. It’s also crucial for physicians and nurses to pay close attention to the medical history of patients and educate them on risks and benefits of the drug, which is further discussed in the section below. Pharmacist can then further monitor for toxicity and adverse effects.31

Patient & family education

Patient and family education is important for two reasons. One is because some of these medications are obtained over-the-counter therefore easily accessed and two is because patients may combine medications without being aware of potential interactions. Patients should be educated on the possible side effects of NSAIDs and should notify physicians if they are taking other medications. This is particularly true of medications such as warfarin and clopidogrel because they can increase bleeding time.

A study by the American Academy of Pain Medicine (AAPM) indicated that approximately 10% of patients exceed the daily limit of NSAIDs.32 Patients may not recognize pain medications as NSAIDs and should be educated on dosing directions to avoid excess dosing and adverse effects. This includes the names of specific NSAIDs as well as strength & dosing schedules.

For reference, commonly prescribed NSAIDs include:

NSAIDs-Table-2Download

Of the above, the only fully COX-2 selective currently on the market in the United States is Celecoxib. Diclofenac, meloxicam, and etodolac are considered relatively selective for COX-2 at lower doses.33 The rest are non-selective. Dosing schedules range from once daily (meloxicam, piroxicam) to 3-4x daily (ibuprofen, diclofenac) and have varying starting and maximum doses.

Of note, drug adherence is enhanced when medications are dosed less frequently, which should be taken into consideration when prescribing.

There is increased use of over the counter aspirin for mild pain such as toothaches, headaches, and dysmenorrhea.34 It is important to familiarize patients with the various name brands that contain aspirin and their risk of severe side effects when used at high doses.

Cutting Edge/ Emerging and Unique Concepts and Practice

  • New research has emerged that could help explain differences in clinical outcomes NSAIDs have on the body including cardiovascular, dermatological, and cancerous findings. In a study conducted at Yale it was showed that a subset of NSAIDs activate a protein called nuclear factor erythroid 2- related factor 2 (NRF2) in cell cultures and rodents which triggers anti-inflammatory processes in the body.  Although not confirmed in human subjects yet, several clinical trials are being conducted to evaluate NRF2- activating drugs effective on inflammatory diseases.7
  • A 2018 systematic review & meta-analysis indicated that both non-selective & selective NSAIDs were effective as heterotopic ossification (HO) prophylaxis after total hip arthroplasty (THA). The use of NSAIDs also provided the dual benefit of pain relief[35]. A 2020 Bayesian meta-analysis confirmed this finding with emphasis on using celecoxib as it demonstrated the lowest rates of HO.36
  • There is particular concern surrounding whether NSAIDs impair bone healing after fracture or fusion. Multiple studies have indicated an increased risk of non-union with the use of NSAIDs.37,38 In a recent 2021 meta-analysis, Al Farii et al found no increased risk of non-union for patients that used NSAIDS for short periods (<2 weeks), although for patients that used NSAIDs for greater than 4 weeks, there was a significant increase in non-union.39 In particular indomethacin was associated with significantly higher non-union rates.39 There were limitations to this study including non-standardized primary outcomes, uncommon targeted fracture sites, and limited randomized control trial studies. Overall, the data provided some evidence for the safety of short-term NSAIDs use post-surgically, but when analyzing any duration of NSAID use after surgery, there is a significant increase in risk of non-union. Given the data is not explicitly against all NSAID use after surgery, no specific clinical recommendation can be made regarding the appropriate use of NSAIDs in this context, but current clinical practice of surgeons leans towards the avoidance of increased risk of non-union, and therefore avoidance of NSAIDs in the acute post-operative period.
  • Gut microbiome is an emerging topic throughout the medical field. With known adverse GI effects of NSAIDs, researchers have begun looking into the interconnectedness of microbiota and NSAIDs.  Though there is no definitive evidence at this point, future research may reveal efficacy of probiotics in prevention of NSAID induced enteropathy and gut microbiota influences on efficacy and toxicity of NSAIDs.40
  • Personalized medicine is a developing field that uses an individual’s genetic make-up to guide clinical decision making. Pharmacogenetics looks at how a patient’s genes relate to their response to certain medications. CYP2C9 polymorphisms can influence how one responds to NSAIDS; specifically, CYP2C9 intermediate or poor metabolizers may have increased plasma concentrations of certain NSAIDs, putting them at higher risk of adverse effects.41 More research, as well as lowered cost of genotyping, is needed before this can be used more widely in clinical practice.

Gaps in the Evidence-Based Knowledge

  • Definition of a dose ceiling. As mentioned above, studies have noted similar efficacy of NSAIDs at low vs high doses, with lower doses having significantly less side effects.19 While it is evident that a dose ceiling likely exists, it is unclear exactly what the ceiling is for many current NSAIDs on the market. Further studies regarding dose response could be performed to provide a clearer understanding and to provide a more evidence-based guideline for prescribing patterns that will benefit patients and help reduce adverse events.
  • Class-switching. Patients who do not respond to one particular class of NSAID may obtain benefit by switching classes. However, there is limited data in this regard.
  • Long-term side effects of topical NSAIDs. While several studies indicate fewer GI side effects with topical NSAIDs, we must still consider that topical medications have systemic absorption. More studies are needed in regards to the potential for side effects with long-term use.
  • The effect of NSAIDs in acute musculoskeletal injury. A 2018 study supported the use of NSAIDs in reducing strength loss, soreness & blood creatine kinase levels after an acute muscle injury.42 However, it is unclear what this means in the clinical setting, such as whether a particular dose regimen could be used to help promote healing after an acute injury.
  • The risk of SARS- CoV 2 infection with exposure to NSAIDs continues to be an enticing topic in literature. It was initially warned against to use ibuprofen for mild COVID-19 symptoms due to increased expression of angiotensin converting enzyme-2 (ACE-2) receptor which is a target for cell penetration in the virus.43 However, subsequent systemic review and metanalyses did not suggest an increased risk in obtaining SARS-COV-2 infection or an increase in the severity of symptoms with COVID-19 disease.44,45 More robust studies are needed to confirm the safety of NSAIDS with COVID 19 disease.

References

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Original Version of the Topic

Jose Mena, MD. Nonsteroidal Anti-Inflammatory Medications. 11/05/2012.

Previous Revision(s) of the Topic

Ritika Oberoi-Jassal, MD, Navdeep Singh Jassal, MD, Jaspreet Singh, MD, Young Chang, MD, Joshua Smith, MD. Nonsteroidal Anti-Inflammatory Medications. 9/30/2016.

Karen Morice, MD, Bari Madureira, DO, MPH. Nonsteroidal Anti-Inflammatory Medications. 9/15/2019.

Author Disclosure

Chaitanya Konda, DO
Nothing to Disclose

Chiamaka Ukoha, MD, MEd
Nothing to Disclose

Samuel Moshofsky, MD, MEd
Nothing to Disclose

Mashal Ali, MD, Med
Nothing to Disclose