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COX Inhibitors

Editor: Anterpreet Dua Updated: 2/28/2024 3:40:32 AM


Cyclooxygenase (COX) inhibitors enjoy use in various conditions and diseases for their analgesic, anti-inflammatory, and antipyretic properties. Diseases and conditions in which COX inhibitors are indicated include but are not limited to osteoarthritis, rheumatoid arthritis, musculoskeletal injury, spondyloarthritis, migraines, and colon cancer (aspirin). According to the World Health Organization ladder, COX inhibitors are indicated for mild pain. Most professional societies, including the American College of Rheumatology, recommend the lowest dose and shortest duration regimen due to COX inhibitors' risks and potential adverse events.[1] Indications for aspirin include the secondary prevention of cardiovascular and cerebrovascular events due to its action as a platelet-inactivating agent.[2]

Cyclooxygenase represents a family of isoenzymes that play a role in synthesizing prostaglandins and other prostanoids (eg, thromboxane) from arachidonic acid.[3] Pharmaceutical inhibition of COX (specifically COX-2) can relieve inflammation and pain.[4]

Commonly encountered COX-inhibiting drugs include the following:

  • Ketorolac
  • Diclofenac
  • Naproxen
  • Meloxicam
  • Ibuprofen
  • Nabumetone
  • Indomethacin
  • Etodolac
  • Ketoprofen
  • Celecoxib
  • Aspirin

Mechanism of Action

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Mechanism of Action

The COX enzyme catalyzes the conversion of arachidonic acid into prostaglandin.[5] The enzyme has 2 known isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). There are over 20 COX inhibitors, varying in the amount they inhibit each isoform. COX-2-specific NSAIDs work by preferentially inhibiting COX-2. Aspirin irreversibly inhibits both COX-1 and COX-2 but inhibits COX-1 more than COX-2. 

COX inhibitors divide into non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 selective nonsteroidal anti-inflammatory drugs (c2s NSAIDs), and aspirin. NSAIDs include ibuprofen, naproxen, ketorolac, and indomethacin. The only COX-2-specific inhibitor on the US market at present is celecoxib. Meloxicam and diclofenac are COX inhibitors that are not strictly categorized. The following table shows the ratio of COX-1 to COX-2 inhibition for some common agents based on the COX-1/COX-2 IC50 ratio.[6]

Ibuprofen 0.5


Indomethacin 1.9
Meloxicam 18
Diclofenac 29
Celecoxib 30
Rofecoxib 267

The COX-1 enzyme regulates many cellular processes, including platelet aggregation, kidney afferent arteriole vasodilation, and gastric mucosa acid protection.[7] The COX-2 enzyme is an inducible enzyme and increases during inflammatory processes. COX-1 is present in the brain, kidneys, bones, and female reproductive system.[8]

There have been several other mechanisms of action attributed to COX inhibitors. Among them are the inhibition of neutrophil function and the inducible nitric oxide synthetase.[9][10]


COX inhibitors are most commonly given orally but can be administered rectally or parenterally, depending on the specific agent. Ketorolac administration can be via the intramuscular or intravenous route. Ibuprofen is also available in an injectable formulation. Several COX inhibitors are administered topically, as well. Topical NSAIDs have been shown to have the lowest levels of systemic adverse effects.[11]

Adverse Effects

NSAIDs are implicated in nearly 25% of all adverse drug reactions, with GI irritation being the most commonly reported issue. Adverse effects vary depending on the COX inhibitor used. The mortality rate associated with COX inhibitors is 21 per million and 24.8 per million for NSAIDs and low-dose aspirin, respectively.[2]

Gastrointestinal Effects

COX inhibitors can cause upper and lower gastrointestinal adverse effects ranging from mild irritation to more severe adverse events such as bleeding and perforation. Risk factors include patients older than 65, those with a history of peptic ulcer disease, or who are also on steroids or blood thinners. NSAIDs are best avoided in these patients.[12]

Upper GI adverse effects are reported more frequently.[2] Dyspepsia, heartburn, and nausea are among the upper GI adverse effects. Gastric or duodenal mucosal injury and ulceration may result as well. When ulceration develops into bleeding, endoscopic therapy and high-dose proton pump inhibitors are recommended and decrease mortality.[10]

Lower GI adverse effects are present within 75% of patients taking NSAIDs.[2] Patients can have ulceration, bleeding, strictures, or obstruction. Management always involves stopping the medication but can include endoscopic interventions as well.[13] In severe circumstances, laparotomy and bowel segment resection are necessary. Celecoxib has been found to correlate with fewer GI adverse effects, especially in combination with a proton pump inhibitor.[2] However, proton pump inhibitors have not been shown to decrease the risk of lower GI adverse effects, and their preventative effect does not extend beyond the stomach. Furthermore, there is increasing evidence regarding the concept that PPIs increase the risk of small bowel damage.[13]

Helicobacter pylori (H. pylori) is now implicated in increasing the risk of peptic ulcer disease in patients who are on NSAIDs, and eradication of H. pylori before the initiation of NSAID use has been shown to reduce the risk of upper GI ulcers and can be helpful as a preventative tool.[2]

The current recommendation is the lowest possible dose of celecoxib with a PPI for patients with significant GI bleeding risk who require NSAID therapy.[2]

Cardiovascular Effects

Non-aspirin COX inhibitors increase the risk of cardiovascular events, namely myocardial infarction, cardiovascular-related mortality, and stroke. The risk is small in patients without cardiovascular disease and slightly greater in patients with pre-existing cardiovascular disease.[8] The overall risk is less than the risk of GI adverse effects.[2] In 2015, the FDA strengthened its label warning regarding NSAIDs and the risk of heart attack and stroke. The risk of myocardial infarction has been observed to peak with as little as 7 days of NSAID use. Celecoxib, however, requires 30 days of continuous use. This risk remained sustained for 3 weeks and 3.5 months after discontinuation of non-selective NSAIDs and celecoxib, respectively.[13] In 2016, the PRECISION trial demonstrated that moderate dose celecoxib was not inferior compared to ibuprofen and naproxen in cardiovascular safety.[14]

Furthermore, in the safety analysis of 6 randomized controlled trials, the risk appears to be non-significant with a low dose of celecoxib (eg, 400 mg daily). Therefore, in a patient with high cardiovascular risk requiring NSAID therapy, the current recommendation is celecoxib 200 mg daily. If a patient has a low GI risk, naproxen is also acceptable. Diclofenac has been shown to have the highest cardiac risk.[11] Potential benefits, such as improving quality of life, should be carefully weighed with cardiovascular risks when deciding whether to start an NSAID on a patient.[8]

Renal Effects

The risk of renal effects with COX inhibitors is 1% to 5%.[14] COX inhibitors, non-specific NSAIDs, and COX-2-specific NSAIDs can both have adverse effects on the kidney. They are important players in vasoconstriction at the afferent arteriole level of the kidney. COX inhibitors should be avoided in patients with hypovolemia, prior kidney disease, or hypotension. COX-2, although generally thought to be an inducible enzyme, is constitutively expressed in the kidney.

Acute renal failure, chronic renal failure, acute interstitial nephritis, sodium and fluid retention, and hypertension have all had reports as adverse effects of COX inhibitors. PGE2 and PGI2 act as vasodilators in the kidney; a decrease in them is thought to lead to adverse renal effects. Acute renal failure is dose-dependent, duration-dependent, and reversible and is believed to occur due to a decrease in PGE2 and PGI2.[15] Joint use of angiotensin receptor blockers or diuretics increases the risk of acute renal failure.[14]

NSAIDs may decrease blood flow to the papillae, leading to destruction and renal papillary necrosis. There have been cases reported for both traditional NSAIDs as well as celecoxib. 

Acute interstitial nephritis occurs when there is inflammation within the interstitium of the kidney at the level of tubules; this can be due to a hypersensitivity reaction. Acute interstitial nephritis is reversible and occurs days after exposure; it commonly leads to nephrotic syndrome and can also lead to chronic renal failure. At this time, the mechanism of how NSAIDs cause acute interstitial nephritis is unknown.[12]

NSAIDs can cause sodium retention, leading to weight gain and edema. Hyperkalemia can occur as well. Celecoxib and diclofenac have a higher risk of causing hyperkalemia.[12]

Hematologic Effects

COX inhibitors have been known to cause platelet inhibition by inhibiting thromboxane A2 production. Aspirin causes irreversible inhibition of COX, and therefore, the duration of platelet inhibition lasts until 7 to 10 days after drug discontinuation. Patients with other reasons for increased bleeding, such as alcohol, anticoagulants, or liver failure, have enhanced bleeding risk. 

Platelet inhibition increases bleeding time. NSAIDs cause reversible COX inhibition; therefore, the duration of platelet inhibition depends on specific pharmacokinetics such as drug dosing and half-life.[16] Non-selective NSAIDs inhibit the anti-aggregate effect of aspirin and cause an increase in cardiovascular risk compared to low-dose aspirin alone. COX-2 selective inhibitors do not impede the antiplatelet effect of aspirin.[2]


COX inhibitors have commonly shown favorable effects on cancer rather than adverse ones. Continuous aspirin use has demonstrated effectiveness in colorectal cancer prevention through many colorectal cancer pathways. The recommendation is to select patients who are also at increased cardiovascular risk.[15] Aspirin and NSAIDs have been studied in prostate cancer as well, and results have shown that COX inhibitors could reduce the risk of prostate cancer, but currently, there are no clear guidelines or indications. Furthermore, long-term use has to balance against the adverse effects.[17] Intense non-aspirin COX inhibitors have correlated with increased survival with serous ovarian cancer.[18]

Hypersensitivity Reactions

NSAIDs are among the most common medications to cause hypersensitivity reactions. The number of hypersensitivity reactions caused by NSAIDs is extensive and complex, and classification is evolving. Hypersensitivity reactions vary widely in presentation and mechanism. They can be due to a specific drug, termed selective responder in the literature, or due to any NSAID, termed cross-intolerant. Clinical manifestations include urticaria, rhinitis, asthma, angioedema, bullous or desquamating skin lesions, DRESS syndrome, or toxic epidermal necrolysis. Some reactions are organ-specific clinical entities, causing bile duct syndrome, meningitis, or vasculitis. Mechanisms can be IgE-mediated, T cell-mediated, prostaglandin inhibition-mediated, or are often unknown. Other possible causes are present as well, and clinicians may miss NSAIDs as the primary cause. Ibuprofen is the most common among all NSAIDs to cause a hypersensitivity reaction. 

The most described hypersensitivity reaction is NSAID-exacerbated respiratory disease. This condition has a complex mechanism involving eosinophils and many other mediators. Chronic inflammation leads to symptoms such as rhinitis, nasal polyps, sinusitis, and asthma and can result from an NSAID, which has cross-intolerance. Single NSAID-induced urticaria, angioedema, and anaphylaxis can occur, and symptoms usually occur in less than 1 hour.[19]


Contraindications to COX inhibitors vary based on individual agents, but class effects include:

  • Allergy
  • History of ulcers
  • History of GI bleeding
  • History of coronary artery bypass
  • Renal impairment
  • Cirrhosis
  • Preexisting platelet defects

In 2015, the FDA strengthened its label warning regarding NSAIDs and the risk of heart attack and stroke.


NSAIDs interact with anticoagulants, aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and steroids, and increased monitoring of kidney function, coagulation, and GI effects may be necessary. Kidney function may also require monitoring in patients with renal impairment or who are at risk for renal failure.


Overdose of COX inhibitors is rare and may cause minor symptoms in adults and children. Severe symptoms have occurred, but those patients had taken multiple drugs at the same time.[20] There are no specific antidotes for NSAID poisoning. Patients demonstrating significant toxicity may develop severe acidosis, which requires supportive care and treatment with intravenous sodium bicarbonate.[21]

Enhancing Healthcare Team Outcomes

COX inhibitors are among the most commonly used medications in the world. Although they are available over the counter, they can have serious adverse effects and are associated with mortality. Patients need to speak to their physicians about taking COX inhibitors, especially if they plan to take them for an extended period. Clinicians should educate patients regarding having a list of medications, including over-the-counter medications, available at all times. Patients at risk may require regular monitoring of kidney function as well as an endoscopy exam.[11]

If planning a surgical or other invasive procedure for a patient on aspirin, communication is essential between the prescribing physician and the surgeon. When a patient does have an NSAID-associated complication such as a GI bleed, all interprofessional healthcare team members must be aware of the contraindications and possible adverse effects. This involves communication between gastroenterologists, physicians/advanced practice practitioners, nursing staff, and pharmacists. The contraindication should be communicated to the patient and recorded in their chart. Nurses will carry much of this responsibility since they have more frequent contact with the patient and can assess therapeutic effectiveness and monitor for adverse effects. The pharmacist can verify appropriate dosing, check for drug interactions, and communicate any concerns to the prescriber. All interprofessional healthcare team members must collaborate to make COX inhibitor therapy successful, optimizing patient outcomes.



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