Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.
Common side effects include abdominal pain, nausea, and diarrhea. Serious side effects may include heart attacks, strokes, gastrointestinal perforation, gastrointestinal bleeding, kidney failure, and anaphylaxis. Use is not recommended in people at high risk for heart disease. The risks are similar to other NSAIDs, such as ibuprofen and naproxen. Use in the later part of pregnancy or during breastfeeding is not recommended.
Celecoxib has demonstrated adjunctive benefits in major depression and efficacy in reducing polyp recurrence in familial adenomatous polyposis, while also being investigated for broader psychiatric, anticancer, and chemopreventive applications.
Celecoxib was patented in 1993 and came into medical use in 1999. It is available as a generic medication. In 2023, it was the 111th most commonly prescribed medication in the United States, with more than 6million prescriptions.
Medical uses Celecoxib is indicated for the treatment of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis. It may be used in children with juvenile rheumatoid arthritis who are older than two years of age and weigh more than 10 kg (22 lb).
For postoperative pain, it is more or less equal to ibuprofen. For pain relief, it is similar to paracetamol (acetaminophen) at 3990 mg per day, which is the first line treatment for osteoarthritis.
Evidence of effects is not clear as several studies done by the manufacturer have not been released for independent analysis.
Familial adenomatous polyposis It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, so it is not a good choice for this reason.
Adverse effects Cardiovascular events: NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Individual cardiovascular risk profiles should be evaluated before prescribing. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may impair response to thiazide or loop diuretics), and may contribute to cardiovascular events; monitor blood pressure and use with caution in patients with hypertension. Celecoxib may cause sodium and fluid retention, so its use in patients with edema or heart failure warrants caution. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce the risk of cardiovascular events; alternative therapies should be considered for patients at high risk. The increased risk is about 37%. Gastrointestinal events: NSAIDs may increase the risk of serious gastrointestinal (GI) ulceration, bleeding, and perforation (may be fatal). These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, and the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce the risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with ≤325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (e.g., ulcer) occurs; concomitant gastroprotective therapy (e.g., proton pump inhibitors) is recommended. The increased risk is about 81%. Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin time, partial thromboplastin time, or platelet counts; it does not inhibit platelet aggregation at approved doses.
People with a prior history of ulcer disease or GI bleeding require special precautions. Moderate to severe liver impairment or GI toxicity can occur with or without warning symptoms in people treated with NSAIDs.
In October 2020, the U.S. Food and Drug Administration (FDA) required the prescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.
Allergy Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in people with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs. NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy. Use should be discontinued at the first sign of rash (or any other hypersensitivity).
Heart attack and stroke A 2013 meta-analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo. In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen. As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxib's safety.
The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."
In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug. Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib. In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs". In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.
Drug interactions Celecoxib undergoes metabolism primarily by the enzymes CYP2C9 and CYP3A4, but it also interacts with CYP2D6, inhibiting its activity without being metabolized by it. The CYP2C9 gene exhibits considerable genetic variability, with common polymorphisms, such as rs1799853 and rs1057910, linked to reduced enzyme activity and altered pharmacokinetics of celecoxib. Additionally, the influence of CYP2D6 on celecoxib metabolism is inconsistent, with its effect varying depending on the individual's CYP2C9 genetic profile.
Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. If used concomitantly with lithium, celecoxib increases lithium plasma levels. If used concomitantly with warfarin, celecoxib may result in an increased risk of bleeding complications. The risk of bleeding and gastric ulcers also increases further when selective serotonin reuptake inhibitors (SSRI) are used in combination with celecoxib. The drug may increase the risk of kidney failure with angiotensin-converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.
Mechanism of action
Anti-inflammatory A highly selective reversible inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has analgesic and anti-inflammatory properties. Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Inhibition of COX-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis. COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation (and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.
Anti-cancer For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues.
Celecoxib binds to Cadherin-11 (which may explain the reduction in cancer progression).
Structure-activity relationship
The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib. A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).