Mechanism of action
Diclofenac inhibits both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, thereby reducing the conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. This mechanism underlies its analgesic, anti-inflammatory, and antipyretic effects.
COX-1 inhibition reduces constitutive prostaglandin production in the gastric mucosa, kidneys, and platelets, which explains many adverse effects including gastric ulceration, renal impairment, and antiplatelet activity. COX-2 inhibition reduces inducible prostaglandin production at sites of inflammation, providing the therapeutic anti-inflammatory and analgesic effects.
Diclofenac has relatively higher COX-2 selectivity compared to other traditional NSAIDs like ibuprofen or naproxen, though it is not as selective as the coxibs. This partial selectivity contributes to its efficacy but also to its cardiovascular risk profile, as COX-2 inhibition can shift the thromboxane-prostacyclin balance toward a prothrombotic state.
Topical formulations deliver high local concentrations with lower systemic absorption, reducing but not eliminating systemic adverse effects. Ophthalmic formulations inhibit prostaglandin-mediated inflammation in ocular tissues.
- Diclofenac is a non-selective NSAID with black box warnings for cardiovascular thrombotic events and GI bleeding
- Inhibits both COX-1 and COX-2 enzymes, reducing prostaglandin synthesis and providing anti-inflammatory and analgesic effects
- Higher hepatotoxicity risk than other NSAIDs; monitor liver function tests in chronic therapy
- Contraindicated in third trimester pregnancy due to risk of premature ductus arteriosus closure
- Increases risk of acute kidney injury, especially when combined with ACE inhibitors and diuretics (triple whammy)
- Topical formulations provide local analgesia with lower systemic exposure but still carry systemic risks
- Cross-reacts in aspirin-sensitive asthma; avoid in patients with NSAID hypersensitivity or aspirin triad
- Increases methotrexate and lithium levels by reducing renal clearance
Indications
Diclofenac is indicated for multiple inflammatory and painful conditions:
Musculoskeletal disorders
- Osteoarthritis: relieves pain and improves function
- Rheumatoid arthritis: reduces joint inflammation and morning stiffness
- Ankylosing spondylitis: decreases spinal pain and stiffness
- Acute musculoskeletal injuries: sprains, strains, soft tissue trauma
Pain conditions
- Acute pain: postoperative, dental, trauma
- Chronic pain syndromes: often part of multimodal analgesia
- Dysmenorrhea: primary menstrual pain
- Migraine: acute treatment in some formulations
Ophthalmic uses
- Postoperative ocular inflammation: after cataract surgery
- Photophobia in refractive surgery
- Cystoid macular edema prevention
Topical uses
- Actinic keratoses: topical gel formulation
- Localized musculoskeletal pain: gels and patches
Diclofenac is available in multiple formulations including oral tablets (immediate and delayed release), topical gels and patches, ophthalmic solutions, and rectal suppositories. Formulation choice depends on indication, patient tolerance, and need to minimize systemic exposure.
Pharmacokinetics
Absorption: Oral diclofenac is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations reached in 1-2 hours for immediate-release formulations and 4-6 hours for delayed-release formulations. Bioavailability is approximately 50-60% due to extensive first-pass metabolism. Food delays absorption but does not significantly reduce total bioavailability. Topical formulations have much lower systemic absorption (typically 5-10% of oral bioavailability).
Distribution: Diclofenac is highly protein-bound (>99%, primarily to albumin), resulting in a small volume of distribution. It penetrates into synovial fluid, reaching therapeutic concentrations that persist longer than in plasma. It crosses the placenta and is present in breast milk in low concentrations.
Metabolism: Extensive hepatic metabolism occurs via cytochrome P450 enzymes, primarily CYP2C9 and to a lesser extent CYP3A4 and CYP2C8. The drug undergoes hydroxylation, methoxylation, and glucuronidation. Several metabolites are formed, some with weak anti-inflammatory activity. First-pass metabolism significantly reduces bioavailability.
Excretion: Approximately 65% is excreted in urine (primarily as metabolites and conjugates) and 35% in bile/feces. The elimination half-life is 1-2 hours for diclofenac sodium and 1.5 hours for diclofenac potassium, though synovial fluid concentrations persist longer. Renal or hepatic impairment can prolong elimination and increase toxicity risk.
Adverse effects
Diclofenac carries black box warnings for serious cardiovascular thrombotic events (myocardial infarction, stroke) and serious gastrointestinal adverse events (bleeding, ulceration, perforation). Risk increases with dose and duration.
Gastrointestinal
- Dyspepsia, nausea, abdominal pain: most common, occur in 10-20%
- Peptic ulcer disease: gastric and duodenal ulcers
- GI bleeding and perforation: can be fatal, often without warning
- Hepatotoxicity: elevated transaminases (1-5%), rare acute liver failure
Cardiovascular
- Thrombotic events: increased risk of MI and stroke, particularly with long-term use
- Hypertension: new onset or worsening of existing hypertension
- Heart failure exacerbation: fluid retention worsens CHF
- Edema: peripheral fluid retention common
Renal
- Acute kidney injury: due to inhibition of renal prostaglandins
- Interstitial nephritis: rare hypersensitivity reaction
- Hyperkalemia: due to hypoaldosteronism
- Sodium and water retention: worsens hypertension and edema
Hematologic
- Antiplatelet effect: increased bleeding time
- Anemia: from chronic GI blood loss
- Rare: agranulocytosis, aplastic anemia
Hypersensitivity
- Asthma exacerbation: aspirin-sensitive asthma cross-reacts
- Angioedema and urticaria: type I hypersensitivity
- Stevens-Johnson syndrome/TEN: rare but serious skin reactions
- Anaphylaxis: rare
Dermatologic
- Photosensitivity: with topical use for actinic keratoses
- Contact dermatitis: topical formulations
Ophthalmic (topical use)
- Burning, stinging: transient on instillation
- Corneal effects: superficial punctate keratitis (rare)
Hepatotoxicity with diclofenac may be more common than with other NSAIDs. Liver function monitoring is recommended in patients on chronic therapy.
Contraindications and warnings
Absolute contraindications
- Hypersensitivity to diclofenac, aspirin, or other NSAIDs
- Active peptic ulcer disease or recent GI bleeding
- History of asthma, urticaria, or allergic reaction after taking aspirin or NSAIDs
- CABG surgery perioperative period: within 14 days
- Third trimester of pregnancy: risk of premature ductus arteriosus closure
- Severe hepatic impairment or active liver disease
- Severe renal impairment (CrCl <30 mL/min for systemic formulations)
- History of NSAID-induced asthma (aspirin triad)
Warnings and precautions
Cardiovascular: Use the lowest effective dose for the shortest duration. Patients with known cardiovascular disease or risk factors are at greater risk for thrombotic events. Diclofenac may have higher cardiovascular risk compared to some other NSAIDs like naproxen.
Gastrointestinal: Risk factors for GI bleeding include advanced age, corticosteroid use, anticoagulant use, longer duration of NSAID therapy, smoking, alcohol use, and poor general health. Consider proton pump inhibitor co-therapy in high-risk patients.
Renal: NSAIDs reduce renal blood flow via prostaglandin inhibition. Risk is highest in volume depletion, heart failure, cirrhosis, and pre-existing renal disease. Use with caution in mild to moderate chronic kidney disease (CrCl 30-60 mL/min) with close monitoring of renal function and avoidance of concurrent nephrotoxic drugs. Monitor renal function, especially in elderly patients and those on diuretics or ACE inhibitors.
Hepatic: Borderline elevations of liver enzymes occur in up to 15% of patients. Discontinue if transaminases exceed three times the upper limit of normal or if clinical signs of liver disease develop.
Pregnancy: Avoid in pregnancy, especially after 30 weeks gestation. Use in early pregnancy may increase miscarriage risk. NSAIDs can cause oligohydramnios and premature closure of the fetal ductus arteriosus.
Elderly: Increased risk of serious GI events, renal toxicity, and cardiovascular events. Start with lower doses.
Asthma: Cross-reactivity with aspirin occurs in aspirin-exacerbated respiratory disease (AERD). May precipitate bronchospasm.
Hematologic: Anemia should be investigated. NSAIDs may mask fever and inflammation, delaying diagnosis of infection.
Drug interactions
Anticoagulants and antiplatelets
- Warfarin: increased bleeding risk due to antiplatelet effect and displacement from protein binding
- Aspirin: increased GI toxicity, may reduce cardioprotective effect of low-dose aspirin
- Clopidogrel, other antiplatelets: additive bleeding risk
- DOACs: increased bleeding risk
Antihypertensives
- ACE inhibitors and ARBs: reduced antihypertensive efficacy, increased risk of renal impairment and hyperkalemia
- Diuretics: reduced diuretic efficacy, increased nephrotoxicity risk
- Beta-blockers: reduced antihypertensive effect
Nephrotoxic agents
- Aminoglycosides: additive nephrotoxicity
- Cyclosporine, tacrolimus: increased nephrotoxicity risk
- Methotrexate: NSAIDs reduce renal clearance of methotrexate, increasing toxicity
Lithium
Diclofenac reduces renal lithium clearance, increasing lithium levels and toxicity risk. Monitor lithium concentrations closely.
Corticosteroids
Increased risk of GI ulceration and bleeding when combined with NSAIDs.
SSRIs and SNRIs
Increased risk of GI bleeding due to antiplatelet effects of serotonergic antidepressants.
CYP2C9 substrates and inhibitors
Diclofenac is metabolized by CYP2C9. Inhibitors like fluconazole may increase diclofenac levels. Diclofenac may increase levels of other CYP2C9 substrates.
Alcohol
Increased risk of GI bleeding and hepatotoxicity.
Cholestyramine
May reduce diclofenac absorption; separate administration by several hours.
Other NSAIDs
Combination increases toxicity without added benefit and is not recommended.
Clinical pearls
Black box warnings: Diclofenac carries two black box warnings—cardiovascular thrombotic events and GI bleeding. These risks increase with dose and duration. Always use the lowest effective dose for the shortest time.
Hepatotoxicity monitoring: Diclofenac has higher hepatotoxicity rates than many other NSAIDs. Check baseline liver function tests and monitor periodically in patients on chronic therapy. Discontinue if ALT/AST exceed three times normal.
Cardiovascular risk stratification: Among traditional NSAIDs, diclofenac may carry higher cardiovascular risk than naproxen or ibuprofen. Avoid in patients with recent MI, stroke, or significant cardiovascular disease when possible.
Topical formulations: Topical diclofenac (gel, patch) provides local anti-inflammatory effects with lower systemic absorption, but systemic adverse effects can still occur, especially with prolonged use over large areas.
GI protection: In patients requiring chronic NSAID therapy with GI risk factors (age >65, prior ulcer, concurrent anticoagulants or corticosteroids), co-prescribe a proton pump inhibitor.
Renal considerations: NSAIDs are contraindicated in severe chronic kidney disease (CrCl <30 mL/min). In patients with mild to moderate CKD, use cautiously with close monitoring, especially when combined with ACE inhibitors and diuretics ("triple whammy").
Aspirin interaction: NSAIDs may interfere with the antiplatelet effect of low-dose aspirin by competing for COX-1 binding sites. If both are necessary, take aspirin at least 2 hours before diclofenac.
Pregnancy category: Avoid in all trimesters when possible. After 30 weeks, NSAIDs can cause premature closure of the ductus arteriosus, oligohydramnios, and pulmonary hypertension in the neonate.
Ophthalmic use: Topical diclofenac ophthalmic solution is used to reduce inflammation and pain after cataract surgery and to prevent cystoid macular edema. Systemic absorption from ophthalmic use is minimal.
Actinic keratoses: Topical diclofenac gel is approved for actinic keratoses treatment. It causes local inflammation and photosensitivity during use. Counsel patients about sun protection.
Exam tip: Remember the NSAID triad (aspirin-exacerbated respiratory disease): asthma, nasal polyps, and aspirin/NSAID hypersensitivity. These patients should avoid diclofenac and all other NSAIDs.
Fever masking: NSAIDs suppress fever and may mask serious infections. Use caution in immunocompromised patients or when infection is suspected.
Practice questions
1. A 68-year-old man with a history of hypertension, type 2 diabetes, and chronic kidney disease (creatinine 1.8 mg/dL) presents with worsening knee pain from osteoarthritis. His current medications include lisinopril, metformin, and furosemide. He is prescribed diclofenac for pain control. Three weeks later, he develops fatigue and lower extremity edema. Laboratory studies show creatinine 3.2 mg/dL, potassium 5.9 mEq/L, and BUN 52 mg/dL. Which of the following best explains this patient's acute kidney injury?
2. A 42-year-old woman with rheumatoid arthritis has been taking diclofenac 75 mg twice daily for 6 months with good symptom control. She presents with fatigue and routine laboratory studies show AST 182 U/L (normal 10-40) and ALT 215 U/L (normal 10-40). Bilirubin, alkaline phosphatase, and coagulation studies are normal. She denies alcohol use and hepatitis serologies are negative. Which of the following is the most appropriate next step in management?
3. A 35-year-old woman in her 32nd week of pregnancy presents with severe headache and is found to have preeclampsia. In reviewing her medication history, the obstetrician notes she has been taking diclofenac for chronic back pain throughout pregnancy. Fetal ultrasound shows oligohydramnios. Which of the following fetal complications is most directly associated with maternal NSAID use in the third trimester?
Frequently asked questions
How does diclofenac work?
Diclofenac works by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, which blocks the conversion of arachidonic acid to prostaglandins. Prostaglandins mediate inflammation, pain, and fever, so reducing their production provides analgesic, anti-inflammatory, and antipyretic effects. COX-1 inhibition also affects gastric mucosal protection and platelet function, leading to potential adverse effects like GI bleeding.
What are the side effects of diclofenac?
The most serious side effects include gastrointestinal bleeding and ulceration, cardiovascular thrombotic events (heart attack and stroke), acute kidney injury, and hepatotoxicity. Common side effects include dyspepsia, nausea, abdominal pain, headache, and edema. Diclofenac also increases bleeding risk due to antiplatelet effects and can cause hypersensitivity reactions including bronchospasm in aspirin-sensitive patients.
Is diclofenac a controlled substance?
No, diclofenac is not a controlled substance. It is a nonsteroidal anti-inflammatory drug (NSAID) available by prescription in most formulations, though some lower-strength topical preparations may be available over-the-counter in certain countries. It does not have abuse potential and is not regulated under controlled substance schedules.
Can I take diclofenac while pregnant?
Diclofenac should be avoided during pregnancy, especially after 30 weeks gestation. In the third trimester, NSAIDs can cause premature closure of the fetal ductus arteriosus, oligohydramnios, and pulmonary hypertension in the newborn. Use in early pregnancy may increase the risk of miscarriage. If pain relief is needed during pregnancy, acetaminophen is generally preferred. Consult your healthcare provider before taking diclofenac if you are pregnant or planning to become pregnant.
Diclofenac vs ibuprofen — what is the difference?
Both are non-selective NSAIDs that inhibit COX enzymes, but diclofenac is more COX-2 selective than ibuprofen and may have slightly higher cardiovascular risk. Diclofenac has higher hepatotoxicity rates and is more potent milligram-per-milligram. Both have similar gastrointestinal and renal side effects. Ibuprofen is available over-the-counter at lower doses, while diclofenac typically requires a prescription. The choice between them depends on individual patient factors, tolerability, and the specific condition being treated.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: D11AX18WHO ATC/DDD index: M01AB05
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.