What is diclofenac?

What is Diclofenac?

Diclofenac is a potent nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class that provides analgesic, anti-inflammatory, and antipyretic effects by inhibiting cyclooxygenase (COX) enzymes, particularly COX-2 more than COX-1. 1

Mechanism of Action

• Diclofenac works by blocking prostaglandin synthesis through inhibition of both COX-1 and COX-2 enzymes, with greater potency against COX-2 compared to traditional NSAIDs 1, 2
• This inhibition reduces prostaglandins in peripheral tissues, which are mediators of pain and inflammation 1
• The drug achieves substantial concentrations in synovial fluid (the proposed site of action), where it persists even after plasma levels decline 1, 3

Clinical Uses

Diclofenac is indicated for treating pain and inflammation in multiple musculoskeletal conditions: 4

• Osteoarthritis (100-150 mg/day in divided doses with food) 4
• Rheumatoid arthritis (150-200 mg/day in divided doses with food) 4
• Ankylosing spondylitis (100-150 mg/day) 4
• Acute musculoskeletal injuries (sprains, strains, soft tissue trauma) 5
• Acute pain conditions including postoperative pain, dysmenorrhea, renal colic, and biliary colic 6

Available Formulations

Diclofenac comes in multiple formulations designed for different clinical scenarios: 2

• Oral tablets: Immediate-release (diclofenac potassium 25mg, 50mg, 75mg) for rapid pain relief 1
• Delayed/extended-release tablets: Diclofenac sodium for once-daily dosing in chronic conditions 2
• Topical gel: Preferred for localized pain, especially in elderly patients ≥75 years, with significantly fewer gastrointestinal side effects than oral forms 4, 5
• Intramuscular injection: For acute severe pain when oral administration is not feasible 7, 6

Pharmacokinetics

• Absorption: 100% absorbed orally but only 50% bioavailable due to first-pass metabolism; peak levels occur at approximately 1 hour 1, 3
• Distribution: >99% protein-bound to albumin; volume of distribution 1.3 L/kg 1
• Metabolism: Extensively metabolized in the liver via CYP2C9 (primary), CYP2C8, and UGT2B7 1
• Elimination: Terminal half-life approximately 2 hours; 65% excreted in urine and 35% in bile as conjugated metabolites 1

Critical Safety Warnings

Cardiovascular Risk (Black Box Warning)

Diclofenac carries the highest cardiovascular risk among non-selective NSAIDs and should be avoided in patients with significant cardiac disease: 8, 4

• Relative risk of 1.63 (95% CI: 1.12-2.37) for vascular events versus placebo 8, 4
• Relative risk of 1.54 (95% CI: 1.23-1.93) for recurrent myocardial infarction 8, 4
• Relative risk of 2.40 (95% CI: 2.09-2.80) for mortality 8, 4
• Contraindicated for perioperative pain in coronary artery bypass graft (CABG) surgery 8
• Risk increases with dose and duration of use, particularly beyond 6 months 9

Gastrointestinal Risk (Black Box Warning)

• NSAIDs cause increased risk of serious GI adverse events including bleeding, ulceration, and perforation, which can be fatal 8
• These events can occur at any time without warning symptoms 8
• Elderly patients are at greater risk 8
• Use gastroprotection (proton pump inhibitor or misoprostol) in patients with any GI risk factors 4, 9

Renal Considerations

• Contraindicated in chronic kidney disease stage IV or V (eGFR <30 mL/min) 4
• Use cautiously on a case-by-case basis in stage III CKD (eGFR 30-59 mL/min) 4
• No dosage adjustment needed for mild-moderate renal impairment as renal elimination is not a significant pathway 1

Comparative Efficacy

• Diclofenac demonstrates equivalent efficacy to other established NSAIDs (aspirin, indomethacin, ibuprofen, naproxen) for rheumatic conditions 7, 10
• Shows superior results at days 1-2 compared to piroxicam and ibuprofen for acute ankle sprains 5
• Topical diclofenac is equivalent to oral diclofenac for knee/hip osteoarthritis pain but with markedly fewer GI adverse events 4, 5

Clinical Pitfalls to Avoid

• Never use diclofenac as first-line NSAID in patients with cardiovascular disease or risk factors—naproxen has lower CV risk (RR 0.92) 8
• Do not combine with aspirin for cardioprotection without gastroprotection, as this increases GI bleeding risk 4
• Avoid high doses (>150 mg/day) and prolonged duration to minimize cardiovascular and mortality risks 8, 4
• Always use the lowest effective dose for the shortest duration necessary 8
• Prefer topical over oral formulations when treating localized musculoskeletal pain, especially in elderly or high-risk patients 4, 5