What is diclofenac (Nonsteroidal Anti-Inflammatory Drug, NSAID)?

Diclofenac: A Potent NSAID with Analgesic, Anti-inflammatory, and Antipyretic Properties

Diclofenac is a potent non-steroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX) enzymes with greater selectivity for COX-2 than COX-1, providing analgesic, anti-inflammatory, and antipyretic effects while carrying significant cardiovascular and gastrointestinal risks that require careful consideration in clinical use. 1, 2

Mechanism of Action

• Diclofenac works primarily by inhibiting cyclooxygenase (COX) enzymes, which are responsible for prostaglandin synthesis 1
• Unlike many traditional NSAIDs, diclofenac exhibits greater potency in inhibiting COX-2 than COX-1 2
• Prostaglandins are mediators of inflammation, pain sensitization, and fever, explaining diclofenac's therapeutic effects 1
• Diclofenac may also have additional mechanisms including:
  • Synergistic effects on peroxisome proliferator-activated receptor-γ (PPAR-γ) activation 3
  • Suppression of neuronal hyperexcitability through blockage of neuronal K+ channels 3
  • Ability to cross the blood-brain barrier, enhancing central analgesic effects 3

Pharmacokinetics

• Diclofenac is 100% absorbed after oral administration but has only about 50% bioavailability due to first-pass metabolism 1
• Peak plasma levels are achieved approximately 1 hour after administration in fasting individuals 1
• The drug is more than 99% bound to human serum proteins, primarily albumin 1
• Diclofenac has a relatively short elimination half-life of approximately 1.5-2 hours in plasma 1, 4
• Despite its short half-life, diclofenac persists longer in synovial fluid, which may contribute to its sustained efficacy in joint conditions 1, 4
• The drug undergoes extensive hepatic metabolism with subsequent urinary and biliary excretion of metabolites 1

Clinical Applications

• Diclofenac is used for treating various painful and inflammatory conditions, including:
  • Rheumatoid arthritis 5, 4
  • Osteoarthritis 6, 4
  • Ankylosing spondylitis 4, 7
  • Acute pain conditions including renal and biliary colic 5
  • Acute ankle sprains 6
• Available in multiple formulations:
  • Oral tablets (immediate-release, delayed-release, extended-release) 2
  • Topical preparations (particularly useful for osteoarthritis of the knee) 6
  • Injectable forms for acute pain management 5

Cardiovascular and Gastrointestinal Risks

• Diclofenac carries significant cardiovascular risks:
  • Increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke 6
  • Meta-analyses show diclofenac has a higher risk profile compared to other NSAIDs like naproxen 6
  • Risk ratio for vascular events is 1.63 (95% CI 1.12-2.37) compared to placebo 6
  • Risk of recurrent MI (1.54,95% CI 1.23-1.93) and mortality (2.40,95% CI 2.09-2.80) is elevated 6
• Gastrointestinal adverse effects are common:
  • Risk of serious gastrointestinal events including inflammation, bleeding, ulceration, and perforation 6
  • Elderly patients are at greater risk for serious gastrointestinal events 6
• Topical diclofenac may offer a safer alternative for osteoarthritis of the knee:
  • Associated with markedly fewer gastrointestinal adverse events compared to oral NSAIDs 6
  • Equivalent efficacy to oral diclofenac for knee osteoarthritis pain 6

Drug Interactions and Precautions

• Diclofenac has important drug interactions that require monitoring:
  • May reduce effectiveness of antihypertensive medications and diuretics 1
  • Can increase serum concentration and prolong half-life of digoxin 1
  • May increase risk of methotrexate toxicity when used concomitantly 1
  • Can increase nephrotoxicity when used with cyclosporine 1
• Special precautions:
  • Contraindicated for perioperative pain in coronary artery bypass graft (CABG) surgery 6
  • Use with caution in patients with cardiovascular disease or risk factors 6
  • May delay or prevent ovulation, potentially causing reversible infertility in some women 1
  • Requires careful consideration in elderly patients due to increased risk of adverse effects 6

Clinical Considerations

• For osteoarthritis of the knee, topical diclofenac offers advantages:
  • Similar efficacy to oral formulations with fewer systemic side effects 6
  • Particularly beneficial for patients at high risk for NSAID-related adverse events 6
• For acute ankle sprains:
  • Diclofenac has shown superior results for reducing pain during motion compared to other NSAIDs like piroxicam and ibuprofen 6
• In patients with cardiovascular risk factors:
  • Consider alternatives with lower cardiovascular risk profiles, such as naproxen 6
  • Follow a stepped care approach starting with safer alternatives like acetaminophen before considering NSAIDs 6

Recent Innovations

• Pharmaceutical technology has led to development of improved diclofenac formulations:
  • SoluMatrix diclofenac with submicron particles for efficacy at lower doses 2
  • Various topical formulations to minimize systemic absorption 2
  • Liquid-filled soft gel capsules and powder for oral solution for faster onset of action 2