Diclofenac

Diclofenac is a phenylacetic acid NSAID with relative COX-2 preference. It is potent and widely used for musculoskeletal, postoperative and renal colic pain, and it carries a cardiovascular risk comparable with the coxibs.

Class. NSAID (acetic acid derivative), preferential COX-2 inhibitor.

Mechanism. Inhibition of cyclo-oxygenase, with greater activity at COX-2. It also reduces arachidonate availability.

Pharmacokinetics. Well absorbed, but first-pass metabolism leaves bioavailability near 50%. Peak 1 to 2 hours (2 to 3 hours for gastro-resistant tablets, delayed by food). Protein binding over 99%. Plasma half-life is 1 to 2 hours, but synovial concentrations persist longer. Hepatic CYP2C9 hydroxylation and glucuronidation; renal and biliary excretion.

Indications are inflammatory and degenerative joint disease, acute musculoskeletal pain, acute gout, dysmenorrhoea, renal colic, postoperative pain and migraine (as a fast-acting sachet in some markets).

Adults

• Oral (immediate release or gastro-resistant): 50 mg two to three times daily; 75 to 150 mg daily in divided doses. Acute gout: 50 mg three times daily until the attack settles.
• Modified release: 75 mg once or twice daily, or 100 mg once daily.
• Rectal: 100 mg once daily, usually at night.
• Intramuscular: 75 mg once daily deep into the upper outer buttock; a second 75 mg dose after several hours may be used in severe pain (renal colic). Maximum 2 days.
• Intravenous: 75 mg diluted in 100 to 500 mL of 0.9% sodium chloride or 5% glucose (buffered with sodium bicarbonate) and infused over 30 to 120 minutes. A second dose may follow after at least 4 to 6 hours. Maximum 2 days.
• Maximum 150 mg in 24 hours from all routes combined. No loading dose.

Children. Not a first-line choice. Juvenile idiopathic arthritis (specialist, child over 1 year): 1 to 3 mg/kg daily in 2 to 3 divided doses, maximum 150 mg daily.

Topical. Gel 1% to 2.32% applied 3 to 4 times daily to a localised site has low systemic exposure and is preferred in older adults with joint pain.

Contraindications. Established ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, heart failure (New York Heart Association class II to IV); active or previous gastrointestinal ulcer, bleeding or perforation; severe renal, hepatic or cardiac impairment; third trimester; aspirin-sensitive asthma; around coronary artery bypass surgery; suspected dengue.

Boxed-warning-level risks. Arterial thrombotic events (risk higher with high dose and long duration); gastrointestinal haemorrhage and perforation; hepatotoxicity that can be severe.

Adverse effects. Common: dyspepsia, abdominal pain, nausea, headache, dizziness, raised transaminases, fluid retention and hypertension. Serious: gastrointestinal bleeding, acute kidney injury, hepatitis and acute liver failure, heart failure, myocardial infarction, stroke, severe skin reactions and anaphylaxis. Intramuscular injection can cause injection-site necrosis (Nicolau syndrome) and sciatic nerve injury.

Interactions. As with other NSAIDs: anticoagulants, antiplatelets, corticosteroids and SSRIs (bleeding); ACE inhibitors, angiotensin receptor blockers and diuretics (kidney injury); lithium, methotrexate, ciclosporin, tacrolimus and digoxin (raised levels or toxicity). CYP2C9 inhibitors (voriconazole, fluconazole) increase exposure. Co-prescription with other hepatotoxic drugs (antituberculosis therapy) adds to liver injury risk.

Common prescribing errors. Exceeding 150 mg daily by stacking oral, rectal and parenteral routes; repeating intramuscular doses beyond 2 days; using in a patient with cardiovascular disease because of its potency.

Special groups

• Pregnancy: avoid from 20 weeks and absolutely in the third trimester. Before 20 weeks, use only if necessary.
• Breastfeeding: low milk levels; short-term use acceptable, though ibuprofen is preferred.
• Older adults: lowest dose, gastroprotection, renal checks; topical route preferred.
• Kidney impairment: avoid if creatinine clearance is under 30 mL/min; caution in mild to moderate.
• Liver impairment: avoid in severe disease; monitor enzymes in mild to moderate.
• Regional: where intramuscular injection is used for acute pain, inject deep into the upper outer buttock using sterile technique. Avoid in people on antituberculosis therapy where an alternative exists.

Formulations. Tablets 25 and 50 mg, gastro-resistant 50 mg, modified release 75 and 100 mg, suppositories 12.5 to 100 mg, injection 75 mg in 3 mL, topical gel.

Administration. Oral doses are best taken with or after food. Intravenous diluent must be buffered with 0.5 mL of 8.4% sodium bicarbonate (or 1 mL of 4.2%) to avoid precipitation, and bolus injection is not given. Give intramuscular injections deep into the buttock.

Baseline. Blood pressure, cardiovascular history, creatinine and eGFR, liver enzymes if prolonged treatment is planned, ulcer history, volume status and concurrent medicines.

Monitoring. Blood pressure and creatinine within 1 to 2 weeks in high-risk patients. Liver enzymes at baseline, within the first 8 weeks and periodically during long-term use. Haemoglobin if gastrointestinal symptoms occur.

Therapeutic drug monitoring. Not used.

Stopping thresholds. Stop for aminotransferases rising above 3 times the upper limit of normal, jaundice, gastrointestinal bleeding, creatinine rise of 30% or more, new heart failure or chest pain, or severe rash.

Referral and escalation. Chest pain, melaena, jaundice, anuria or hypersensitivity needs emergency evaluation. Long-term use in a person with cardiovascular risk needs a safer alternative.