Diclofenac

Respiratory

Oral diclofenac caused eosinophilic pneumonitis in a 67-year-old man [ ] and also during long-term topical use in a 62-year-old woman [ ].

• A 62-year-old woman developed a chronic cough and bilateral infiltrates on the chest X-ray. She had been taking diclofenac emulgel for 10 years for osteoarthritis. Bronchoscopy showed eosinophilic alveolitis. After ruling out other possible causes, eosinophilic pneumonia was diagnosed. Diclofenac was withdrawn and oral glucocorticoids started. Within 7 days the bilateral pulmonary infiltrates on CT scan resolved.

Nervous system

The frequency of central nervous system adverse effects is 1–9%. Headache, dizziness, vertigo, insomnia, drowsiness, and agitation have been reported. Hallucinatory symptoms and generalized tonic-clonic seizures have also been described [ , ]. Toxic encephalitis can be part of a general toxic reaction [ ]. Diclofenac provoked aseptic meningitis in patients with systemic lupus erythematosus [ ].

Sensory systems

Hyperemia, burning of the eyes, eyelid allergic contact dermatitis, and conjunctivitis can occur in patients who use diclofenac eye-drops [ , ].

Diclofenac can cause reduced corneal sensitivity, starting from 15 minutes after instillation and measurable after 1 hour [ ]. This corneal hypesthesia can be useful in reducing pain and discomfort in ocular inflammation and after surgery. In chronic treatment, however, the effect of diclofenac on corneal nerves can cause either increased healing time of the corneal epithelium or a neurotrophic epitheliopathy in patients with conditions that predispose to epithelial damage, such as dry eyes. In contrast, flurbiprofen, indometacin, and ketorolac tromethamine did not cause corneal hypesthesia.

Keratolysis (corneal melting) occurred after 5 days during the use of topical preservative-free diclofenac qds after laser-assisted subepithelial keratectomy in a 25-year-old man [ ]. There was corneal edema with Descemet′s membrane striae and epithelial microcysts and a vertical epithelial defect (1.0 × 2.0 mm), with 30% tissue loss in the affected area. After withdrawal of diclofenac topical dexamethasone produced improvement but not complete healing.

Electrolyte balance

Severe hyponatremia developed in an elderly woman treated with intramuscular diclofenac [ ].

NSAIDs can cause hyperkalemic acidosis and should be used with caution in the presence of renal impairment [ ].

• A 76-year-old woman developed quadriparesis associated with hyperkalemia after taking diclofenac 100 mg/day for 10 months for gouty arthritis. She had a metabolic acidosis with a normal anion gap and mild renal impairment. Her weakness resolved after withdrawal of diclofenac and correction of the hyperkalemia.

Mineral balance

At least three reports of severe hyponatremia have been described [ , , ]. In the last case the withdrawal of diclofenac and fluid restriction led to normal fluid and electrolyte balance within 10 days, despite concomitant treatment with nabumetone.

Hematologic

In an analysis of 447 adverse effects in 194 patients worldwide [ ], 20 had blood abnormalities, including two cases of agranulocytosis and one of granulocytopenia. One of these patients, who was sensitive to pyrazolone, had taken a pyrazolone compound as well. Immune-mediated agranulocytosis and thrombocytopenia have been reported [ , ].

Reversible hemolytic anemia [ ], two cases of severe immune hemolytic anemia with acute renal insufficiency [ , ], and fatal hemolytic anemia have occurred [ ].

Occasionally, for unknown reasons, patients who develop either immune hemolysis or thrombocytopenia while taking diclofenac may simultaneously be sensitized to both erythrocytes and platelets.

• Two patients developed antibodies against platelets and red blood cells while taking diclofenac [ ]. One developed severe hemolysis and significant thrombocytopenic purpura, and the other developed thrombocytopenia but no hemolysis. Standard serological tests for antibodies against platelets and erythrocytes were carried out in the presence and absence of diclofenac and its metabolites. Both patients had a positive direct antiglobulin test and drug-dependent and/or metabolite-dependent antibodies against erythrocytes and platelets.

A systematic evaluation of 12 patients who had diclofenac-induced immune hemolysis has provided evidence that patients with diclofenac-induced immune hemolysis produce a broad spectrum of anti-diclofenac erythrocyte antibodies [ ]. The metabolite 4′-OH-diclofenac seems to be the most immunogenic metabolite. Nevertheless, all patients’ sera samples contain a mixture of antibodies that recognize several distinguishable epitopes, which consist of different drug metabolites and a target protein on the erythrocyte surface, which appears to be the Rh complex in many, but not all, cases. However, when serum samples were processed to detect platelet antibodies to diclofenac or diclofenac metabolites, none of the 12 patients gave positive results. Additional target proteins remain to be identified.

Diclofenac can cause panmyelopathy [ ]. Data from the International Agranulocytosis and Aplastic Anemia Study showed an increased risk of aplastic anemia (multivariate rate-ratio 8.8) [ ]. Fatal aplastic anemia has also been described [ ], as have purpura and thrombocytopenia, although not always with certainty. Spontaneous bleeding (subcutaneous bruises, hematoma, greater wound drainage) has been associated with diclofenac [ ].

Bone marrow necrosis has been attributed to diclofenac [ ].

• A 26-year-old man who received 12 doses of intramuscular diclofenac 75 mg at 30-minute intervals for renal colic developed fever and bone pain 5 days later. His hemoglobin was 7.7 g/dl and there was leukopenia (1.6 × 10 ⁹ /l) and neutropenia (0.5 × 10 ⁹ /l) but no thrombocytopenia (179 × 10 ⁹ /l). Bone marrow aspiration smears showed striking necrosis and nearly absent intact hemopoietic cells; bone marrow biopsy showed bone marrow necrosis. He recovered after blood transfusion.

The authors attributed the bone marrow necrosis to cytokine release because of the large dose of diclofenac.

Gastrointestinal

Gastrointestinal adverse effects are particularly frequent, and affect some 14–25% of patients; the incidence of the most serious, peptic ulcer and bleeding were 0.16–0.34% and 0.16–0.17%, respectively [ ]. A prospective 12-week endoscopic study documented better gastrointestinal tolerability with diclofenac than naproxen [ ]. Upper gastrointestinal hemorrhage has been associated with transdermal application of diclofenac, with massive bleeding in two of four patients [ ].

Perforation of the terminal ileum occurred in one patient who had taken a high dose (400 mg/day) of modified-release diclofenac [ ].

Colonic stricture, similar to ileum “diaphragm” disease, developed in a patient during prolonged administration of modified-release diclofenac [ ]. Pseudomembranous colitis and colonic ulceration, with or without a diaphragm-like colonic stricture, have been reported [ ]. Dispersible diclofenac is a formulation from which absorption is more rapid than the usual formulation, but gastrointestinal adverse events still occur [ ].

Non-specific colitis has been reported in a 69-year-old man who took modified-release diclofenac 200 mg/day [ ].

Rectal administration caused adverse effects in 16% of patients [ ]; anorectal lesions (erosions, ulcers, stenosis of the anal margin) occurred after a relatively short period of suppository use [ ].