Allergy to pholcodine: first case documented by oral challenge


  • We report the first documented case of allergy to pholcodine proved by positive oral challenge.

Pholcodine (morpholinyl-ethyl-3 morphine) is an anti-tussive opiate indicated for the symptomatic treatment of cough. This substance is a component of many medicinal products. We report the first documented case of allergy to pholcodine proved by positive oral challenge.

In 1992, a female, 33 years old, presented with facial angio-edema 8 h after taking Respilène® (Coopération Pharmaceutique Française, Melun, France), syrup containing pholcodine associated with domperidone, tixocortol and bacitracine, for a sore throat. Symptoms resolved after i.v. administration of corticosteroids.

She had a history of facial angio-edema related to a β-lactam for 8 years.

Prick tests to routine airborne allergens were negative. Intradermal test (IDT) to 5 μg/ml pholcodine (Coopération Pharmaceutique Française) was positive: the diameter of the papula was 3 mm after injection and the diameter of the wheal at 15 min was 7 mm, surrounded by erythema. The patch test (20% in vaseline) was negative at 48 h. Skin tests with domperidone, tixocortol, bacitracine and β-lactams were negative (1, 2).

The basophil activation test and leukotriene release test were negative to pholcodine and to amoxicillin.

Open oral challenge with pholcodine was performed with 5 and 15 mg, 1 h apart. Results were positive with the total 20-mg dose: laryngeal angio-edema occurred 9 h after the second dose, disappearing a few hours after corticosteroid i.v. injection. An oral challenge to amoxicillin, 500 mg, was negative.

No case of allergy to pholcodine was found either in the literature or in the French pharmacovigilance database. One case of recurring eosinophilic cellulitis (Wells’ syndrome) has been reported, involving other drugs including pholcodine (3). The diagnosis was confirmed by histology. Circulating immune complexes and a peri-vascular deposit of IgG and C3 were detected by direct immunofluorescence. An immunological mechanism mediated by drug-induced immune complexes was postulated. Pholcodine was not formally involved.

This case report documents allergy to pholcodine demonstrated by clinical history, positive skin test and oral challenge at a total 20-mg dose. This reactogenic dose is compatible with the presumed intake: two spoonfuls of Respilène® contain 12 mg of pholcodin. The allergic mechanism involved in this reaction was not formally established: the positive intradermal test indicates an IgE-mediated allergy, but the delay before the reaction is unusual. During the interview, the patient mentioned history of suspected allergy to β-lactams. However, this incident reported might be related to a concomitant intake of pholcodine.