Cluster-like headache attacks triggered by nitrofurantoin intake

Abstract

Sir,A wide spectrum of drugs can induce headache, which is infact one of the most common adverse drug events [1, 2].Although headache is usually a nonserious, unwanted effect,itcould bedifficult toquickly and correctly diagnose, leadingto repeated medical consultations, prescription of laboratoryor instrumental examinations, and even hospitalization [1].The International Headache Classification (IHC), inChapter 8, includes these secondary headaches as adversereactions to drugs [3]. Whereas some drug-related headachesare well characterized, others lack specific and accuratedefinition [1]. We present a patient experiencing cluster-likeattacks after nitrofurantoin consumption.A previously healthy 42-year-old man with no personal orfamily history of migraine, tension, or cluster headachepresented to the emergency room (ER) complaining of asevere unilateral left-sided headache. The pain was describedas lancinating, centered on the left eye and extending toperiorbital, supraorbital, and temporal regions. It wasaccompanied by conjunctival injection, lacrimation, eyelidedema, facial swelling, nasal congestion, and rhinorrhea ontheaffectedside.Theattackquicklyworsened,peakingwithin5–10 min, with a duration of about 60 min; both pain and theaccompanying autonomic signs spontaneously resolved. Theheadache began about 1 h after he took a tablet ofnitrofurantoin (50 mg) for a urinary tract infection. The daybefore, just after the first-ever consumption of nitrofurantoin,he had a headache attack with the same clinical presentation,the same latency between drug consumption and pain onset,and the same duration. Physical and neurologicalexaminations were normal, as were routine hematologicaltests and brain magnetic resonance imaging. As both attacksfollowed the intake of nitrofurantoin, the patient was advisedto stop taking the drug, which was replaced with a differentantibiotic agent (ciprofloxacin 500 mg twice daily).Thereafter, he experienced no further headache attacks.During a 2-year follow-up, he remained headache free.Theclosetemporalassociationbetweenthedrugintakeandthe appearance of headache on two occasions suggests acausal relationship. Nitrofurantoin is a widely used drug fortreating and preventing urinary tract infections. Headache is awell-known and one of the most common adverse effects,occurring in about 4–6 % of users [4, 5]; others side effectsinclude immune-mediated liver and lung reactions andpulmonary fibrosis. Nitrofurantoin-induced headache isusually described as severe to moderate; no specific featureshave been reported, and the pathogenetic mechanisms are notfully elucidated. Some authors [1] have categorized thisheadache as type C reactions arising from chronic use [6].Nitrofurantoin is usually included in the list of drugs that caninducebenignintracranialhypertension[7]andthenheadacherelated to raised intracranial pressure [2]. Our patient,however, had cluster-like attacks in close association withdrug intake. Several studies have demonstrated thatnitrofurans can release nitric oxide (NO) [8, 9], which is animportant neurotransmitter and regulates the vascular tone,acting as a potent vasodilator by diffusing into vascularsmooth-muscle cells. Moreover, NO is thought to play a rolein processing sensory information and pain sensitization [10].NO donors induce an immediate headache in healthyindividuals and in headache sufferers, with a delayedheadache with the characteristics of migraine, tension-type,orclusterheadacheinpatientssufferingfromtheseheadaches[10, 11]. In particular, cluster headache sufferers develop