Precipitation of long duration hypnic headaches after ACE inhibitor withdrawal

Abstract

Sirs: Hypnic headache is a rare headache disorder characterised by recurrent attacks of pain occurring during sleep. Headaches tend to occur in the middle or later stages of the night and patients are abruptly awakened from sleep. We present an unusual case of an 84-year-old female who developed hypnic headaches, although lasting longer than classically described, after stopping her angiotensin converting enzyme (ACE) inhibitor. These resolved completely when the ACE inhibitor was re-started. An 84-year-old female had her ACE inhibitor (enalapril, 5 mg) and a benzodiazepine (flurazepam) stopped abruptly. She immediately developed a distinctive pattern of headache, which would wake her from sleep at 3 a. m. each night. The pain was bi-temporal and it would last approximately 10 hours. Paracetamol and ibuprofen were not effective, and indomethacin was not tried. There were no other symptoms associated with the headache; in particular there were no autonomic features. Her consumption of tea and coffee had not changed, and she did not drink alcohol. There was no previous history of headache and the only significant past medical history was hypertension for which she had been taking enalapril for four years. She had also taken flurazepam and chlordiazepoxide. The enalapril had been stopped by her general practitioner as her blood pressure was considered acceptable at approximately 150/85. Her daytime blood pressure off the enalapril did rise to approximately 180/100. Although we think it unlikely that this rise is significant enough to cause the headache, this does remain a possibility. Neurological and general physical examination was otherwise normal. A biochemical profile, full blood count and computed tomography head scan were normal. Benzodiazepine re-prescription for 2 months did not alleviate the headache, therefore her enalapril was restarted. Her headache responded immediately and one week after recommencing enalapril, her headache had completely resolved. There is general agreement that the mechanisms that underlie sleep regulation and nociception are fundamentally linked although the specific nature and underlying neurochemical processes are poorly defined [4]. The pathogenesis of hypnic headache as a specific sleep related headache, however, remains speculative. There is evidence for a role for the renin-angiotensin system (RAS) in the aetiology of some headache types. The ACE inhibitor lisinopril has been shown to have a prophylactic effect in migraine [5] and migraineurs with a DD genotype have both a higher ACE activity and frequency of attacks than other migraineurs [3]. It has also been shown that dialysis headache, where the headache is not related to blood pressure changes or a ‘dysequilibrium syndrome’, can improve after treatment with ACE inhibitors [2]. We feel that our case report suggests that the RAS may be implicated in the aetiology of hypnic headache. It is not clear how ACE inhibitors mediate the beneficial effect in migraine. Angiotensin II is a neuropeptide produced within the central nervous system (CNS) and may function as a neurotransmitter, influencing neurotransmission and excitability of neurons via glutaminergic and GABAergic neurons [3]. As well as inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also increase prostacyclin synthesis and inhibit the breakdown of bradykinin, encephalin and substance P. Hypnic headache is considered by many to be a rapid-eye movement (REM) sleep-phase phenomenon. In a meta-analysis of 71 cases of hypnic headache, four had headache during polysomnography, three emerging from REM sleep and one from slow wave sleep. The reason for the association with REM sleep is unknown, but it has been suggested that certain areas of the brain of fundamental importance to antinociception, for example the locus coeruleus, an area which is normally inactive during REM sleep, might be impaired [1]. This may perhaps provide a link with the RAS as this is one area of the brain in particular which has been demonstrated to possess high numbers of angiotension receptors [3]. In conclusion, a potential association between hypnic headache and the RAS is suggested. The posLETTER TO THE EDITORS