Headache after frequent use of serotonin agonists zolmitriptan and naratriptan

Abstract

The introduction of serotonin (5-HT) agonists such as sumatriptan into the therapy of migraine combines high efficacy with good tolerability when compared with ergotamine derivatives. Enthusiasm has been hampered, however, by the observation that sumatriptan can cause an increase in migraine frequency and chronic daily headache. Second-generation 5-HT agonists, such as zolmitriptan and naratriptan-possess an improved pharmacological profile with higher oral bioavailability and extended half-life, resulting in higher efficacy and better tolerability at lower dosages. We report drug-induced headache after the use of zolmitriptan and naratriptan. The clinical details of each patient are listed in the table. All patients had used zolmitriptan or naratriptan for at least 6 months. Four patients (GM, MoM, GY, PM) developed chronic daily headache, three (KR, WA, MM) suffered from a daily migraine-type headache, and four patients (PD, BA, DP, SA) had an increase in migraine attacks, of which all remained responsive to triptans. Migraine attacks up to 48 h after initially successful treatment were considered as recurrent headaches and not considered as a new attack. Six patients had used other types of medication before, five patients had never taken any triptans or ergotaminederivatives (PD, YG, MM, DP, SA) but developed the druginduced headache or a severe increase of attack frequency within 6 months from the first drug intake. In all patients the drugs were discontinued, in most cases (PD, KR, PM, MoM, WA, YG, BA, MM, DP) in hospital. All patients underwent neurological examinations as well as additional diagnostic procedures such as computed tomography scan, Doppler/duplex sonography, and other routine laboratory screening. Up to the present, nine of 11 patients have benefited from drug withdrawal (table). These cases reveal important aspects of the new 5-HT agonists. In contrast to initial expectations, there is evidence now that all members of the triptan family are able to cause drug-induced headache. The weekly dosages necessary to initiate drug-induced headache with new highly effective 5HT agonists are lower than initially thought. At the time of admission four patients consumed 7·5–10 mg of zolmitriptan or 10–12 mg of naratriptan weekly, suggesting that the critical dosage in some patients is lower than 7·5 mg or three tablets weekly. The time of onset of drug-induced headache might be shorter with the new triptans which have a significantly higher affinity and intrinsic activity at the 5-HT receptor site when compared with sumatriptan or ergotamine derivatives. In patients receiving triptans, increasing attack frequency may be the first sign of a developing drug-induced headache. The new 5-HT agonists further increase treatment options for migraine attacks, but the improved pharmacological properties may cause a faster onset of drug-induced headache, and at lower dosages.