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Headache after frequent use of serotonin agonists zolmitriptan and naratriptan
RESEARCH LETTERS
Headache after frequent use of serotonin agonists zolmitriptan and naratriptan Volker Limmroth, Zaza Kazarawa, Günther Fritsche, Hans-Christoph Diener
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.1,2 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.3,4 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.3,4 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. 1 2
3
4
Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573. Gaist D, Tsirpoulus I, Sindrup SH, et al. Inappropriate use of sumatriptan: population based register and interview study. BMJ 1998; 316: 1352–53. Martin GR, Robertson AD, MacLennan SJ, et al. Receptor specifity and trigemino-vascular inhibitory actions of a novel 5-HT1B/D receptor partial agonist, 311C90 (zolmitriptan). Br J Pharmacol 1997; 121: 157–64. Gunasekara NS, Wiseman LR. Naratriptan. CNS Drugs 1997; 8: 402–08.
Department of Neurology, School of Medicine, University of Essen, 45122 Essen, Germany (H-C Diener e-mail: [email protected])
Patient, age, sex
Primary Prior headache treatment since with ergotderivatives
Prior treatment with triptans
Triptan since (month), last dosage in previous 3 month
Chronic daily headache, type
Increase in attack frequency (initial/final)
Comments
Effects of withdrawal
PD, 51, f
M, 20 y
No
No
No
2 to 6 monthly
KR, 44, f
M, 24 y
Yes
No
M, 20 y
Yes
Yes, sumatriptan
Yes, daily migraine-like Yes, daily TTH-like
Initially yes
BM, 46, f
10 m, 1232·5 mg monthly 12 m, 2432·5 mg monthly 12 m, 1232·5 mg monthly
Significant reduction in frequency Complete relief of daily headache Complete relief of daily headache, significant reduction in frequency
MoM, 44, f M, 6 y TTH 20 y
No
Yes, sumatriptan
12 m, 1032·5 mg monthly
Yes, daily TTH-like
No
WA, 63, f
M, 40 y
Yes
No
MwA, 17 y No
No
Yes, daily migraine-like Yes, daily TTH-like
No
YG, 29, f
12 m, 3032·5 mg monthly 12 m, 3032·5 mg monthly
BA, 50, f
M, 10 y
Yes
2 to 8 monthly
M, 23 y
No
8 m, 1232·5 mg monthly 18 m, 1832·5 mg monthly
No
MM, 43, f
Yes, sumatriptan No
Yes, daily migraine-like
Initially yes
Increase in frequency under monotherapy with zolmitriptan Daily migraine-like headache under monotherapy with zolmitriptan Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence and increase in migraine attacks Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence Daily migraine-like headache under monotherapy with zolmitriptan Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence Increase in frequency under monotherapy with zolmitriptan Daily migraine-like headache under monotherapy with zolmitriptan
DP, 25, f
M, 10 y
No
No
No
SA, 42, f
M, 22 y
No
No
KM, 48, f
M, 19 y
No
Yes, sumatriptan
12 m, 1232·5 mg monthly 6 m, 1532·5 mg monthly 5 m, 2032·5 mg monthly
3 to 10 monthly Increase in frequency under monotherapy with zolmitriptan 5 to 15 monthly Increase in frequency under monotherapy with naratriptan 2 to 12 monthly Daily TTH-like headache under various substances (NSAID and sumatriptan), under monotherapy with naratriptan worsening and increase in migraine attacks
No Yes, daily TTH-like
2 to 8 monthly
No
Complete relief of daily headache
Complete relief of daily headache Complete relief of daily headache
Significant reduction in frequency Complete relief of daily headache, significant reduction in frequency Still to be determined Still to be determined Complete relief of daily headache, significant reduction in frequency
M=migraine without aura, MwA=migraine with aura, TTH=tension-type headache, f=female, m=month, y=year.
Clinical characteristics of patients
378
THE LANCET • Vol 353 • January 30, 1999
Headache after frequent use of serotonin agonists zolmitriptan and naratriptan Volker Limmroth, Zaza Kazarawa, Günther Fritsche, Hans-Christoph Diener
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.1,2 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.3,4 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.3,4 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. 1 2
3
4
Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573. Gaist D, Tsirpoulus I, Sindrup SH, et al. Inappropriate use of sumatriptan: population based register and interview study. BMJ 1998; 316: 1352–53. Martin GR, Robertson AD, MacLennan SJ, et al. Receptor specifity and trigemino-vascular inhibitory actions of a novel 5-HT1B/D receptor partial agonist, 311C90 (zolmitriptan). Br J Pharmacol 1997; 121: 157–64. Gunasekara NS, Wiseman LR. Naratriptan. CNS Drugs 1997; 8: 402–08.
Department of Neurology, School of Medicine, University of Essen, 45122 Essen, Germany (H-C Diener e-mail: [email protected])
Patient, age, sex
Primary Prior headache treatment since with ergotderivatives
Prior treatment with triptans
Triptan since (month), last dosage in previous 3 month
Chronic daily headache, type
Increase in attack frequency (initial/final)
Comments
Effects of withdrawal
PD, 51, f
M, 20 y
No
No
No
2 to 6 monthly
KR, 44, f
M, 24 y
Yes
No
M, 20 y
Yes
Yes, sumatriptan
Yes, daily migraine-like Yes, daily TTH-like
Initially yes
BM, 46, f
10 m, 1232·5 mg monthly 12 m, 2432·5 mg monthly 12 m, 1232·5 mg monthly
Significant reduction in frequency Complete relief of daily headache Complete relief of daily headache, significant reduction in frequency
MoM, 44, f M, 6 y TTH 20 y
No
Yes, sumatriptan
12 m, 1032·5 mg monthly
Yes, daily TTH-like
No
WA, 63, f
M, 40 y
Yes
No
MwA, 17 y No
No
Yes, daily migraine-like Yes, daily TTH-like
No
YG, 29, f
12 m, 3032·5 mg monthly 12 m, 3032·5 mg monthly
BA, 50, f
M, 10 y
Yes
2 to 8 monthly
M, 23 y
No
8 m, 1232·5 mg monthly 18 m, 1832·5 mg monthly
No
MM, 43, f
Yes, sumatriptan No
Yes, daily migraine-like
Initially yes
Increase in frequency under monotherapy with zolmitriptan Daily migraine-like headache under monotherapy with zolmitriptan Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence and increase in migraine attacks Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence Daily migraine-like headache under monotherapy with zolmitriptan Daily TTH-like headache under various substances (NSAID, ergots, sumatriptan), under monotherapy with zolmitriptan persistence Increase in frequency under monotherapy with zolmitriptan Daily migraine-like headache under monotherapy with zolmitriptan
DP, 25, f
M, 10 y
No
No
No
SA, 42, f
M, 22 y
No
No
KM, 48, f
M, 19 y
No
Yes, sumatriptan
12 m, 1232·5 mg monthly 6 m, 1532·5 mg monthly 5 m, 2032·5 mg monthly
3 to 10 monthly Increase in frequency under monotherapy with zolmitriptan 5 to 15 monthly Increase in frequency under monotherapy with naratriptan 2 to 12 monthly Daily TTH-like headache under various substances (NSAID and sumatriptan), under monotherapy with naratriptan worsening and increase in migraine attacks
No Yes, daily TTH-like
2 to 8 monthly
No
Complete relief of daily headache
Complete relief of daily headache Complete relief of daily headache
Significant reduction in frequency Complete relief of daily headache, significant reduction in frequency Still to be determined Still to be determined Complete relief of daily headache, significant reduction in frequency
M=migraine without aura, MwA=migraine with aura, TTH=tension-type headache, f=female, m=month, y=year.
Clinical characteristics of patients
378
THE LANCET • Vol 353 • January 30, 1999