Hi Sissy,
there was a study in 2003 in Vienna/Austria. hope this info helps a bit
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Eletriptan for the short-term prophylaxis of cluster headacheKarin Zebenholzer MD,
Christian Wöber MD,
Marion Vigl MD,
Peter Wessely MD
Department of Neurology, University of Vienna Medical School, Vienna, Austria
Corresponding author:
Dr. Karin Zebenholzer
Department of Neurology
University of Vienna Medical School
Abstract
Background: We observed a beneficial prophylactic effect of eletriptan 40 mg in a single patient with cluster headache and performed an open-label study for further evaluating the efficacy of eletriptan in the short-term prophylaxis of cluster headache.
Methods: We included 18 patients aged 40.5 ± 9.9 years. The number of cluster headache attacks was recorded during a baseline period of 6 days and during 6 days of treatment with eletriptan 40 mg twice daily. Primary outcome measure was the reduction in the number of attacks during the treatment period.
Results: Two patients were lost to follow-up. In the 16 patients who completed the study the mean total number of attacks decreased from 10.9 ± 5.6 during baseline to 6.3 ± 3.7 during treatment with eletriptan (p=0.01) The reduction in the number of attacks exceeded 50% in six patients and 40% in another two.
Conclusion: This open-label pilot study suggests that eletriptan 40 mg twice daily might be useful for the short-term prophylaxis of cluster headache.
Key-words: cluster headache, eletriptan, prophylaxis
Introduction
Cluster headache is characterized by attacks of very severe, unilateral pain, usually localised (peri-)orbitally and/or temporally. The headache is accompanied by trigeminal autonomic symptoms such as conjunctival injection, lacrimation and rhinorhoea on the side of the pain. The attacks last 15 to 180 minutes and occur with a frequency of one every other day to eight per day episodically for several weeks followed by remission periods in 85% of the patients and chronically (without remission periods) in the remaining ones (1, 2, 3).
The severe to unbearable intensity of the attacks requires fast acting acute medication. Subcutaneous sumatriptan is the treatment of first choice (3, 4). Alternatively, nasal sumatriptan or intramuscular, intravenous, subcutaneous or nasal dihydroergotamine may be used (3, 5, 6, 7). Some patients benefit from oxygen inhalation (8) or oral zolmitriptan (9).
The daily occurrence of attacks calls for additional preventive medication such as verapamil and lithium (10, 11). In addition, short-term prophylaxis providing fast onset of action is warranted in many patients. From the clinical point of view, corticosteroids appear to be effective within a few days in many patients, but controlled studies are lacking (3, 12). Recently, a possible prophylactic effect of naratriptan was reported in two single case reports and one case series (13, 14, 15) showing substantial improvement in nine out of a total of 11 patients taking 2.5 mg naratriptan twice daily.
We observed a promising prophylactic effect of eletriptan in a single patient with cluster headache that prompted us to perform an open-label pilot study. In the following, we want to report on the efficacy of eletriptan in the prevention of cluster headache presenting the case report as well as the findings of the pilot study.
Case report
A 48 years old male patient was seen at our outpatient clinic for the first time 15 years after onset of episodes with recurrent headache attacks. The attacks were typical of episodic cluster headache according to the criteria of the International Headache Society (1), but the diagnosis had not been established prior to this visit. Even small amounts of alcohol precipitated an attack obligatorily during active cluster periods. The current series of attacks had started a week before. Usually, the patient had one attack in the evening and occasionally another one during the night. In total, the patient had ten attacks lasting up to three hours during the week before his first visit.
Subcutaneous sumatriptan was recommended for acute therapy, but the patient refused and asked for oral medication. Eletriptan 40 mg p.o. was prescribed. At the next visit five days later, the patient reported that he had taken one tablet at the onset of each attack (usually in the evening) and got pain-free within 45-60 minutes (previous attacks lasted 60 - 180 minutes). In contrast to the time before eletriptan, he had not experienced any night-time attacks and the number of attacks had decreased to six. In addition, he pointed out that he had tolerated small amounts of alcohol without getting an attack. The patient continued taking one tablet of eletriptan 40 mg at the beginning of an attack. During the following two weeks the frequency of attacks decreased to four and two per week, respectively, and from day 19 after the first attack he was pain-free again. During the entire period the patient took no other medication. Previous cluster episodes had been lasting 10 - 21 days.
In this patient, eletriptan had some effect in the acute therapy of cluster headache. More interestingly, however, eletriptan might have had a prophylactic effect, as night-time attacks and sensitivity to alcohol did not occur after the patient had started to take eletriptan.
This observation and the favourable half-life of eletriptan brought us to initiate a pilot study to examine the efficacy of eletriptan 40 mg twice daily in the short-term prophylaxis of cluster headache.
Patients and Methods
We included 18 consecutive patients (17 male, 1 female) from our headache outpatient clinic aged 40.1 ± 10.3 years (range: 22-60) suffering from cluster headache according to the criteria of the International Headache Society (1). Sixteen patients had episodic cluster headache. The remaining two patients had no remission period for 1.5 and 2 years, respectively, and were classified as secondary chronic cluster headache. They were included, since they reported a recent exacerbation in attack frequency. All patients gave informed consent to participate in the study.
The patients underwent a clinical neurological examination and routine blood tests, including blood chemistry, white and red blood count, clotting factors and thyroid hormones showing no clinically relevant abnormalities. Cranial computer tomography and/or magnetic resonance imaging was normal in all patients. If necessary, further examinations were performed to exclude symptomatic cluster headache.
We excluded patients with cerebrovascular and cardiovascular disorders, hypertension, severe renal and hepatic disorders and subjects with an overuse of alcohol and/or medication. In addition, we excluded patients taking ergotamines on a regular basis.
The patients took eletripan 40 mg at fixed times in the morning and evening (approximately 8 a.m. and 8 p.m.). In order to examine the efficacy of eletriptan 40 mg in the prevention of cluster headache, we compared the number of attacks before and during treatment with eletriptan. The baseline and treatment periods lasted six days each. In responders, we evaluated additionally the number of attacks during six days following the discontinuation of eletriptan. The number of attacks during baseline was recorded retrospectively at the first visit. The number of attacks during and after treatment was recorded prospectively in a headache diary kept by the patients. Follow-up visits were scheduled at the end of the treatment period as well as at the end of the post-treatment period.
Responders were defined by a decrease in attack frequency of more than 50%. Primary outcome measure was the reduction in the number of attacks during treatment with eletriptan compared to baseline. Secondary outcome measure was the increase in the number of attacks after discontinuation of eletriptan in responders.
For comparing the frequency of attacks between baseline and treatment period and between treatment and post-treatment period, we calculated two-tailed paired t-tests using SPSS 10.0 software. An intention-to-treat analysis was planned if any drop-outs should appear using a two-tailed t-test. The level of statistical significance was set to p<0.05.
Results
Of 18 patients included, two (both male) were lost to follow-up, because they did not come to the clinic any more and could not be reached by phone and mail. Among the remaining 16 patients (15 male, 1 female), 14 patients had episodic cluster headache and two had an exacerbation of secondary chronic cluster headache. The mean time since onset of cluster headache was 11.3 ± 6.3 years (range: 4 – 25). The mean duration of previous episodes was 49.0 ± 33.8 days (range: 14 – 135) and the mean duration of the current episode at the beginning of the treatment period was 33.0 ± 28.8 days (range: 4 – 98). Further details are shown in table 1.
The mean number of attacks was 10.9 ± 5.6 (range: 6 - 24) during baseline and decreased to 6.3 ± 3.7 (range: 0 – 12) during treatment with eletriptan (Table 1). This decrease in the frequency of attacks was statistically significant (p = 0.01, T = 2.97, df = 15). Six patients were responders and ten patients were non-responders. Among the latter, two patients reported a decrease in frequency by more than 40% and one patient by more than 30%. Responders and non-responders did not differ statistically significantly concerning the number of attacks during baseline, the past response to triptans and the presence of sleep-induced attacks. The response to oxygen was examined in few patients only. Therefore, a comparison between eletriptan responders and non-responders was not possible.
Considering that two patients were lost to follow-up, we performed an intention-to-treat-analysis. Comparing the baseline data of all 18 patients to the data of the treatment period in the 16 patients who completed the study showed also a statistically significant reduction in attack frequency (baseline 13.3 ± 12.9, treatment period: 6.3 ± 3.7; p < 0.001, T = 6.79, df = 15).
After discontinuation of eletriptan the frequency of cluster attacks increased in five of six responders (from a mean of 3.3 in the treatment period to 6.8 in the post-treatment period). This increase did not reach the level of statistical significance. One responder was sustained pain-free.
Seven patients treated attacks of cluster headache occurring during intake of eletriptan with subcutaneous sumatriptan (30 attacks), oral zolmitriptan 2.5 mg (6 attacks), or rizatriptan 10 mg (3 attacks). None of these patients reported any side effects. Two of the responders used sumatriptan two to four times in the treatment period, one responder used sumatriptan seven times during the treatment period and the other triptan users were non-responders. None of the patients had taken ergotamines at any time before or during the study.
Six patients had a preventive treatment with verapamil (mean 366.7±186.6 mg/day), two of them used topiramate in addition. The type and dose of the long-term prophylaxis was stable for at least ten weeks before the patients were included in this study. The long time of stable treatment exceeding considerably the mean duration of the current cluster episodes is explained by the fact that five patients with episodic cluster headache continued to take the preventive medication after the end of their previous cluster episodes.
Supplementary, we want to note that two patients (both responders) experienced another cluster episode several months after the study. Eletriptan 40 mg (twice daily in one patient and three times in the other one) resulted again in a decrease in the attack frequency by more than 50%.
Discussion
In this open-label study, the frequency of cluster headache attacks decreased statistically significant during treatment with eletriptan 40 mg twice daily compared to baseline. Eight out of 16 patients experienced a meaningful relief in attack frequency.
It is unlikely that this positive effect was caused by spontaneous remissions since the mean duration of the current cluster episodes at the beginning of the treatment with eletriptan was significantly shorter than that of previous episodes. In addition, the increase in frequency after discontinuation of eletriptan among the responders (although statistically not significant), is an argument against spontaneous remissions as well as against an influence of the concomitant therapy with verapamil and topiramate, respectively.
In 1995, Monstad et al. (16) investigated the prophylactic effect of oral sumatriptan 100 mg three times per day in a double-blind placebo-controlled trial including a total of 169 patients. This study did not show any prophylactic potential of oral sumatriptan even at a high dose. Recently, Eekers et al. (14) and Loder (15) reported on single patients with chronic cluster headache who were successfully treated by administration of naratriptan 2.5 mg twice daily. Mulder et al. (13) found substantial improvement after preventive treatment with naratriptan 2.5 mg once or twice daily in addition to high doses of verapamil in 7 out of 9 patients. The possible preventive effect of naratriptan and eletriptan might be explained by the longer half-life of 6 hours and 4 - 5 hours, respectively compared to sumatriptan with a half-life of only 2 hours (13, 14, 15).
Eletriptan 40 mg twice daily seems to be a safe and well-tolerated treatment, because no side effects were reported. Single doses of 80 mg of eletriptan were studied for the treatment of acute migraine attacks and had been tolerated well (17). Studies on higher doses of eletriptan (up to 120 mg ) demonstrated a dose related increase in mild and transient adverse events but no changes in the electrocardiography or laboratory tests (18).
For the acute treatment of severe attacks during the regular intake of eletriptan the patients were allowed to use not more than one dose of subcutaneous sumatriptan 6 mg (or an alternative triptan) per day. This decision was made contradictory to official recommendations. In daily clinical practice many patients with frequent cluster headache report that they take subcutaneous sumatriptan more than twice daily without side effects. A study on the safety and efficacy of subcutaneous sumatriptan in cluster headache showed that the number and severity of adverse events is comparable to those found in migraine trials, even though patients with cluster headache use sumatriptan more frequently than migraineurs (19). In a dose comparison study of 6 mg versus 12 mg subcutaneous sumatriptan in cluster headache, patients reported on slightly more adverse events on sumatriptan 12 mg, but the nature and severity of adverse events were similar to those of sumatriptan 6 mg (20). In our study, the patients using subcutaneous sumatriptan, rizatriptan or zolmitriptan for acute treatment in addition to eletriptan did not report on side effects, even though they used up to three doses against our recommendation.
In conclusion, this open-label pilot study suggests that eletriptan 40 mg twice daily might be useful for the short-term prophylaxis of cluster headache. A placebo-controlled trial seems to be worthwhile for further evaluating the efficacy and safety of eletriptan in this indication.
References
1. Headache Classification Committee of the International Headache Society. Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain. Cephalalgia 1988;Suppl.7:1-96
2. Rasmussen BK. Epidemiology of cluster headache. In: Olesen J, Goadsby PJ, eds. Cluster headache and related conditions. Oxford, London: Oxford University Press 1999:23-26
3. Ekbom K, Hardebo JE. Cluster Headache. Aetiology, diagnosis and management. Drugs 2002;62:61-69
4. Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N Engl J Med 1991;325:322-326
5. Zakrzewska JM. Cluster headache: review of the literature. Br J Oral Maxillofac Surg 2001:103-113
6. Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. A double-blind trial versus placebo. Cephalalgia 1986;6:51-54
7. Mather PJ, Silberstein SD, Schulman EA, Hopkins MM. The treatment of cluster headache with repetitive intravenous dihydroergotamine. Headache 1991;31:525-532
8. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981;12:1-4
9. Bahra A, Gawel MJ, Hardebo JE, Millson D, Breen SA, Goadsby PJ. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology 2000;541832-1839
10. Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 2000;54:1382-1385
11. Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M, Manzoni GC, Nappi G. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990;30:411-417
12. Cianchetti C, Zuddas A, Marchei F. High dose intravenous methylprednisolone in cluster headache (letter). J Neurol Neurosurg Psychiat 1998;64:418
13. Mulder LJMM, Spierings ELH. Naratriptan in the preventive treatment of cluster headache. Cephalalgia 2002;22:815-817
14. Eekers PJE, Koehler PJ. Naratriptan prophylactic treatment in cluster headache. Cephalalgia 2001;21:75-76
15. Loder E. Naratriptan in the prophylaxis of cluster headache. Headache 2002;42:56-57
16. Monstad I, Krabbe A, Micieli G, Prusinski A, Cole J, Pilgrim A, Shevlin P. Pre-emptive oral treatment with sumatriptan during a cluster period. Headache 1995;35:607-613
17. Goadsby PJ, Ferrari MD, Olesen J, Stovner LJ, Senard JM, Jackson NC, Poole PH for the Eletriptan Steering Committee. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000;54:156-163
18. Milton KA, Allen MJ, Abe S, Grimwood VC, James GC, Rance DJ, Eve MD. The safety, tolerability and pharmacokinetics of oral eletriptan (UK-116,044) a potent and selective ‘5HT1D-like’ receptor agonist. Cephalalgia 1996;16:382-283
19. Ekbom K, Krabbe A, Micieli G, Prusinski A, Cole JA, Pilgrim AJ, Noronha D for the Sumatriptan Cluster-Headache Long-term Study Group. Cluster headache attacks treated for up three months with subcutaneous sumatriptan (6 mg). Cephalalgia 1995;15:230-236
20. Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. Acta Neurol Scand 1993;88:63-69
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