Abstract
We describe the preventive use of naratriptan, mostly as add-on to high-dose verapamil treatment, in nine patients with cluster headache. The addition of the naratriptan further improved the headaches in seven of the nine patients.
Introduction
The treatment of cluster headache is well established (1): for the abortive treatment, most effective are the sumatriptan subcutaneous injection (2), oxygen inhalation (3) and ergotamine sublingual tablet (3); for the preventive treatment, most effective are verapamil (4–6), prednisone (7) and lithium (5, 7). Naratriptan is an effective and well-tolerated abortive antimigraine medication (8) and has been used preventively in transformed migraine (9). It has been suggested for preventive treatment of cluster headache, along with frovatriptan, because of its long half-life (10). A recent case report, in actual fact, described its effective preventive use in a patient with (chronic) cluster headache (11). Here, we report on nine patients with cluster headache preventively treated with naratriptan. The rationale for its use is its cranial vasoconstrictor action, mediated through stimulation of serotonin 1B receptors.
The patients had cluster headache as defined by the International Headache Society (12) and were otherwise healthy, except for chronic obstructive pulmonary disease in one (MV). They were enrolled consecutively in the study between August 1999 and August 2000 and only if they did not respond adequately to the maximum tolerated dose of verapamil. Other adjunct treatments employed by the authors under such circumstances are with lithium and/or ergotamine. The follow-up of the patients who responded to the adjunct treatment with naratriptan amounted to 1–2 years, without loss of efficacy.
Case reports
Patient 1 is a 40-year-old-man with primary chronic cluster headache since age 19 years. On verapamil 960 mg slow release per day, he still experienced headaches once every 1 or 2 days. The headaches occurred only at night, waking him up out of sleep. The addition of naratriptan, 2.5 mg at bedtime, prevented these nocturnal headaches from occurring.
Patient 2 is a 43-year-old man with episodic cluster headache since age 37 years. His remissions are less than a month in duration. On verapamil, 960 mg slow release per day, he still experienced headaches once or twice per 24 h. The addition of naratriptan, 2.5 mg twice daily, reduced the frequency of the headaches to once per week.
Patient 3 is a 43-year-old man with primary chronic cluster headache since age 9 years. On verapamil, 960 mg slow release per day, he still experienced one headache per 24 h. The addition of naratriptan, 2.5 mg once daily, did not provide further relief of the headaches. Ergotamine, 1 mg once daily, in addition to the verapamil, rendered him free of headaches.
Patient 4 is a 43-year-old man with episodic cluster headache since age 29 years. On verapamil, 960 mg slow release per day, he still experienced three or four headaches per 24 h. The addition of naratriptan, 2.5 mg twice daily, rendered him free of headaches within a week. He was treated within 2 weeks of a new episode; in the past, the episodes always lasted longer than 6 months.
Patient 5 is a 47-year-old man with episodic cluster headache since age 24 years. On verapamil, 960 mg slow release per day, he still experienced six headaches per 24 h although much less intense. The addition of naratriptan, 2.5 mg twice daily, reduced the frequency of the headaches to once per 48 h. Ergotamine, 1 mg once daily, in addition to the verapamil, had not rendered him free of headaches in the past.
Patient 6 is a 51-year-old man with primary chronic cluster headache since age 40 years. The headaches occurred almost daily, once per day, and lasted for 1 h. They were moderate in intensity and mostly occurred between 4 and 5 AM, waking him up out of sleep. Oxygen inhalation was effective in relieving them. Naratriptan, 2.5 mg at bedtime, failed to prevent the nocturnal headaches from occurring.
Patient 7 is a 52-year-old man with cluster headache since age 33 years, which has been chronic since age 46 years. On verapamil, 960 mg slow release per day, he still experienced one to three headaches per 24 h. The addition of naratriptan, 2.5 mg at bedtime, rendered him almost free of headaches for 1/2 year.
Patient 8 is a 53-year-old man with episodic cluster headache since age 27 years. The episodes occur once per year and last for 5–6 months. On verapamil, 720 mg slow release per day, he still experienced two headaches per 24 h. The addition of naratriptan, 2.5 mg twice daily, rendered him free of headaches after 3 days. At that time, he was in the first month of a new episode.
Patient 9 is a 71-year-old woman with cluster headache since age 61 years, which has been chronic since age 69 years. On verapamil, 480 mg slow release per day, she still experienced one headache per 24 h. The dose of the verapamil could not be further increased because of pedal oedema. The addition of naratriptan, 2.5 mg at dinnertime, rendered her free of headaches after an additional attack.
Discussion
Seven of the nine patients treated experienced benefit from the addition of naratriptan, 2.5 mg once or twice daily (Table 1). In all but one of the patients, the naratriptan was added to a regimen of verapamil, 480–960 mg slow release per day (4). Verapamil is the preventive treatment of choice in cluster headache because it is very effective and generally well tolerated. However, a high dose may be required, especially in chronic cluster headache, which may not always be attainable because of side-effects, such as severe constipation, pedal oedema, or slowing of atrioventricular conduction. The addition of a small dose of lithium, for example, 150 mg twice daily, may then provide full relief of the headaches but, as shown above, the same can be accomplished with the addition of a daily dose of naratriptan. However, with either ergotamine or naratriptan as add-on treatment, the sumatriptan subcutaneous injection and ergotamine sublingual tablet cannot be used any longer for headache abortion.
Clini cal summary of the patients with cluster headache treated with naratriptan, 2.5 mg once or twice daily, their previous medication use, and the results of treatment
The patients tolerated the daily use of naratriptan well without side-effects and, in the absence of cardiovascular illness, such treatment can be considered safe. It is safer than the adjunct treatment with daily ergotamine because in mediating in vivo contraction of human coronary artery, its maximum effect (Emax) is only half that of ergotamine and the molar concentration required to elicit half of this maximum effect (EC50) is 10 times higher (13). In addition, the binding of naratriptan to the receptor mediating contraction of the human coronary artery, the serotonin 2 A receptor, is much less strong than that of ergotamine, allowing a much shorter duration of action.
The patients who had experience with daily use of ergotamine preferred naratriptan because of fewer side-effects, although it was somewhat less effective in one patient. In addition, it should be noted that three of the six patients who responded positively to the addition of the naratriptan had chronic cluster headache. This makes it rather unlikely that the observed benefit was due to spontaneous remission of the headaches. Nevertheless, it has to be remembered that the above finding is based on an open-label study only; a random-ized, double-blind, placebo- or comparator-controlled study is warranted.