Cluster Headache—Acute and Prophylactic Therapy

Avi Ashkenazi, MD; Todd Schwedt, MD


Headache. 2011;51(2):272-286. 

In This Article


The 5-HT1B/1D agonists (known as triptans), in an injectable or intranasal preparation, are a mainstay of acute CH treatment.[1–3]


Sumatriptan, injected subcutaneously, is the drug of choice for acute CH attacks.[1] The efficacy of the drug for this indication was examined in a number of well-designed studies.[4–7] In 1 randomized, placebo-controlled study the efficacy of subcutaneous sumatriptan (6 mg) for acute CH treatment was examined.[4] Data from 39 patients were evaluated. Headache severity decreased within 15 minutes in a significantly higher proportion of sumatriptan-treated, as compared with placebo-treated, attacks (74% vs 26 %). Also, a significantly higher proportion of sumatriptan-treated patients were pain free 15 minutes after injection, as compared with those who received placebo (46% vs 10%). Sumatriptan was well tolerated. In another controlled study, subcutaneous sumatriptan at a dose of either 6 mg or 12 mg, or placebo, was given to 134 CH patients.[5] Fifteen minutes after injection, the proportion of patients who experienced headache relief was 80%, 75% and 35% for sumatriptan 12 mg, sumatriptan 6 mg, and placebo, respectively. The higher dose of sumatriptan was not significantly superior to the lower dose, and was associated with more adverse effects (AEs). In an open-label study from the same group, the long-term safety and efficacy of subcutaneous sumatriptan was examined in 138 CH patients.[6] Each patient treated a maximum of 2 attacks per day with a single injection per attack. A total of 6353 attacks, that occurred over 3 months, were evaluated. Headache relief was obtained in 96% of attacks. There was no evidence for decreased efficacy of the drug with continued use. Sumatriptan was well tolerated, and there was no increase in AEs with higher frequency of using the drug. In another open-label study, the efficacy and tolerability of sumatriptan in CH treatment were evaluated over a period of up to 1 year.[7] The maximum daily dose of sumatriptan was 12 mg. A total of 2031 attacks, experienced by 52 patients, were evaluated. In 88% of the attacks, treatment was effective within 15 minutes after injection, and 57% of patients were pain free at that time point. There was no significant change in the efficacy of the drug with repeated use. The response to treatment of patients who had chronic CH (CCH) was somewhat less robust, and slower to occur, as compared with that of ECH patients. Adverse effects were reported by 62% of patients. Withdrawal rate was 33%, with 4 (8%) patients withdrawing because of AEs Table 1.

The efficacy of intranasal sumatriptan in the treatment of acute CH attacks was examined in 1 placebo controlled study.[8] Patients with ECH or CCH, whose attacks lasted at least 45 minutes, were given intranasal sumatriptan 20 mg, or placebo. Data from 154 attacks, experienced by 118 patients, were analyzed. At 30 minutes after treatment, headache response rates were significantly higher for sumatriptan- compared with placebo-treated attacks (57% vs 26%). The corresponding pain-free rates at that time were 47% and 18%. The drug was well tolerated. Another study, that was open label, reported on lower efficacy of intranasal, as compared with subcutaneous sumatriptan, in acute CH treatment.[9] A limitation of that study, in addition to its open-label design, was the fact that treatment outcomes were evaluated at a relatively early time point (15 minutes post treatment).

In summary, injectable sumatriptan is effective and well tolerated for the majority of CH patients. The drug has a rapid onset of action. It remains well tolerated and effective even when taken frequently (up to twice daily) during a cluster period. The recommended dose is 6 mg, although lower doses (2-3 mg) may be effective in some patients.[10] Intranasal sumatriptan appears to be less effective, and to have a slower onset of action than the injectable preparation. Sumatriptan is contraindicated in patients with coronary artery disease or cerebrovascular disease. Because CH typically afflicts middle aged men, many of whom smoke, a clinical evaluation, oriented toward the risk of vascular diseases, needs to be done before prescribing the drug.


The efficacy of intranasal zolmitriptan for acute CH attacks has been studied in 2 controlled trials.[11,12] In 1 study, 92 patients received either intranasal zolmitriptan (5 mg or 10 mg) or placebo, for acute attacks.[11] Thirty minutes after treatment, headache relief rates were significantly higher for zolmitriptan compared with placebo (62%, 40%, and 21% for zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo, respectively). Patients with ECH had higher response rates to zolmitriptan (and to placebo) compared with those who had CCH. Zolmitriptan was well tolerated. In a similarly designed study, 52 CH patients treated 151 attacks with intranasal zolmitriptan (10 mg or 5 mg) or placebo.[12] Zolmitriptan, at both doses, was superior to placebo with regards to headache relief at 30 minutes (63%, 50% and 30% for zolmitriptan 10 mg, zolmitriptan 5 mg, and placebo, respectively). The corresponding pain-free rates at that time point were 47%, 39%, and 20%. Zolmitriptan, at both doses, was well tolerated.

Oral zolmitriptan was evaluated as an acute treatment for CH attacks in a randomized controlled study.[13] The drug was found to be superior to placebo in ECH, but not CCH, patients. Thirty minutes after treatment, headache response rates in ECH patients were 47% and 29%, for zolmitriptan 10 mg and placebo, respectively.

In summary, intranasal zolmitriptan may be used for the acute treatment of CH, with comparable efficacy to that of intranasal sumatriptan. Oral zolmitriptan has only limited efficacy for this purpose. As with sumatriptan, zolmitriptan is contraindicated in patients with a history of cardiovascular or cerebrovascular disease.


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