Acute Treatment of Cluster Headache
Sumatriptan 6mg subcutaneous is approved in a variety of countries for the acute treatment of migraine headache. Additionally, it is approved for the acute treatment of cluster headache attacks in the United States as the result of clinical trials. Two studies using subcutaneous sumatriptan 6mg, both reported by Ekbom,1,2 examined the 6mg subcutaneous dose. The combined results included 131 subjects on active treatment and 17 on placebo. 75% of those receiving sumatriptan had headache relieved at 15 minutes as compared to 32% in the placebo arms of these two studies. In the report from 1993,2 Ekbom also reported on a population of patients who were treated with a total of 12mg of sumatriptan via subcutaneous administration. A total of 88 subjects were treated with 53 subjects (60.2%) achieving pain relief by 15 minutes as compared to 18 (20.4%) being given placebo injections.
More recently, Gregor et al3 showed that doses as low as 2mg by subcutaneous injection were effective in some patients with cluster headache and with improved tolerability at the lower doses of 2 to 3mgs compared to the traditional 6mg dose for parenteral administration. The use of these lower doses of sumatriptan require the patient to use the single dose 6mg vials of sumatriptan and self-administer a correctly measured dose of sumatriptan by subcutaneous administration. Recently, a 4 mg sumatriptan formulation utilizing an auto-injector device has become available. It has similar pharmacokinetic parameters to the 6mg dose except for the peak serum concentration (Cmax), which is proportionally reduced.4 Despite the lower dose, it was anticipated that patients should have a similar response to the 4mg dose delivered with an auto-injector comparable to the 6mg dose but with an improved tolerability based on clinical experience.
The objective of this study was to evaluate the safety and efficacy of a single dose of sumatriptan 4mg delivered with an auto-injector as acute therapy for cluster headache. Additionally, we assessed the consistency of response across three attacks; including recurrence rates, pain free treatment outcomes and adverse events.
This was a proof of concept open label trial of a single dose of 4 mg subcutaneous sumatriptan using an auto-injector for the treatment of cluster headache in up to three cluster headache attacks. Since it was a proof of concept trial, a total of 20 subjects were targeted for enrollment. The recommendations of the committee on cluster headache trial design5 were widely used in formulating the protocol. Subjects enrolled in the study had either episodic or chronic cluster headache as defined by the IHC criteria. Subjects entering the study received instruction in self administration using the 4mg auto-injector device. They agreed to use at least one dose of study medication for each of the three headaches to be treated.
At the screening visit, subjects provided written informed consent. Subjects gave a brief medical, surgical and headache history. The cluster headache history met the IHC criteria for the disorder with a frequency as few as one every two days to as high as five per day. Cluster headache duration needed to be at least 30 minutes in duration. Patients with chronic cluster headache were on a stable regimen of medication for at least one month and, despite preventive therapy, continue to experience cluster headache attacks at least one every two days, up to five attacks per day. Patients with episodic cluster headache were not to start preventative therapy during the time of the study. A brief physical and neurological examination along with vital signs was obtained at baseline. Women of childbearing potential had a urine pregnancy test performed. Patients were allowed to use non-triptan or ergotamine-derived medications—either for acute or for preventative therapy during the course of the trial. Subjects meeting all inclusion criteria and none of the exclusion criteria were enrolled. They received training in the use of the auto-injector device as well injection site location training. Subjects were provided diaries and instructed in their completion.
Subjects were instructed to return no longer than 14 days following treatment of their third attack. At this visit, subjects underwent an interim medical and headache history, had vital signs recorded and their diaries reviewed for clarity and accuracy. Women of childbearing potential had a urine pregnancy test performed.
Subjects were instructed to use the study medication as early in the attack as possible after the pain had become at least moderate (using a headache pain rating: none , mild , moderate , severe , excruciating ) but also only if it was less than one hour in duration. Subjects recorded the date and time of onset of their cluster headache, the time at which they took the study medication, the severity of the headache immediately before dosing, and any associated autonomic symptoms. They recorded response data at 5, 10, 15, 30, 45, and 60 minutes after injection. This included the time at which they first experienced meaningful relief of their cluster headache. They also recorded any adverse events they experienced. Other medications used for any reason were also recorded for each 24 hour period pre- and post-treatment.
Subjects were asked to refrain from taking rescue medication until at least 30 minutes after the administration of study drug. Rescue medications included a second dose of the study medication, if the relief obtained from the first dose was incomplete and if greater than one hour had transpired since the original treatment dose, another medication for cluster headache, or an analgesic. They were prohibited from using another triptan, dihydroergotamine or other ergotamine derivative. If the patient became pain free with a dose of study medication and had headache recurrence at one hour or later following the treatment with the first dose of study medication, the patient could use another medication for the acute treatment of the cluster headache recurrence other than another dose of the study medication, another triptan, dihydroergotamine, or other ergotamine derivative.
The primary efficacy parameter was the percentage of cluster headache attacks that resulted in the pain being reduced to mild or none following a single dose of 4mg subcutaneous sumatriptan at 15 minutes. Secondary efficacy parameters included: