RENEW OR SUBSCRIBE TO PPM
Subscription is FREE for qualified healthcare professionals in the US.
11 Articles in Volume 10, Issue #9
Activated Glia: Targets for the Treatment of Neuropathic Pain
Acute Herpes Zoster Neuritis and Postherpetic Neuralgia
Acute Treatment of Cluster Headache
Chronic Overuse Sports Injuries in the Adolescent/Pediatric Population
Clinical Recognition of Central Abnormal Neuroplasticity
H-Wave® Stimulation: A Novel Approach In Electromedicine
Homeopathy Enters Contemporary Pain Practice
Immune-modulating Effects of Therapeutic Laser
Pain and Addiction: Words, Meanings, and Actions in the Age of the DSM-5
Partial Plantar Fasciectomy With Autologous Platelet Concentrate
Tethered Spinal Cord Syndrome: Pathophysiology and Radiologic Diagnosis

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.

Study Objectives

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.

Study Design

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 [0], mild [1], moderate [2], severe [3], excruciating [4]) 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:

  • percentage of attacks that produced a pain free response to a single dose of sumatriptan 4mg subcutaneous at 15 minutes, 30 minutes and at one hour,
  • percentage of cluster attacks that resulted in resolution of all associated symptoms of cluster headache present at the time of treatment with the study medication, as well as achieving a pain free response within one hour,
  • percentage of patients who achieved pain reduced to mild or none at 15 minutes for all three treated headache attacks,
  • percentage of patients who achieved pain reduced to mild or none at 15 minutes for two out of three treated headaches,
  • percentage of attacks in which the pain was reduced to moderate or mild and for which the patient took a second and/or a third dose of the study medication, and
  • percentage of attacks in which the patient became pain free at, or before, one hour and experienced a recurrence of cluster headache for which a second or third dose of study medication was taken.

Finally we assessed the number of patients reporting adverse effects to the study medication, the type of adverse event reported and the percentage of attacks that are associated with the adverse effect. Given the open label design and size of this trial, no statistical parameters were planned.

Results

The commercial availability of 4mg sub-cutaneous sumatriptan with an auto-injector contributed to difficulties in enrolling patients in this clinic trial. Only a total of 14 patients were enrolled. One patient was lost to follow-up and five patients failed to treat even a single headache with the study medication. Their demographics were omitted from further evaluation and inclusion. Two of the eight patients had chronic cluster headache and the remainder was classified as having episodic cluster headache. Because only two of eight patients had chronic cluster headache all patients were considered together.

Demographics

The mean age of the patient was 45.9 (22-64) years, three were female, and five were male. Only one was of other than Caucasian extraction. The mean age of onset of cluster headache was 27.9 (22-39) years and the mean age at time of first diagnosis was 32.3 (22-42) years.

Historically, there was a broad distribution of primary pain areas with most patients having more than one (see Table 1). Similarly, the majority of patients offered more than one descriptor for their pain but again distributed in a uniform fashion. The most common associated symptoms of cluster headache occurred in seven of eight patients and were tearing of the eye and rhinorrhea. The least common symptoms occurred in two patients and were miosis and eyelid edema. The only seasonal propensity was a fall occurrence in half of the patients. All of the patients had experienced in excess of 10 cycles of headache. The frequency of the cycle averaged nearly three cycles per year each lasting for approximately two months and followed by a remission of nearly three months. All of the patients had cluster headache daily in cycle and averaged nearly four attacks per day. Untreated attacks of cluster headache ranged in average duration from 115 minutes, at the minimum, to 185 minutes, at the maximum. Past treatments reduced the duration of cluster headaches to an average of 47 minutes, minimum, and 121 minutes, maximum. Six of the eight patients found they were prone to headache recurrence with their usual medicine despite initial control of the headache. Five of the eight had found that taking preventative medicine during cluster headache cycles improved their response to acute medicine as well as reducing the attack frequency burden.

Efficacy

The primary efficacy parameters (see Table 2) were the percentage of cluster headache attacks that resulted in the cluster headache pain being reduced to mild or none following a single dose of 4 mg subcutaneous sumatriptan at 15 minutes. Eighteen of 24 treated headaches (75%) achieved this outcome.

The number of attacks that resulted in a pain free response to a single dose of sumatriptan 4mg subcutaneous at 15 minutes, 30 minutes and at one hour was achieved by 6 of 24 (25%) at 15 minutes, 13 of 24 (54%) at 30 minutes, and 16 of 24 (67%) at one hour. The number of attacks of cluster attacks that resulted in resolution of all associated symptoms of cluster headache present at the time of treatment, as well as achieving a pain free response within one hour, occurred in 9 of 24 (37.5%) attacks. Consistent improvement to mild or no pain at 15 minutes for all three treated headache attacks occurred in 3 of 8 (37.5%) patients and in 6 of 8 (75%) patients. Two of eight patients were pain free at 15 minutes and for all three attacks. None of the patients had headache pain of moderate or mild intensity at one hour that required a second dose of the study medicine nor had subsequent headaches in the 24 hour post treatment period. None of the patients who were pain free at, or before, one hour experienced a recurrence of cluster headache nor experienced a second headache in the following 24 hours after initial treatment that required a second dose of study medicine.

Adverse Events

Three patients reported a total 12 adverse events over a total of 24 attacks. The most common was neck pressure in five attacks experienced by two patients. One patient experienced an atypical headache following treatment for all three attacks, nausea occurred in one patient during two attacks.

Conclusions and Discussion

Subcutaneous sumatriptan 4mg with an auto-injector was studied in open label fashion in patients with episodic and chronic cluster headache for treatment of up to three headache attacks. 75% of patients met the primary endpoint for relieve of cluster headache by 15 minutes. Additionally, pain freedom occurred by 15 minutes in 25% of the patients and by one hour in 64%. No patients had recurrence of cluster headaches or required a second dose of study medicine despite being a problem historically in two thirds of these patients. Additionally, treatment with a single dose of 4mg subcutaneous auto-injector sumatriptan for one cluster headache resulted in none of the patients having additional cluster headaches in the 24 hour evaluation period—when, historically, these patients averaged four attacks per day. A little over a third of patients had mild or no pain after not more than 15 minutes for all three attacks they treated. One quarter of all patients had pain freedom by 15 minutes in all three attacks. There were no serious adverse events; the side effects reported were ones commonly seen for sumatriptan and were mild and transient. No one discontinued the study early due to adverse events.

Given the historical predisposition for these patients to have attacks typically lasting from nearly two hours up to almost three hours and to experience headache recurrence in the majority of their situations—with multiple attacks in a 24 hour period—it was most significant to find that not only was there a brisk response for almost all the patients but nearly two thirds of attacks were resolved, or nearly resolved, by one hour. Further, none of the patients had the cluster recur that would require a follow on dose of the study medicine nor experienced any additional cluster attacks in the subsequent 24 hours after initiating treatment. This would suggest that the natural history of these patients’ cluster headaches had been altered by treatment with 4mg subcutaneous sumatriptan in this study situation. How this might occur is unclear. Was it the result of treatment with the drug itself or the effects of the peak serum concentration (Cmax) achieved with this formulation combined with its prompt time to maximum concentration in serum (Tmax), or was it just that these participants’ cluster headaches cycles were atypical from their historic norms. The latter we cannot address since specific information on the frequency and duration of each participant’s specific attacks were not recorded prior to starting treatment in this study. As to the former potential reasons, this remains an area for further study of comparative doses, formulations and probably placebo controlled crossover trials.

This study was hampered in recruitment as noted by one of the investigators (Fred Freitag) because of the widespread use of not only the auto-injector formulation of sumatriptan but of the 4mg version as well. Many potential candidates to participate in the study declined to do so since they were already successfully using this treatment and participation would require them to keep additional paperwork rather than attend to their personal affairs.

Last updated on: March 7, 2011
close X
SHOW MAIN MENU
SHOW SUB MENU