For the majority of cluster headache sufferers, the traditional preventative and abortive medications provide adequate relief. These include (among others) verapamil, lithium, cortisone, sodium valproate, and indomethacin as preventatives.1 The abortives include oxygen, triptans, lidocaine nasal spray, etc.1
Many cluster patients do not achieve adequate relief from the usual medications. Botulinum toxin has shown some promise for the treatment of migraine. At times, therapies that have proven helpful for migraine are also useful for cluster headache as well. This study evaluated 13 patients with refractory cluster headache who were given botulinum toxin type B (BTB).
MATERIALS AND METHODS:
There were 11 male patients and 2 females, ages 28 to 68, in this study. Nine patients had chronic cluster headache, and three suffered from episodic clusters. Each patient had been refractory to the usual cluster preventative medications. The patients kept a headache diary for 4 months after the injections. A visual analog scale was utilized to evaluate the results. Twelve injections of 100 units each of BTB were utilized, 1200 units per patient, which is a low dose. Eight injections were given frontally and temporally ipsilateral to the pain, and four in the contralateral frontal area. Each injection was done utilizing an insulin syringe.
Chronic Cluster Patients (9): (1). 63 year old man in an exacerbation (4 per day). BTB decreased the frequency of the clusters by 50% for 3 months. (2). 68 year old man with complete resolution for 4 months following BTB. (3). 42 year old man, the first BTB treatment resulted in a 30% reduction in the frequency of attacks, for one month. The second treatment was of no benefit. (4). 62 year old man, no benefit from the BTB. (5). 46 year old man with 50% reduction in frequency of attacks, lasting for 3 months post-treatment. (6). 45 year old woman with no relief from BTB. (7). 47 year old man with 60% reduction in cluster frequency; relief lasted only 2 weeks. (8). 28 year old man with 50% reduction in frequency; relief lasting only 2 weeks. (9). 31 year old man with no relief from the BTB.
Episodic Cluster Patients (4): (1). 50 year old woman with no relief from BTB. (2). 38 year old man with 50% reduction in attack frequency, lasting the duration of the episode. (3). 49 year old man with no relief. (4). 47 year old man with no relief.
There were no adverse events reported by the patients.
SUMMARY OF RESULTS:
For chronic cluster, BTB was ineffective for 3 patients. Moderate relief was obtained by 5 of the chronic sufferers, but this was short-lived in 3 of these patients. Complete resolution, with no recurrence, was reported by one patient.
There were 4 episodic cluster patients. Three experienced no relief, while one reported moderate relief that lasted the duration of the cluster cycle.
This small study demonstrates that, for some refractory cluster sufferers, botulinum toxin may provide some benefit. While expensive, botulinum toxin is a relatively safe therapy that, although expensive, is relatively easy to administer. It is possible that larger doses than the low amounts utilized in this study may prove to be more effective.
Numerous studies have been published on the use of botulinum toxin for migraine and tension headache. Cluster headache and BTA / BTB has been the focus of several small studies.
Migraine: Optimal dosing of BTA has been evaluated in several studies. The dosing for migraine has ranged widely, from 10 units to 150 units per patient. One multicenter double-blind study of 123 patients demonstrated that 25 units (low dose BTA) was adequate to significantly decrease migraines. In addition, when 25 units was compared to 75 units, there were significantly fewer adverse events. In this study, the patients reported decreased severity of migraines, fewer number of days utilizing migraine medications, and reduced migraine-associated vomiting2. A further retrospective study of BTA with 77 migraineurs noted 46% with complete headache improvement, 30% with partial improvement, and the remainder as non-responders. The mean dose in this study was 35.5 units of BTA per patient3 . Another study, open label over 3 years, utilized 80-150 units of BTA per patient. Sixty-seven percent of migraine sufferers responded favorably in this study4.
As to where to inject, the studies have involved different protocols. Glabellar injections may lead to more complete relief 3. Several double-blind, placebo-controlled studies injected combinations of frontalis, temporalis, and glabellar sites2. Other studies utilized suboccipital sites, although for posterior muscles larger doses are necessary to achieve an effect. Although there is some indication that injecting posteriorally adds to efficacy of botulinum toxin for migraine, further studies are necessary to delineate optimal sites for injection. If injections are done primarily in the frontal and temporal regions, it appears that low dose botulinum may be as, or more, effective than higher doses2.
Chronic Tension-Type Headache: Studies on botulinum toxin for tension headache have not been as favorable as those for migraine5,6,7,8. In one study where higher doses of BTA were utilized (80-150 units), 58% of those with CDH did achieve positive outcomes4. These same investigators then conducted a double-blind, placebo-controlled, randomized study involving 40 patients with chronic tension-type headache4. The number of headache-free days was significantly increased in the BTA group at 3 months post treatment. Other studies have not been quite as positive for tension-type headache, however. One study that was double-blind, placebo-controlled and randomized revealed no significant differences through 12 weeks for chronic tension-type headache9 .
A recent study (by Robbins) of BTA for refractory chronic daily headache evaluated 87 patients in an open-label fashion10. The results of this study are as follows:
This was an open label, non-randomized, non-blinded study. Eighty-seven participants, aged 23-67, were enrolled, and 79 patients completed the study. Each patient had the diagnosis of moderate or severe chronic daily headache, refractory to the usual preventive medications. The patients recorded headache severity utilizing a visual analog scale for one month prior to treatment, and three months following treatment.
Each patient received low dose BTA injections, 12 injections of 2 units BTA each. The symmetrical injections, 6 on each side, were done frontally and temporally.
The results were: Thirty-six of 79 patients (46%) did not respond to the injections (response = at least a 2 point decrease on a 10 point visual analog scale). Forty-three of 79 (54%) were considered positive responders. Among the positive responders, 44% had a mild response (2 to 3 point decrease on the vas). Forty-seven percent had a moderate response (4 to 5 point decrease on the vas), while 9% had an excellent response (more than 5 point decrease on the vas).
In summary, this study revealed a modest effect of BTA on CDH, but only 24 of 79 patients achieved a moderate or excellent response.
Adverse events were generally mild, with 6 patients reporting mild ptosis, 2 with bilateral edema of the eyelids, and 2 reported a dramatic increase in headache10.
Cluster Headache: A limited number of studies have been performed regarding botulinum toxin in patients with cluster headache. One study with 2 patients yielded excellent results, where both patients had no further clusters after 1 week of treatment. The effects lasted 10-12 weeks11. A recent study12 on botulinum toxin for cluster headache (by Robbins) concluded that botulinum toxin was not very effective for most of the cluster patients in the study. However, several cluster sufferers did obtain excellent relief from the toxin. One other cluster study found that 2 of 4 patients improved, with doses ranging widely from 24 to 150 U.13.
CONCLUSIONS: BTB may be effective for certain selected patients with cluster headache. The safety of low dose botulinum toxin has been well established. There are a number of unanswered questions regarding the use of botulinum toxin in headache patients. The optimal sites of injection have yet to be delineated. While studies have indicated that low dose botulinum may be as, or more, effective than higher doses, this may not be true for posterior injections. Further studies are needed in order to determine the possible role of botulinum toxin in headache patients.
This study was supported by a grant from Elan Pharmaceuticals.
- Robbins L. Management of Headache and Headache Medications 2nd ed. New York: Springer-Verlag 2000; 139-153.
- Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000; 40:445-450.
- Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A (Botox) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg 2000; 123:669-676.
- Smuts JA, Baker MK, Smuts HM, Rheta Stassen JM, Rossouw E, Barnard PWA. Prophylactic treatment of chronic tension-type headache using botulinum toxin type A Eur J Neurology 1999; 6(suppl 4): S99-S-102.
- Porto M. Botulinum toxin type A injections for myofascial pain syndrome and tension-type headache. Eur J Neurology 1999; 6(suppl 4): S103-S109.
- Relja M. Botulinum toxin type A in the treatment of tension-type headache. Presented at the 9th World Congress on Pain, Vienna, Austria, August 22-27, 1999, and at the International Conference 1999: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins, Orlando, FL, November 16-18, 1999.
- Wheeler AH. Botulinum toxin A, Adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 1998; 38:468-471.
- Schulte-Mattler WJ, Wieser T, Zierz S. Treatment of tension-type headache with botulinum toxin: a pilot study. Eur J Med Res 1999; 4:183-186. These data also presented at the International Conference 1999: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins, Orlando, FL, November 16-18, 1999.
- Rollnik JD, Tannenberger O, Schubert M, Schneider U, Dengler R. Treatment of tension-type headache with botulinum toxin type A: A double-blind, placebo-controlled study. Headache 2000; 40:300-305
- Robbins L. Botulinum Toxin A for Refractory Chronic Daily Headache. Abstract presented at the 10th Congress of the International Headache Society; New York, New York; June 29-July 2, 2001.
- Freund BJ, Schwartz M. The use of Botulinum toxin-A in the treatment of refractory cluster headache: case reports. Presented at Headache World 2000, London, England, Sept. 3-7, 2000, and published as an abstract in: Cephalalgia 2000; 4:329.
- Robbins L. Botulinum toxin for cluster headache, 10 patients. Presented at the 10th Congress of the International Headache Society; New York, New York; June 29-July 2, 2001.
- Smuts JA, Barnard PWA. Botulinum toxin type A in the treatment of headache syndromes: a clinical report of 79 patients. Cephalalgia 2000: 20:332.