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Botulinum Toxin A for Refractory Chronic Daily Headache
 
Posted August 2001
 

Objective
To evaluate the efficacy of low-dose botulinum toxin type A (BTA) for refractory chronic daily headache sufferers.

Background
Many chronic daily headache patients do not achieve a satisfactory response from preventive medications. In addition, the preventive medications often have intolerable side effects. Botulinum toxin type A injections have been demonstrated to reduce the pain associated with migraine headache, cervical dystonia, and myofascial pain syndrome. Studies on botulinum toxin for tension-type headache have yielded conflicting results.

Design and Methods
This was an open label, non-randomized non-blinded study. Eighty-seven participants, aged 23-67, were enrolled in the study, 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.

Results
Thirty-six of 79 patients (46%) did not respond to the injections (response = at least a 2 point decrease on a 10 point vas). 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).

Among the mild responders (19 of 43 = 44% of responders), in the second month, 16% declined to no response, 63% continued to have a mild response, while 10.5% of these mild responders had a moderate response and 10.5% reported an excellent response. During the 3^rd month with these mild responders, 68% now had no response, 10.5% had a mild response, 10.5% had a moderate response, and 10.5% reported an excellent response.

For the moderate responders (20 of 43 = 47% of total responders), during the 2^nd month 15% now had no response, 15% had only a mild response, while 70% continued with a moderate response. During the 3^rd month, 50% now declined to no response, 10% continued with a mild response, while 40% continued with a moderate response.

For the excellent responders, which were only 4 of 43 responders in total, during the 2^nd month all 4 remained excellent. During the 3^rd month 2 of the 4 declined to a mild response, 1 had a moderate response and 1 of the 4 patients continued with an 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 headache.

Conclusions
For refractory chronic daily headache sufferers, low-dose botulinum toxin type A is a safe therapeutic option that may, in a minority of patients, result in a reduction in headache severity. However, in this study, for 70% of the patients enrolled, the response was either none or only mild.

Key Words: Headache, chronic daily headache, botulinum toxin.

Abbreviations: BTA = botulinum toxin type A, vas = visual analog scale.

INTRODUCTION
Patients with chronic daily headache (cdh) often have an inadequate response to preventive medications. One previous study indicated that over a long period of time (at least 9 months) only 46% of patients found any preventive medication to be of sustained benefit.

These patients often overuse nonprescription and prescription analgesics, which can lead to rebound headache.

For those with cdh that is refractory to the usual first and second-line medications, and the non-medication therapies, the choices are limited. These include monamine oxidase inhibitors, long-acting opioids, stimulants, daily triptans, intravenous dihydroergotamine, etc. Botulinum toxin injections present one more possibility for these difficult to treat patients.

Previous studies have indicated that botulinum toxin may be useful for the prevention of migraine headache. The studies have varied as to the utility of botulinum toxin for muscle contraction headache. The purpose of this study was to evaluate botulinum toxin A (BTA) for the prevention of headache in refractory cdh patients.

SUBJECTS AND METHODS
This was an open label non-randomized study. The subjects were patients at the Robbins Headache Clinic. For one month prior to treatment, and three months following treatment, the patients recorded headache severity utilizing a visual analog scale (vas). Assessment of the patient and headache calendars was done by the treating neurologist. The patients were continued on their preventive and abortive medications after the injections.

Each patient received low dose BTA injections, 12 injections of 2 units BTA each. The symmetrical injections, 6 on each side, were done with two in the anterior superior portion of the temporoparietalis muscle, and 4 in the frontalis muscle.

Patient Characteristics
The 87 participants were men and women aged 23 to 67. Each patient had the diagnosis of moderate or severe chronic daily headache, according to International Headache Society (IHS) criteria. The patients had been refractory to the usual preventive medications including antidepressants, anticonvulsants, beta blockers, muscle relaxants, etc. They were eligible for the study if they were assessed to have refractory cdh, without significant rebound headache.

Exclusionary criteria included:
1. a co-existing history of complicated migraine;
2. a medical condition that may put the person at risk by receiving BTA;
3. pregnancy;
4. significant analgesic medication overuse.

Those who did not complete the study (return for scheduled visits) were dismissed from the study.

Outcome Measures
Efficacy was assessed from the patients’ calendars, and via the interview with the treating neurologist. The change in frequency and severity of headache from baseline was assessed using the visual analog scale. The change was evaluated at one, two, and three months post-injection. To be considered a responder, the patient must have had at least a 2 point decrease, on a 10 point vas scale, in severity. A 2 to 3 point decrease was considered a mild response, 4 to 5 points a moderate response, and more than 5 points an excellent response to the injections.

RESULTS
Eighty-seven subjects received the injections. Eight patients were not compliant with follow-up, and were dropped from the study. The following results only include the 79 patients who remained in the study. All patients were considered moderate to severe cdh sufferers, and the patients’ baseline severity, on a 10 point scale, ranged from 8 to 10.

TABLE 1
First Month Results

Thirty-six of 79 patients (46%) did not respond to the injections (response=at least a 2 point decrease, on a 10 point vas).

Forty three of 79 (54%) were considered positive responders.

Among the positive responders:

44% were mild (2 to 3 point decrease in the vas)
47% had a moderate response (4 to 5 point decrease),
9% had an excellent response (more than 5 point decrease on vas).

TABLE 2
2^nd and 3^rd Month Results of the Initial Mild Responders
(19 of 43 total responders)

2^nd Month Results:
16% = no response
63% = continued to have a mild response
10.5% = moderate response
10.5% = excellent response

3^rd month results of the initial mild responders:
68% = no response
10.5% = mild response
10.5% = moderate response
10.5% = excellent response

TABLE 3
2^nd and 3^rd Month Results of the Initial Moderate Responders
(20 of 43 = 47% of total responders)

2^nd month results:
15% = no response
15% = mild response
70% = continued with a moderate response

3^rd month results of the initial moderate responders:
50% = no response
10% = mild response
40% = continued moderate response

TABLE 4
Excellent Responders (4 of 43) 2^nd and 3^rd Month Results

2^nd month results:
100% (4 of 4) = remained excellent

3^rd month results:
50% (2 of 4) = mild response
25% = moderate response
25% = excellent response

TABLE 5
Adverse Events
The side effects were generally mild, and the medication was well tolerated. Six patients reported a mild unilateral ptosis for up to 3 weeks, and 2 experienced mild bilateral edema of the eyelids, which resolved over weeks. Two patients experienced a dramatic increase in headache.

COMMENTS
In this study, 54% of the patients responded favorably to the low dose BTA injections. During the first month, a total of 24/79 patients reported a moderate or excellent response, with 19 having a mild response. Most of the mild responders continued to have a mild positive response the 2^nd month, but the majority reverted to no response by the 3^rd month. Most of the moderate responders continued with the same response for the 2^nd month, but during the 3^rd month, 50% of this group had no response to the injections. The study did demonstrate that some patients with refractory cdh will have a favorable response to low dose BTA injections.

Previous botulinum toxin studies, in headache patients, have yielded conflicting results. For the treatment of migraine, one multicenter double-blind study of 123 patients demonstrated that subjects in the low dose (25 units total of BTA) group had significantly fewer migraines per month. In addition, the patients had decreased severity of the migraines, less number of days utilizing migraine medications, and reduced migraine-associated vomiting. Another retrospective study, after BTA, of 77 migraineurs revealed 46% with complete headache improvement, 30% with a partial response, and the remainder were nonresponders. The mean dose in this study was 35.5 units of BTA per patient.

Another open-label study over a three year period did include a small number of cluster headache patients. The doses were higher in this study, 80-150 units of BTA. Fifty-eight percent of patients with chronic tension-type headache achieved positive outcomes, 67% of migraine sufferers responded favorably, and 2 of the 4 patients with cluster headache had positive responses. In these cluster patients, a positive response was determined by termination of the cluster episode within 3 weeks of BTA injections. These same investigators went on to conduct a double-blind, placebo-controlled, randomized study involving 40 patients with chronic tension-type headache. The number of headache-free days was significantly increased in the BTA group at 3 months post-treatment. Other studies have not been 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 headache. One further report on 2 patients with episodic cluster headaches revealed complete relief after 50 units of BTA. These injections were given ipsilateral to the pain.

Another study of botulinum toxin for cluster headache revealed that the injections were moderately effective for 3/7 chronic cluster sufferers, and extremely effective for one. The botulinum toxin was not effective for 3 of the chronic cluster patients in this study. Low doses were utilized, either 24 units total of BTA or the equivalent of botulinum toxin type B (1200 units total). Of the 3 episodic cluster sufferers, 1 obtained complete relief and 1 had moderate relief. The 3^rd achieved complete relief with the first set of injections, but only moderate improvement after a further set of injections one year later.

Regarding headache, the mechanism of action of botulinum toxin is unclear. One explanation would be that the injections may help via a decrease in pericranial muscle contractions. Botulinum may, however, affect pain via unknown pathways, as these toxins are general exocytotic inhibitors

This study demonstrates that BTA may be helpful for a minority of refractory cdh sufferers. However, we do not yet know the optimum dosing, the best sites for injection, or which patients should be injected.

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