Abstract
Sixty patients with headaches of more than 15 days per month were recruited for this double-blind, placebo-controlled, parallel study of botulinum toxin type A (BTX) for chronic tension type and chronic migraine headaches. The primary efficacy point was the number of headache-free days as assessed by diary for 12 weeks after BTX injection. Secondary efficacy points included global impressions, the use of abortive headache medications, and palpation. After recruitment, subjects kept diaries for 4 weeks prior to randomization, at which time they received either 200 U of BTX or matching placebo and were followed. After the week-12 evaluation, patients were offered 200 U of BTX (open label), and were similarly followed for another 12 weeks. The mean days with headache of the 60 subjects (49 female, mean age 47 ± 11 years) was 23 ± 7 out of 30. Both groups were demographically similar (58 completed). Over a 12-week period after injections, headache-free days had improved in the BTX group from week 8 to 12 (P < 0.05), and strongly tended to improve over the entire 12-week period, 33 ± 23 vs. 24 ± 16 days without headache (P = 0.07), but did not meet the a priori significance criteria. The subject global impressions (P < 0.05), subject change in headache impressions (P < 0.005), and investigator global impressions (P < 0.001) all improved in the BTX group compared with placebo. Adverse events were mild and did not differ between groups. At week 24 (open label), headache-free days were less in the twice BTX injected group compared with the once injected group, 40 ± 26 vs. 26 ± 19 (P < 0.05). BTX may help chronic daily headache and appears to have a cumulative effect with subsequent injections. The treatment was very well tolerated.
Introduction
Chronic daily headache (CDH) is a heterogeneous disorder, generally defined by> 15 headache days per month (1) and affecting 3–5% of the population (2, 3). It is the most common headache seen in headache specialty clinics (4), and has enormous medical and socio-economic ramifications. CDH patients also suffer from high rates of anxiety and mood disorders, which predict a more intractable course (5, 6). More than 90% of CDH patients initially report episodic headaches (7). Analgesic overuse is clearly associated with an evolution toward CDH, although the exact causal role is not clear (8). The most common CDH subtypes are chronic tension-type headache (CTTH) and chronic migraine (CM). However, many patients report overlapping clinical features making definite segregation problematic.
Botulinum toxin type A (BTX; Botox®, Allergan) inhibits endocytosis of neurotransmitters from the nerve terminal. The drug is most commonly used to reduce muscle contraction, which results from inhibition of acetylcholine release at the neuromuscular junction. In fact, only recently has inhibition of other neurotransmitters been explored for possible therapeutic mechanisms.
BTX has been reported to improve a variety of headache types (9–20). Many of these trials, however, suffer from methodological shortcomings, including the lack of control groups, small sample sizes, and unsystematic data acquisition. We have therefore designed a double-blind, placebo-controlled parallel design trial to assess the efficacy of BTX for both CM and CTTH.
Methods
Sixty patients, age 18–80 years, with headaches of> 15 days per month, were recruited from the Baylor College/Methodist Hospital Headache Clinic. Inclusion was not predicated on the suspected subtype of CDH, but 14 were felt to have CM, 46 were felt to have CTTH based on Silberstein's criteria (4).
This was a double-blind, placebo-controlled, parallel design with a subsequent open-label injection. The study was approved by the Baylor College of Medicine Internal Review Board, and informed consent was obtained from all patients. If subjects passed the screening questionnaire regarding headache frequency, they were enrolled, and then kept diaries of days with and without headaches. After 4 weeks, they returned to clinic and were randomized (1 : 1) to receive 200 U of BTX or matching placebo. The injection locations were at the discretion of the injecting physician (W.G.O.), but generally employed a ‘follow the pain’ strategy. Masseter muscles were injected in some cases. (Table 1). After 4 weeks, patients returned for their initial post-injection evaluation. After eight additional weeks they returned for the final blinded evaluation. All patients were then offered open-label BTX injections. They again returned at 4 and 12 weeks after the second injection for identical assessments.
Patient demographics and preinjection data
CDM, Chronic daily migraine; CMH, chronic migraine headache; CTTH, chronic tension-type headache; BDI, Beck Depression Inventory; PAIS, Psychosocial Adjustment to Illness Scale.
The primary efficacy point was headache-free days on headache diaries. Secondary efficacy points included global impressions, the use of abortive headache medications, palpation scores (rated 0–4 at 24 separate points around the head), the Beck Depression Inventory (BDI) (21), the Psychosocial Adjustment to Illness Scale (PAIS) (22), and adverse events (AEs). These were obtained at each clinic visit.
Statistical analysis of continuous variables included Student's t-test. Dichotomous variables used Fisher's exact tests. For patients who did not complete the second 12-week assessment, we used a mean substitution intention-to-treat analysis.
Two stepwise regression models with backward deletion were then constructed to determine factors that correlated with greater improvement. The first compared headache-free days during the preinjection period (weeks − 4–0) vs. weeks 0–12 (blinded period) for those randomized to BTX. The second compared the preinjection period (weeks − 4–0) vs. weeks 12–24 (open-label period) for all subjects. Demographic variables included age, gender, headache type, initial palpation scores, and initial BDI scores. Technique variables included injection locations (primarily posterior vs. primarily anterior vs. masseter muscles), and initial randomization (for open-label weeks 12–24 only).
Results
The mean age of the 60 subjects (49 female) was 47 ± 11 years and the mean days with headache were 23 ± 7 out of 30. A single 16-year-old female was included as a protocol violation due to her severe refractory CDH and her inability to receive injections off protocol. Five patients were eliminated at screening. Two subjects (one in each group) were lost to follow-up immediately after injections, and are not included in any data analysis (Fig. 1). The subjects had tried and discontinued an average of 4.5 ± 2.4 (range 0–13) abortive medications and 4.0 ± 3.0 (range 0–18) prophylactic medications prior to entering the study. There were no demographic, phenotypic, or injection technique differences between the drug and placebo groups (Table 1).
Recruitment and drop-out rates.
Compared with placebo, headache-free days improved in the BTX group from week 8 to 12 (P < 0.05, t-test), but tended to improve strongly only over the entire period of weeks 0–12, 33 ± 23 vs. 24 ± 16 (P = 0.07) fewer headache days, the primary efficacy point (Fig. 2). Overall effect size was moderate based on the η squared statistic (η2 = 0.073). The subject ‘global’ impressions (P < 0.05, Fisher's exact test), subject ‘change in headache’ impressions (P < 0.005), and investigator ‘global’ impressions (P < 0.001) all improved in the BTX group, compared with placebo (Table 2). The number of abortive headache medications used tended to improve only over the entire 12-week period in the BTX group (106 ± 76 vs. 135 ± 81; P = 0.16). Palpation scores, the BDI, and PAIS scores did not change.
▪, Placebo; •, BTX.
Global impressions
AEs were mild and did not differ between groups. Only a single patient with eyelid ptosis was thought to have a definite BTX-related AE. Overall, 33 AEs were reported in the drug group and 39 were reported in the placebo group. None of these was rated as serious or resulted in discontinuation.
Only one patient who completed the controlled trial elected not to receive open-label injections. Seven patients, however, did not complete the entire subsequent 12-week open-label evaluation within protocol because they did not faithfully complete headache diaries (n = 3), started a new headache medication (n = 3, including one who had BTX-A injected elsewhere), or moved (n = 1). At week 24, comparisons between the group that had received two BTX injections (n = 26 completed) vs. the group which received only one BTX injection (n = 25 completed) showed that the twice-injected group had fewer headache days over the 12-week period, 40 ± 26 vs. 26 ± 19 (P < 0.05) (Fig. 2).
In the demographic analysis of the original 30 subjects who were randomized to BTX [age, gender, headache type, palpation score, BDI, analgesic overuse (>12 doses/month)], only the lack of analgesic overuse correlated with a better response [odds ratio − 0.4 (95% confidence interval − 0.77 to − 0.03), P < 0.05]. However, when assessing the response at 12–24 weeks for all patients who received open-label injections, narcotic overuse no longer predicted improvement. Only female gender tended to predict a better response (P = 0.07).
In the technique analysis of the original 30 BTX recipients, subjects who received injections into the masseter (n = 9) improved less than those who did not receive masseter injections (P < 0.05). Masseter injections, however, no longer predicted a worse response when assessing the entire open-label group. Those who received two BTX injections did better than those who received only one BTX injection (P < 0.05).
Discussion
Our findings suggest, but do not confirm, that BTX improves chronic headache pain. AEs were minimal. Interestingly, subject global impressions robustly improved whereas daily headache diaries only strongly tended to improve, suggesting that unmeasured features may contribute to patient satisfaction. Finally, subjects randomized to BTX further improved after their second BTX injection, suggesting that multiple injections may be required to optimize results.
Although not an a priori data assessment, we also noted a large number of patients who subjectively admitted to probable nocturnal bruxism, most of whom were not previously diagnosed. Self-report of bruxism is only moderately reliable (23) and we did not objectively assess for bruxism via dental examination or polysomnographic studies. Bruxism is also common in the general population. Nevertheless, we feel that this association warrants further study, even though injection into the masseter did not seem to help these headache patients.
Unlike oral medications, results from BTX injection studies are technique dependent. We used a relatively high-dose (200 U), highly concentrated solution (100 U/ml) and a ‘follow the pain’ strategy without EMG guidance. A variety of doses and techniques are used to treat headache, but no data comparing optimal techniques for headache exist.
Our results generally support those of two other controlled trials of BTX-A for CTTH (19, 24). Freund et al. conducted a placebo-controlled, parallel design study in 26 patients with chronic ‘cervicogenic’ headache. Using 100 U diluted into 1 cm3, they injected five cervical trigger points. At 4 weeks, BTX-A subjects reported less subjective pain using a visual analogue scale. Smuts et al. reported a double-blind, placebo-controlled, parallel design trial of 37 subjects with CTTH associated with disorders of pericranial muscles. They injected posterior and temporalis muscles with 100 U BTX-A in 2 ml. Headache severity scores and days without headache improved on drug during a 3-month post-injection period. Schmitt et al. showed mixed results in a 60-patient, controlled parallel trial injecting only 20 U of BTX into frontal and temporal muscles in patients with CTTH (25). In contrast, Gobel et al. in a 20-patient parallel study, employing 10 U into the frontalis, 10 U into the auricularis, and 20 U into the splenius capiti, did not demonstrate a reduced number of headache days in CTTH (26).
Consistent with our results, long-term open-label data suggest that CDH patients report further improvement with multiple subsequent injections (27). The mechanisms by which this occurs are speculative, but may involve gradual effects on central nervous system desensitization.
The mechanism by which BTX improves headache pain is not known. A variety of neuropeptides that are targeted by BTX-A, including substance-P and calcitonin gene-related peptide (CGRP) (28–30), are also implicated in headache (31–34). In fact, triptan 5-HT(1B/1D) agonists may improve migraine pain using similar, although less focal, mechanisms to BTX (35). Relaxation of muscle tightness may also contribute, especially since our patients with CTTH tended to improve more than those with CM.
Potential weaknesses of this study include non-optimized injection technique and dose. Our subjects were seen at a tertiary referral centre and may represent a more refractory population. Purely subjective outcome measures are also an intrinsic weakness to all headache studies. We can only speculate that secondary measures such as global impressions improved more robustly due to improved pain intensity, improved response to abortive medications, or some other unknown measure that is not captured in simple diaries. Finally, injection of normal saline and ‘dry needle’ injections have been shown to improve headache (36). Therefore, BTX studies are actually compared against a potentially active treatment, which may account for some of the ‘placebo’ response. Nevertheless, we feel that our result warrants larger controlled trials for CDH.
Footnotes
Acknowledgements
Statistical analysis and database development were by Integrated Research Inc. (Montreal, Canada).