Migraine is a common medical complaint that causes significant disability, reducing the patient’s quality of life and capacity for work. In North American and European populations, the frequency of migraines varies between 14.8 and 18.5 percent1 , 2 and represents a serious public health problem, with an estimated annual cost of approximately $17 billion.3
Botulinum toxin type A was discovered in 1998 by Binder to treat headaches and other facial pains after cosmetic injections, and was used for hyperkinetic facial lines.4 Its effect is explained by the local activity of botulinum neurotoxin on the neuromuscular junction and peripheral signals. The resulting protein complex produced by Clostridium botulinum blocks release of acetylcholine within the neuromuscular junction, and decreases peripheral sensory signals by reducing muscle activity and release of neuromediators such as glutamate, substance P, and calcitonin gene-related peptide.5 , 6 This inhibition of inflammatory mediators partially explains its ability to reduce pain.
The U.S. Food and Drug Administration approved botulinum toxin type A for the prophylactic treatment of chronic migraine in October of 2010. This was primarily based on two phase-3, placebo-controlled, multicenter studies [PREEMPT 1 and 2 (Phase-3 REsearch Evaluating Migraine Prophylaxis Therapy)].7 , 8 The literature provides contradictory results on the efficacy of this treatment. Thus, the objective of this meta-analysis, which includes double-blind randomized clinical trials, was to assess the effectiveness of botulinum toxin type A injections on changes in the frequency of migraines, its impact on the quality of life, but also its safety versus placebo when injected into pericranial muscles as a preventive treatment for migraines in adults.
MATERIALS AND METHODS
Using Cochrane Handbook instructions, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis principles.9
Studies included in the meta-analysis were randomized, double-blinded, and placebo-controlled trials that compared patients receiving botulinum toxin versus placebo injections into head and neck muscles as preventive treatment for migraine, as defined by the criteria of the International Headache Society.10 Acute migraine therapies were authorized to end the crisis stage (i.e., nonsteroidal antiinflammatory drugs, triptans, acetaminophen, and dihydroergotamine).
Two researchers (E.B. and B.C.), using MEDLINE, Embase, and the Cochrane Library from inception to August of 2016, reviewed the electronic data. Keywords used were “migraine” AND “botulinum toxin type A” OR “Onabotulinum toxin” OR “BOTOX.” We also conducted a manual search using citations from included trials and reviewed similar articles. We included foreign-language articles, and there was no restriction of countries in which the trial was performed. We also searched for ongoing trials using ClinicalTrials.gov11 and the Centre Watch Clinical Trials listing service.12 The online search was supplemented with the bibliographies of identified articles to retrieve any other relevant published material.
The two researchers included articles in the meta-analysis after reading titles, abstracts, and full texts. Descriptive data including study features (i.e., methods, participants, interventions, and outcomes) and quantitative data on primary or secondary outcomes (i.e., frequency, global assessment scales, and adverse events) were then extracted independently. If original data were missing, we contacted the authors by e-mail (twice) and by mailed letter. Reviewers’ discrepancies were resolved after discussion and reaching consensus with the methodologist (E.B.). We excluded open-label studies, retrospective studies, and nonrandomized studies. We also excluded non–placebo-controlled trials13 , 14 and studies without a well-defined migraine population or those including other headache disorders, such as tension headaches, chronic daily headache, dystonia, and all secondary headaches. We also selected studies with a minimum 3-month follow-up without considering analgesic medications and other symptomatic treatments. Studies included were evaluated using the Review Manager program to assess level of evidence and risk of bias.15
We considered episodic and chronic migraine according to the International Headache Society criteria10: chronic migraine was defined by at least 15 headache attacks per month for more than 3 months, with typical features of migraine on at least 8 days per month. Episodic migraine refers to syndromes in patients who experience frequent migraine attacks but do not meet all the criteria for chronic migraines.
Our primary outcome was the change in the number of headache episodes per month from baseline to month 3. This change was also analyzed from baseline to month 2 as a secondary outcome, together with quality of life and adverse events at month 3. Study results were tabulated according to the total number of subjects receiving botulinum toxin type A or placebo, together with the mean and standard deviation for changes in the numbers of headache episodes per month from baseline to month 3, and from baseline to month 2. Missing standard deviations for changes were assessed according to the formula for variance of change:
where cov(X, Y) = r.SD(X).SD(Y), and r was fixed at 0.5. To assess heterogeneity across studies, we used forest plots, Cochran’s heterogeneity statistics, and Higgins I 2 coefficients.16 A value of p < 0.1 or I 2 > 50 percent was considered suggestive of statistical heterogeneity, prompting random-effect modeling. Three studies that reported changes in numbers of headache days per month were also included in the meta-analysis to decrease heterogeneity.8 , 17 , 18
We estimated the mean differences between botulinum toxin type A and placebo groups using an inverse variance approach with 95 percent confidence intervals. We also estimated the standardized mean differences between botulinum toxin type A and placebo groups using scales that reflected quality of life at month 3 (Headache Disability Inventory,19 Beck Depression Inventory–II,20 Migraine Disability Assessment,21 , 22 and Headache Impact Test),23 where higher scores indicate a lower quality of life. Three studies that used a change in quality of life from baseline to month 3 were included in the meta-analysis to decrease heterogeneity.7 , 8 , 24 We also calculated the risk ratio of adverse events with botulinum toxin type A versus placebo, and produced funnel plots to assess small-study effects.24 Review Manager 5.3 software was used for all analyses.15
Our literature screening process identified 18 articles: the process for selection of studies is shown in Figure 1. Our initial search had produced 582 articles on migraines and botulinum toxin: of these, 416 were excluded after we read the title. Of the remaining 43 articles, we excluded four non–placebo-controlled trials, three meta-analyses, and seven subgroup analyses after reading of abstracts. After consulting the full articles, we eliminated 11 more studies that had no exclusively migrainous population. Ultimately, we selected 18 studies for inclusion in our meta-analysis but were unable to use the results of one study because of the lack of data.25
Study Characteristics and Patient Demographics
The 17 studies included 3646 patients, of which 3143 were female (86.21 percent), 2095 had episodic migraines (57 percent), and 1551 had chronic migraines (43 percent). Most patients used a fixed-site protocol (16 of 17). The median frequency of migraine crises per month was 6.5 (range, 4.37 to 25.1). The average age of included patients was 42.8 years (range, 18 to 65 years) in studies where they were clearly defined in the inclusion criteria (14 of 17). Prophylactic treatments were allowed in 10 studies but had to have stable doses and regimens given for 1 to 3 months before the first injections and throughout the study. All of the selected studies described symptomatic treatments and the use of analgesic medications (Table 1).
Our analysis included 17 trials, of which six evaluated chronic migraine and 11 evaluated episodic migraine attacks (Fig. 2). Funnel plots did not show any evidence of small-study bias.
Changes in Numbers of Headache Episodes per Month between Baseline and Month 3
Overall analyses (Fig. 3) found a tendency for less frequent episodic and chronic migraines with botulinum toxin type A compared to placebo at month 3, with a mean difference of change in migraine frequency (per month) of −0.23 (95 percent CI, −0.47 to 0.02; p = 0.08). More precise statistical analyses revealed a significant reduction in the frequency of chronic migraines with botulinum toxin, with a mean difference in change in migraine frequency per month of −1.56 (95 percent CI, −3.05 to −0.07; p = 0.04), with no statistical heterogeneity (I 2 = 37 percent; p = 0.16). Frequency of episodic migraines was not significantly reduced, but there was a tendency toward a reduction, with a mean difference in change of migraine frequency (per month) of −0.17 (95 percent CI, −0.41 to 0.08; p = 0.18), with statistical heterogeneity (I 2 = 52 percent; p = 0.001), which prompted random-effect modeling.
Change in Frequency of Headache Episodes per Month between Baseline and Month 2
Overall analyses indicated that botulinum toxin tended to be more effective than placebo at month 2, with a mean difference in rates of migraines (per month) of −0.21 (95 percent CI, −0.47 to 0.06; p = 0.13) (Fig. 4). More specifically, month 2 statistical analyses revealed a significant reduction in the frequency of chronic migraines with botulinum toxin type A, and a mean difference in rates of migraine (per month) of −1.60 (95 percent CI, −2.72 to −0.47; p = 0.005), with no statistical heterogeneity (I 2 = 8 percent; p = 0.005) (Fig. 4).
The mean change of reduction in episodic migraine rates (per month) at month 2 was not significant (−0.12; 95 percent CI, −0.39 to 0.14; p = 0.36), and had statistical heterogeneity (I 2 = 57 percent; p = 0.0002), which prompted random-effect modeling (Fig. 4).
Quality of Life at Month 3
There was significant improvement in patients’ quality of life at month 3 (higher scores indicating lower quality of life) in the botulinum toxin type A group, with a standardized mean difference of −0.43 (95 percent CI, −0.59 to −0.27; p < 0.00001) (Fig. 5). Statistical heterogeneity was not significant (I 2 = 41 percent; p = 0.09).
Adverse Events at Month 3
More adverse events were reported in the botulinum toxin type A group than in the placebo group at month 3, with a statistically significant risk ratio of 1.32 (95 percent CI, 1.11 to 1.57) (p = 0.002) (Fig. 6). Statistical heterogeneity was significant (I 2 = 66 percent; p < 0.0001), which prompted random-effect modeling. No severe side effects were reported; any side effects were mild in severity, transient, and resolved without sequelae.
The Lancet Global Burden of Disease Study 201526 has ranked migraine as the seventh highest cause of disability worldwide. Since 2005, the prevalence of migraines has increased by 15.3 percent. Headache disorders, including migraine, tension type headache, and medication overuse headache, are third in the worldwide classification of disabilities and are an extensive public health problem.27 Disability caused by chronic migraines has a significant impact on quality of life and increases use of health resources.
The significant results of the two PREEMPT trials7 , 8 regarding injectable botulinum toxin for chronic migraines have led to the validation of botulinum toxin as a prophylactic treatment for chronic migraine by the U.S. Food and Drug Administration in October of 2010. The primary result of our meta-analysis is that botulinum toxin type A is superior to placebo for chronic migraines at month 3. Significant results were also apparent at month 2. The analysis of intermediate results shows that botulinum toxin type A is rapidly effective (within 2 months), which has not been highlighted previously.28 , 29 The toxin also tends to be effective when taken for episodic migraines at month 3. Previous studies had reported a stronger effect of botulinum toxin when given for chronic migraines,30 but our meta-analysis demonstrates effectiveness against episodic migraines in accordance with subgroup analysis results in a retrospective study by Janis et al.31
Concerning quality of life, our study shows significant improvement in patient quality of life at month 3 in the botulinum toxin type A group. To date, this improvement has not been reported in other meta-analyses.28 , 29 In accordance with other studies, this amelioration is linked directly to a reduction in depressive symptoms.32–34 It can be explained by the reduced impact of headaches and migraine-related disability, thus reducing symptoms of depression and anxiety.
Our meta-analysis identified a greater incidence of adverse events in botulinum toxin type A groups than in placebo groups at month 3. Treatment-related adverse events included muscle weakness, diplopia, blepharoptosis, myalgia, dizziness, sedation, asthenia, dyskinesia, hypesthesia, sinus infection, neck pain, dysphagia, and skin tightness. No severe side effects were reported. Botulinum toxin was shown to have a beneficial safety and tolerability profile to treat migraines in analyses by Naumann and Jankovic35 and Silberstein.,36 In contrast, prophylactic oral medications have potentially troublesome systemic side effects (e.g., weight gain, drowsiness, fatigue, dizziness, and decreased libido); some are even dangerous (e.g., allergy, anaphylactic shock).37 Moreover, incremental cost-effectiveness, too, favors the use of botulinum toxin.38 , 39
Our results show a statistical tendency (p = 0.18) for injections of botulinum toxin to reduce the frequency of episodic migraines. These findings were contradicted by Shuhendler et al.,29 who did not find a statistical difference between botulinum toxin type A injection and placebo. Their negative results led to acknowledgment of the inefficacy of botulinum toxin for episodic migraines by the American Academy of Neurology in 2008.40 This lack of significance, particularly for episodic migraines, could be explained by a high response rate to placebo, which is often encountered in trials that explore pain disorders such as migraine.41 , 42
A recent study by et al. reported that placebo response ranged from 14 to 50 percent in clinical trials that analyzed preventive migraine treatments.43 The placebo effect is also closely dependent on the desire to take part in a botulinum toxin type A trial versus placebo. In this setting, the cosmetic benefits of injecting botulinum toxin and its associated low-risk side effects compare favorably with other prophylactic migraine medications, thus increasing patients’ willingness to enter such studies and inflating the placebo effect. Indeed, open-label studies emphasize a greater favorable association between botulinum toxin type A and migraines. The statistical tendency of botulinum toxin to reduce the frequency of episodic migraines needs to be assessed further in double-blind, placebo-controlled, randomized trials.
Nonetheless, the cosmetic use of botulinum toxin type A may have reduced efficacy in botulinum groups. The occurrence of muscular paralysis, mainly in the frontalis, procerus, and corrugators, can reveal—both to the blinded patient and to the investigator—which treatment they are receiving. This can thus increase the placebo effect and reduce the response to botulinum toxin type A. According to Solomon,44 the loss of treatment blinding was highlighted in two randomized, double-blind, placebo-controlled trials that evaluated how many patients guessed which treatment they had received. Mathew et al.45 reported that 85.1 percent of patients had correctly identified they were receiving botulinum toxin. This clearly shows the importance of blindness in randomized, double-blinded, placebo-controlled trials that evaluate the prophylactic effects of botulinum toxin.
Concomitant prophylaxis can also confound the outcomes of migraine trials. In seven studies of our meta-analysis, patients included were asked to stop other prophylactic medications. The third edition of guidelines for controlled trials on migraine drugs46 recommends stopping any prophylactic medications for migraines. Other medications, not taken for migraines, can be continued at doses stable for the previous 3 months, but only if they have few side effects and no clinical interactions with migraines. Acute medications are permitted for the duration of the study, but must be logged.46
The overuse of headache medications needs to be considered. Sandrini et al. evaluated the effect of botulinum toxin in reducing treatment consumption for medication overuse headache.18 They found a significant reduction in the consumption of drugs for acute pain even though reduction in overall headache days was not significant. Finally, a 2-year prospective trial led by Negro et al.47 demonstrated the efficiency and safety of long-term treatment with botulinum toxin in patients affected by chronic migraine and overuse of headache medications.
Other studies have evaluated responses to botulinum toxin A. Lee et al.48 analyzed the ratio of mean arterial blood flow between the internal carotid artery and the homolateral middle cerebral artery using transcranial Doppler sonography. The ratio was higher in botulinum toxin responders than in nonresponders (p = 0.027), even after controlling for covariates (p = 0.025). Cernuda-Morollón et al. measured interictal calcitonin gene-related peptide and vasoactive intestinal peptide levels in peripheral blood to predict the response to botulinum toxin.49
In conclusion, a major strength of this updated meta-analysis is the exhaustiveness of our research, which includes three additional studies compared to the meta-analysis of Jackson et al.28 Furthermore, analysis of intermediate results (starting at 2 months) shows that botulinum toxin had rapid efficacy, which has not been previously highlighted.
We have, for the first time, included criteria reflecting quality of life, which is significantly improved at month 3 in the botulinum toxin type A group for both chronic and episodic migraines.
However, our study has some limitations. First, despite our attempts to contact the authors, we were unable to obtain all patient-level data and had to work using aggregate data; nevertheless, this may have avoided discrepancies between the studies included (particularly for episodic migraines, where statistical heterogeneity was significant). Second, outcomes were various, such as the clustering of migraine frequency when presented as migraine-days per month and number of crises per month. However, the data between groups were clinically similar, and our inclusion of data from all of the trials in the analyses reduced statistical heterogeneity.
Finally, we did not include controlled trials examining other prophylactic oral medications in our meta-analysis. Other studies have compared botulinum toxin injections to various prophylactic oral medications, such as topiramate,14 amitriptyline,13 valproate,50 and methylprednisolone.51 These studies do not demonstrate any superiority of other oral treatments over botulinum toxin.
This meta-analysis reveals that botulinum toxin type A was superior to placebo for chronic migraines at 3 months, and was also significant at 2 months. There was also a tendency for botulinum toxin type A to be effective for episodic migraines at 3 months. This finding needs to be investigated further to identify the causes of statistical heterogeneity between studies. For the first time, our analysis highlights the significant (p < 0.00001) improvement in patients’ quality of life at 3 months in the botulinum toxin type A group, which exhibited few and mild adverse events. Botulinum toxin type A is a safe and well-tolerated treatment that should be offered to patients with migraine.
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