Secondary Logo

Share this article on:

Botulinum Toxin versus Placebo

A Meta-Analysis of Prophylactic Treatment for Migraine

Bruloy, Eva, M.D.; Sinna, Raphael, Ph.D., M.D., M.B.A.; Grolleau, Jean-Louis, M.D.; Bout-Roumazeilles, Apolline, M.D.; Berard, Emilie, M.D.; Chaput, Benoit, M.D., Ph.D.

Plastic and Reconstructive Surgery: January 2019 - Volume 143 - Issue 1 - p 239–250
doi: 10.1097/PRS.0000000000005111
Reconstructive: Head and Neck: Original Articles
Discussion
Press Release

Background: The purpose of this study was to assess the efficacy of botulinum toxin in reducing the frequency of migraine headaches.

Methods: The MEDLINE, Embase, and Cochrane Library databases were searched to identify randomized, double-blind, placebo-controlled trials that compared patients receiving botulinum toxin versus placebo injections in the head and neck muscles, for the preventive treatment of migraine. The primary outcome was change in the number of headache episodes per month from baseline to 3 months.

Results: There were 17 studies including a total of 3646 patients. Overall analysis reported a tendency in favor of botulinum toxin over placebo at 3 months, with a mean difference in the change of migraine frequency of −0.23 (95 percent CI, −0.47 to 0.02; p = 0.08). The reduction in frequency of chronic migraines was significant, with a mean differential change of −1.56 (95 percent CI, −3.05 to −0.07; p = 0.04). Analysis of chronic migraine frequency was also significant after 2 months. The findings also highlighted an improvement of the patient’s quality of life at 3 months in the botulinum toxin group (p < 0.00001). Further adverse events were traced in the botulinum toxin type A group with a statistically significant risk ratio of 1.32 (p = 0.002).

Conclusions: This meta-analysis reveals that botulinum toxin type A injections are superior to placebo for chronic migraines after 3 months of therapy. For the first time, a real benefit in patient quality of life is demonstrated with only few and mild adverse events.

CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Amiens and Toulouse, France

From the Department of Plastic Reconstructive and Aesthetic Surgery, University Hospital of Picardie, Amiens Picardie University Hospital; the Department of Plastic, Reconstructive and Aesthetic Surgery, CHRU Rangueil; and the Department of Epidemiology, Health Economics and Public Health, UMR1027 INSERM-Université de Toulouse III, Centre Hospitalier Universitaire de Toulouse.

Received for publication December 6, 2017; accepted July 20, 2018.

This trial is registered under that name “Botulinum Toxin for Treatment of Migraine: A Meta-Analysis,” PROSPERO identification number CRD42016048772 (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048772).

Disclosure: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.

Benoit Chaput, M.D., Plastic and Reconstructive Surgery Unit, CHU Rangueil, 1, Avenue Jean Poulhès, Toulouse, France, benoitchaput31@gmail.com

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.

Back to Top | Article Outline

MATERIALS AND METHODS

Using Cochrane Handbook instructions, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis principles.9

Back to Top | Article Outline

Inclusion Criteria

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).

Back to Top | Article Outline

Search Strategy

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.

Back to Top | Article Outline

Data Extraction

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

Back to Top | Article Outline

Statistical Analyses

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

Back to Top | Article Outline

RESULTS

Literature Search

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

Fig. 1

Fig. 1

Back to Top | Article Outline

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).

Table 1

Table 1

Back to Top | Article Outline

Efficacy

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.

Fig. 2

Fig. 2

Back to Top | Article Outline

Primary Outcome

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.

Fig. 3

Fig. 3

Back to Top | Article Outline

Secondary Outcomes

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).

Fig. 4

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).

Back to Top | Article Outline

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).

Fig. 5

Fig. 5

Back to Top | Article Outline

Safety

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.

Fig. 6

Fig. 6

Back to Top | Article Outline

DISCUSSION

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.

Back to Top | Article Outline

CONCLUSIONS

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.

Back to Top | Article Outline

REFERENCES

1. Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: Updated statistics from government health surveillance studies. Headache 2015;55:21–34.
2. Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. Epidemiology of headache in Europe. Eur J Neurol. 2006;13:333–345.
3. Lawrence D, Goldberg MD. The cost of migraine and its treatment. Am J Manag Care 2005;11(Suppl): 262–267.
4. Binder WJ. U.S. Patent No. 5714468. A method for reduction of migraine headache pain. February 1998.
5. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005;26:785–793.
6. Mathew NT. Pathophysiology of chronic migraine and mode of action of preventive medications. Headache 2011;51(Suppl 2):84–92.
7. Aurora SK, Dodick DW, Turkel CC, et al; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010;30:793–803.
8. Diener HC, Dodick DW, Aurora SK, et al; PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010;30:804–814.
9. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg. 2010;8:336–341.
10. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd ed (beta version). Cephalalgia 2013;33:629–808.
11. U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/. Accessed October 17, 2017.
12. Available at: http://centrewatch.com/. Accessed May 16, 2016.
13. Magalhães E, Menezes C, Cardeal M, Melo A. Botulinum toxin type A versus amitriptyline for the treatment of chronic daily migraine. Clin Neurol Neurosurg. 2010;112:463–466.
14. Cady RK, Schreiber CP, Porter JA, Blumenfeld AM, Farmer KU. A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache 2011;51:21–32.
15. Review Manager (RevMan) Version 5.3 (computer program). 2014.Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration.
16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560.
17. Vo AH, Satori R, Jabbari B, et al. Botulinum toxin type-a in the prevention of migraine: A double-blind controlled trial. Aviat Space Environ Med. 2007;78(Suppl):B113–B118.
18. Sandrini G, Perrotta A, Tassorelli C, et al. Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: A multicenter, double-blind, randomized, placebo-controlled, parallel group study. J Headache Pain 2011;12:427–433.
19. Jacobson GP, Ramadan NM, Aggarwal SK, Newman CW. The Henry Ford Hospital Headache Disability Inventory (HDI). Neurology 1994;44:837–842.
20. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess. 1996;67:588–597.
21. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: A comparison of chronic migraine with episodic migraine. Headache 2003;43:336–342.
22. D’Amico D, Mosconi P, Genco S, et al. The Migraine Disability Assessment (MIDAS) questionnaire: Translation and reliability of the Italian version. Cephalalgia 2001;21:947–952.
23. Bjorner JB, Kosinski M, Ware JE Jr. Using item response theory to calibrate the Headache Impact Test (HIT) to the metric of traditional headache scales. Qual Life Res. 2003;12:981–1002.
24. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61:991–996.
25. Anand KS, Prasad A, Singh MM, Sharma S, Bala K. Botulinum toxin type A in prophylactic treatment of migraine. Am J Ther. 2006;13:183–187.
26. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545–1602.
27. Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P. Headache disorders are third cause of disability worldwide. J Headache Pain 2015;16:58.
28. Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: A meta-analysis. JAMA 2012;307:1736–1745.
29. Shuhendler AJ, Lee S, Siu M, et al. Efficacy of botulinum toxin type A for the prophylaxis of episodic migraine headaches: A meta-analysis of randomized, double-blind, placebo-controlled trials. Pharmacotherapy 2009;29:784–791.
30. Mathew NT, Kailasam J, Meadors L. Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache. Headache 2008;48:194–200.
31. Janis JE, Barker JC, Palettas M. Targeted peripheral nerve-directed onabotulinumtoxin A injection for effective long-term therapy for migraine headache. Plast Reconstr Surg Glob Open 2017;5:e1270.
32. Hawlik AE, Freudenmann RW, Pinkhardt EH, Schönfeldt-Lecuona CJ, Gahr M. Botulinum toxin for the treatment of major depressive disorder (in German). Fortschr Neurol Psychiatr. 2014;82:93–99.
33. Boudreau GP, Grosberg BM, McAllister PJ, Lipton RB, Buse DC. Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: An open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety. Int J Gen Med. 2015;8:79–86.
34. Maasumi K, Thompson NR, Kriegler JS, Tepper SJ. Effect of onabotulinumtoxinA injection on depression in chronic migraine. Headache 2015;55:1218–1224.
35. Naumann M, Jankovic J. Safety of botulinum toxin type A: A systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981–990.
36. Silberstein SD. The use of botulinum toxin in the management of headache disorders. Semin Neurol. 2016;36:92–98.
    37. D’Amico D, Solari A, Usai S, et al; Progetto Cefalee Lombardia Group. Improvement in quality of life and activity limitations in migraine patients after prophylaxis: A prospective longitudinal multicentre study. Cephalalgia 2006;26:691–696.
    38. Khalil M, Zafar HW, Quarshie V, Ahmed F. Prospective analysis of the use of onabotulinumtoxinA (BOTOX) in the treatment of chronic migraine; real-life data in 254 patients from Hull, U.K. J Headache Pain 2014;15:54.
    39. Ruggeri M. The cost effectiveness of Botox in Italian patients with chronic migraine. Neurol Sci. 2014;35(Suppl 1):45–47.
    40. Naumann M, So Y, Argoff CE, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review). Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70:1707–1714.
    41. Couch JR Jr. Placebo effect and clinical trials in migraine therapy. Neuroepidemiology 1987;6:178–185.
    42. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25:10390–10402.
    43. Speciali JG, Peres M, Bigal ME. Migraine treatment and placebo effect. Expert Rev Neurother. 2010;10:413–419.
    44. Solomon S. OnabotulinumtoxinA for treatment of chronic migraine: The unblinding problem. Headache 2013;53:824–826.
    45. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C; BOTOX CDH Study Group. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: A randomized, double-blind, placebo-controlled trial. Headache 2005;45:293–307.
    46. Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012;32:6–38.
    47. Negro A, Curto M, Lionetto L, Martelletti P. A two years open-label prospective study of onabotulinumtoxinA 195 U in medication overuse headache: A real-world experience. J Headache Pain 2015;17:1.
    48. Lee MJ, Lee C, Choi H, Chung CS. Factors associated with favorable outcome in botulinum toxin A treatment for chronic migraine: A clinic-based prospective study. J Neurol Sci. 2016;363:51–54.
    49. Cernuda-Morollón E, Martínez-Camblor P, Ramón C, Larrosa D, Serrano-Pertierra E, Pascual J. CGRP and VIP levels as predictors of efficacy of onabotulinumtoxin type A in chronic migraine. Headache 2014;54:987–995.
    50. Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache 2008;48:210–220.
    51. Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache. Curr Rev Pain 2000;4:31–35.
    ©2019American Society of Plastic Surgeons