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Review |

Botulinum Toxin A for Prophylactic Treatment of Migraine and Tension Headaches in Adults:  A Meta-analysis FREE

Jeffrey L. Jackson, MD, MPH; Akira Kuriyama, MD; Yasuaki Hayashino, MD, DMSc, MPH
[+] Author Affiliations

Author Affiliations: Department of General Internal Medicine, Zablocki Veterans Affairs Medical Center, and Department of Medicine, Medical College of Wisconsin, Milwaukee (Dr Jackson); Department of General Internal Medicine, Rakuwakai Otowa Hospital, Kyoto, Japan (Dr Kuriyama); and Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine and Public Health, Kyoto, Japan (Dr Hayashino).


JAMA. 2012;307(16):1736-1745. doi:10.1001/jama.2012.505.
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Context Botulinum toxin A is US Food and Drug Administration approved for prophylactic treatment for chronic migraines.

Objective To assess botulinum toxin A for the prophylactic treatment of headaches in adults.

Data Sources A search of MEDLINE, EMBASE, bibliographies of published systematic reviews, and the Cochrane trial registries between 1966 and March 15, 2012. Inclusion and exclusion criteria of each study were reviewed. Headaches were categorized as episodic (<15 headaches per month) or chronic (≥15 headaches per month) migraine and episodic or chronic daily or tension headaches.

Study Selection Randomized controlled trials comparing botulinum toxin A with placebo or other interventions for headaches among adults.

Data Extraction Data were abstracted and quality assessed independently by 2 reviewers. Outcomes were pooled using a random-effects model.

Data Synthesis Pooled analyses suggested that botulinum toxin A was associated with fewer headaches per month among patients with chronic daily headaches (1115 patients, −2.06 headaches per month; 95% CI, −3.56 to −0.56; 3 studies) and among patients with chronic migraine headaches (n = 1508, −2.30 headaches per month; 95% CI, −3.66 to −0.94; 5 studies). There was no significant association between use of botulinum toxin A and reduction in the number of episodic migraine (n = 1838, 0.05 headaches per month; 95% CI, −0.26 to 0.36; 9 studies) or chronic tension-type headaches (n = 675, −1.43 headaches per month; 95% CI, −3.13 to 0.27; 7 studies). In single trials, botulinum toxin A was not associated with fewer migraine headaches per month vs valproate (standardized mean difference [SMD], −0.20; 95% CI, −0.91 to 0.31), topiramate (SMD, 0.20; 95% CI, −0.36 to 0.76), or amitriptyline (SMD, 0.29; 95% CI, −0.17 to 0.76). Botulinum toxin A was associated with fewer chronic tension-type headaches per month vs methylprednisolone injections (SMD, −2.5; 95% CI, −3.5 to −1.5). Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis, skin tightness, paresthesias, neck stiffness, muscle weakness, and neck pain.

Conclusion Botulinum toxin A compared with placebo was associated with a small to modest benefit for chronic daily headaches and chronic migraines but was not associated with fewer episodic migraine or chronic tension-type headaches per month.

Figures in this Article

Migraine and tension-type headaches are common. Although up to 42% of adults experience tension-type headaches sometime in their life, most do not seek medical advice. Migraines are less common, with a worldwide prevalence between 8% and 18%,13 but are associated with greater disability.4,5 Migraine headaches are responsible for $1 billion in medical costs and $16 billion in lost productivity per year6 in the United States alone.

Headache treatment is either abortive or prophylactic. Abortive treatment manages the acute headache and prophylactic treatment aims to reduce the frequency or severity of the attacks. Common prophylactic medications include anticonvulsants, β-blockers, calcium channel blockers, serotonin reuptake inhibitors, and tricyclic antidepressants.7 Botulinum toxin A injections were first proposed as headache treatment when it was observed that patients with chronic headaches receiving cosmetic botulinum injections experienced headache improvement, prompting several case series that suggested benefit.810 In October 2010, the US Food and Drug Administration approved botulinum toxin A for prophylactic treatment of chronic migraine headaches at a dose of 155 units divided among 31 injection sites, repeated as needed every 12 weeks, based on 2 clinical trials conducted in Europe and the United States.11,12 However, the literature on botulinum effectiveness for headaches is mixed. We performed a systematic review to assess the association of botulinum toxin A with reducing headache frequency when used for prophylactic treatment of migraine, tension, or chronic daily headaches in adults.

We followed the PRISMA guideline13 and accordingly followed a protocol (available to readers upon request). We searched for randomized trials of botulinum toxin A for headaches in adults using MEDLINE and EMBASE, the bibliographies of published systematic reviews, the Cochrane libraries (Database of Clinical Trials; Pain, Palliative, and Supportive Care Trials Register; Central Register of Controlled Trials), and performed a review of the bibliographies of all articles retrieved (eTable 1). The last search date was March 15, 2012. The search was supplemented by searches performed by medical librarians at our institution. We did not attempt to contact authors for original data or search for unpublished literature.

We included randomized clinical trials that evaluated botulinum toxin A treatment and its association with the reduction in frequency or severity of headaches. Trials had to be at least 4 weeks in duration. Treatment could be combined with other prophylactic and analgesic medications. Quiz Ref IDWe excluded headaches associated with other disorders, such as cervical dystonia and secondary headaches, such as postlumbar puncture headaches. Because the definition of headaches has changed over time, we reviewed each study's inclusion and exclusion criteria and attempted to categorize trials as episodic (<15 headaches per month) or chronic (≥15 headaches per month) and as migraine or tension. Some trials investigated chronic daily headaches14 and included chronic headaches of either tension or migraine type.

At least 2 authors (J.L.J., A.K., Y.H.) independently abstracted data, including study characteristics (setting, country of origin, language, and inclusion and exclusion criteria), information about the intervention (design, treatment characteristics, including dose and duration), subject characteristics (age, sex, ethnicity, assessment of comorbid psychiatric disease), and headache outcomes (frequency, intensity/severity, duration, global improvement/relief, analgesics used, adverse events).

For our primary outcome analysis, we followed International Headache Society recommendations15,16 and preferentially abstracted and pooled headache frequency (number of headaches per month) using weighted mean differences in a random-effects model. For studies not reporting headache frequency, outcomes were abstracted preferentially in this order: headache severity or a headache index that included frequency and severity.

We required all outcomes to be patient reported. For continuous outcomes, we abstracted the number of participants and the mean and variance of reported outcomes. Missing variances were calculated by using the sample size and means from reported P values.17 For dichotomous outcomes, we required at least 50% clinical improvement. We abstracted this data into 2×2 tables. For both continuous and dichotomous outcomes, we abstracted the outcome at all time points reported. We assessed article quality independently and in duplicate using the Cochrane Risk of Bias assessment tool18 and the Jadad scale (original 0-8 scale),19 with good interrater agreement (Jadad scale: intraclass correlation coefficient, 0.89-0.97). Disagreements were resolved by consensus.

For studies with more than 1 treatment group, we followed the Cochrane recommendation and combined groups by pooling the data into a single group.20 Summary effects were calculated by using the DerSimonian and Laird random-effects model.21 We assessed heterogeneity visually using Galbraith plots22 and statistically with Q statistics and I2.23 Our primary analysis was headache frequency, pooling weighted mean differences. We secondarily examined all studies, including those using other measures than frequency by calculating an effect size (standardized mean differences [SMDs]), the absolute difference between groups divided by the standard deviation. By convention, effect sizes more than 0.8 are considered large, those between 0.5 and 0.8 moderate, those between 0.2 and 0.5 small, and those less than 0.2 insignificant.24 To test the robustness of the random-effects models, we also calculated a predictive interval using the methods of Higgins25 and performed a noninformative random-effects Bayesian analysis using Winbugs.26 The Higgins predictive interval asks what range of outcomes could be expected with 95% confidence from future trials based on the observed trial heterogeneity using a t distribution.

Quality assessment was performed by using a component approach in which each domain's potential effect on our results was evaluated. In addition, we tested the effect of study sponsorship and use of intention-to-treat analysis (for trials with losses to follow-up). We assessed for small study effects (publication bias) using the methods of Peters et al27 for dichotomous and Egger et al28 for continuous outcomes. We explored potential sources of heterogeneity using stratified analysis and meta-regression.29 The analysis of the association of placebo with headache outcomes was performed by using random-effects meta-regression, clustered by the specific study.

All analyses were performed by using STATA version 12.0 or Winbugs. In creating our forest plots, we followed standard convention, in which the size of the box for each study is proportional to the contribution (weight) of each study to the pooled summary. The Zablocki Veterans Affairs review board reviewed and approved this manuscript for publication.

Our search produced 315 articles. Application of inclusion and exclusion criteria (eFigure 1) resulted in 27 placebo-controlled randomized trials11,12,3054 and 4 randomized comparisons with other medications (amitriptyline,55 prednisone,56 topiramate,57 and valproate58).

Among placebo-controlled trials, there were 5313 study participants, of which 1938 had episodic migraines, 1544 had chronic migraines (Table 1), 616 had chronic tension-type headaches (Table 2), and 1115 had chronic daily headaches (Table 1). One study with 21 participants evaluated patients with either episodic or chronic tension-type headaches (Table 2). The average age of participants was 42.1 years, with predominantly women (76%) (eTable 2). Trials averaged 19 weeks in duration, ranging between 84 and 270 days (Table 1). Most trials allowed continued use of prophylactic headache medications (85%) if patients were taking a stable dose and all allowed analgesic use.

Table Graphic Jump LocationTable 1. Randomized Controlled Trials of Botulinum Toxin A and Association With Migraine and Chronic Daily Headachesa
Table Graphic Jump LocationTable 2. Randomized Controlled Trials of Botulinum Toxin A and Association With Chronic Tension-Type Headachesa

Different protocols were followed for the botulinum injections (eTable 2). Quiz Ref IDAmong the 27 placebo-controlled trials, 20 used a fixed injection plan, in which patients were injected at a fixed, specific site. Seven trials used a follow-the-pain approach, in which painful points were elicited and injected. One trial used a combination of fixed and follow-the-pain protocols. Twenty-one studies injected botulinum toxin A at a single time point, although 6 studies performed injections at 3 time points spaced 90 days apart. The number of injections varied, ranging between 4 and 58. One trial compared injections into single muscle groups against injections into several muscle groups (range, 4-11).

Placebo-Controlled Trials

Among 27 placebo-controlled trials, 10 evaluated patients with episodic migraine headaches, 5 assessed chronic migraines, 8 evaluated patients with chronic tension-type headaches, 1 evaluated a population of 21 patients with either episodic (n = 16) or chronic (n = 5) tension-type headaches, and 3 trials studied chronic daily headaches (migraine or tension-type headaches occurring >14 days per month [Table 1]), the majority of which (74%) experienced chronic migraine headaches. All but 2 placebo-controlled trials reported outcomes in terms of frequency. The trials of episodic migraines averaged 6.2 (95% CI, 5.0-7.4) headaches per month, trials of chronic migraine averaged 19.5 (95% CI, 14.8-24.2) headaches per month, trials of chronic tension-type headaches averaged 25.2 (95% CI, 22.9-27.8) headaches per month, and trials of chronic daily headaches averaged 17.5 (95% CI, 13.5-21.3) headaches per month. The trial with a combination of episodic tension-type (n = 16) and chronic tension-type (n = 5) headaches averaged 13.9 (95% CI, 11.5-14.7) headaches per month (eTable 2).

Botulinum toxin A was associated with a reduction in headaches per month for both chronic daily headaches (−2.06 headaches per month; 95% CI, −3.56 to −0.56; Q = 2.79, df = 2, I2 = 28.2%; P = .25) and chronic migraine (−2.30 headaches per month; 95% CI, −3.66 to −0.94; Q = 5.9, df = 4, I2 = 32.2%; P = .21) (Figure 1). There was no association of botulinum toxin A with a reduction in the number of episodic migraine headaches per month (0.05 headaches per month; 95% CI, −0.26 to 0.36; Q = 11.43, df = 8, I2 = 30.0%; P = .18) or chronic tension-type headaches (−1.43 headaches per month; 95% CI, −3.13 to 0.27; Q = 15.59, df = 6, I2 = 61.5%; P = .02) (Figure 1). A single trial that included participants with both episodic and chronic tension-type headaches found no association of botulinum toxin A with a reduction in headaches (3.70 headaches per month; 95% CI, −2.85 to 10.26).

Place holder to copy figure label and caption
Figure 1. Change in Number of Monthly Headaches Among Adults in Randomized Controlled Trials of Botulinum Toxin A vs Placebo
Graphic Jump Location

Size of data markers is proportional to study weight.

There were 2 studies (1 chronic tension-type headache and 1 episodic migraine) that reported outcomes as headache indices rather than headache frequency. Reanalysis of these trials using SMDs also found no association of botulinum toxin A with improvement in the headache indices compared with placebo for chronic tension-type headache (SMD, −0.22; 95% CI, −0.51 to 0.07; Q = 15.57, df = 6, I2 = 55.0%; P = .03) or episodic migraine (SMD, −0.13; 95% CI, −0.33 to 0.07; Q = 26.40, df = 9, I2 = 65.9%; P = .002).

Eight studies reported on the likelihood of achieving 50% improvement in headache. Botulinum toxin A was associated with a greater likelihood of experiencing 50% improvement in chronic migraine headaches (2 studies: relative risk [RR], 2.21; 95% CI, 1.30-3.78; Q = 0.03, I2 = 0.0%; P = .86) (Figure 2). Compared with placebo, there was no association of botulinum toxin A with improvement in chronic daily headaches (1 study: RR, 1.15; 95% CI, 0.91-1.45), episodic migraine headaches (2 studies: RR, 1.00; 95% CI, 0.85-1.18; Q = 0.27, I2 = 0.0%; P = .61), or chronic tension-type headaches (3 studies: RR, 1.00; 95% CI, 0.57-1.76; Q = 2.30, df = 2, I2 = 12.9%; P = .15).

Place holder to copy figure label and caption
Figure 2. Relative Risk of 50% Reduction in Number of Headaches per Month Among Adults in Randomized Controlled Trials of Botulinum Toxin A vs Placebo
Graphic Jump Location

Size of data markers is proportional to study weight.

Comparative Effectiveness Trials

There were 4 trials that compared botulinum toxin A with other treatment modalities. In single trials, botulinum toxin A was not associated with reduction in headache frequency compared with topiramate (1.4 headaches per month; 95% CI, −2.5 to 1.3) or amitriptyline (2.1 headaches per month; 95% CI, −1.2 to 5.4) for prophylaxis against chronic migraine headaches. Botulinum toxin A was not associated with a reduction in headache frequency vs valproate in a study of patients with chronic and episodic migraines (0.84 headaches per month; 95% CI, 1.40-3.10) or in a study of patients with episodic migraines (0.3 headaches per month; 95% CI, −1.1 to 0.50). Botulinum toxin A was associated with a greater reduction in average headache severity (0-10 visual analog scale) than methylprednisolone in a single trial among patients experiencing chronic tension-type headaches (−2.5 headaches per month; 95% CI, −3.5 to −1.5).

Sensitivity Analyses

Our data had moderate heterogeneity. Study quality varied, with total Jadad scores ranging between 2 and 8 (eTable 3). There was no relationship between total Jadad score and outcomes or between Jadad scores of more than 3 vs 3 or less and study outcomes. Sixty-five percent of studies used intention-to-treat analysis, although only 42% had adequate sequence generation, 35% concealed allocation, and 61% had adequately described blinding. There was no relationship between the outcomes and intention-to-treat analysis (P = .74), concealed allocation (P = .40), adequacy of sequence generation (P = .17), industry sponsorship (P = .16), blinding (P = .37), or dropouts (P = .40). We explored a number of potential sources of heterogeneity (eTable 4) and found no association of participant age, proportion of women, sample size, study duration, dropout rates, botulinum toxin A dose, or injection strategy with study outcomes. We found no evidence of publication bias for either continuous (Egger method, P = .93) or dichotomous outcomes (Peters method, P = .29). Because the studies were few and the tests for statistical significance depend on assumptions of normality that may not be reasonable with small samples, we reanalyzed our data using the Higgins t distribution and a noninformative Bayesian model. None of these results were statistically significant (eTable 5).

Adverse Events

Patients receiving botulinum toxin A were more likely to report any adverse event than those injected with placebo (25 studies: RR, 1.25; 95% CI, 1.14-1.36), although they were not more likely to withdraw from the study (23 studies: RR, 1.04; 95% CI, 0.85-1.27) (Table 3). Quiz Ref IDSome adverse effects were more common among patients receiving botulinum toxin A, including blepharoptosis (RR, 9.5; 95% CI, 4.7-18.9), muscle weakness (RR, 8.9; 95% CI, 2.5-30.9), neck pain (RR, 4.7; 95% CI, 3.2-6.9), neck stiffness (RR, 3.2; 95% CI, 1.9-5.6), parasthesia (RR, 3.3; 95% CI, 1.3-7.9), and skin tightness (RR, 3.6; 95% CI, 1.6-8.3).

Table Graphic Jump LocationTable 3. Adverse Effects of the Randomized Controlled Trials
Placebo Effect

There was evidence for a favorable improvement in headaches in the placebo-treated study groups. Over the range of study durations (8-39 weeks), patients receiving placebo reported substantial improvement in headaches over time (eFigure 2). The standardized headache effect size decreased from 3.4 (95% CI, 2.62-4.14) to 1.26 (95% CI, −0.13 to 2.65) by day 270, a significant association (β = −0.0075; 95% CI, −0.012 to −0.003; r2 = 20%).

Quiz Ref IDOur analyses suggest that botulinum toxin A may be associated with improvement in the frequency of chronic migraine and chronic daily headaches, but not with improvement in the frequency of episodic migraine, chronic tension-type headaches, or episodic tension-type headaches. However, the association of botulinum toxin A with clinical benefit was small. Botulinum toxin A was associated with a reduction in the number of headaches per month from 19.5 to 17.2 for chronic migraine and from 17.5 to 15.4 for chronic daily headaches. We also found a strong association of placebo with improvement in headaches over time.

Given that botulinum toxin A is not associated with improvement in chronic tension headache, it is likely that the association with reduction in chronic daily headaches is due to its association with improvement among the majority of participants in the trials with chronic migraines. This is consistent with a subgroup analysis from one of the trials of chronic daily headache that demonstrated an association of botulinum toxin A with greater improvement for chronic migraines than chronic tension headaches.59

There does not appear to be a difference in outcomes when botulinum toxin A is injected in a fixed schedule, when certain muscle groups are injected, or when botulinum toxin A is injected using a follow-the-pain method. We found no differences in outcomes between injecting once or performing 3 injections at 90-day intervals. There was no difference in the number of muscle groups injected or the total botulinum toxin A dose used and study outcomes.

Quiz Ref IDOur finding of minimal benefit is contrary to findings from case series and open-label studies that suggested substantial benefits.6079 These differences in results may be due to a strong association of placebo with improved outcomes and the natural history of headaches, in which improvement is observed over time. The favorable placebo association has been reported previously for botulinum80 and has been observed in other symptom-based conditions, such as irritable bowel syndrome,81 overactive bladder,82 low back pain,83 and Crohn disease.84 Our findings underscore the importance of including placebo groups in clinical trials of symptom syndromes.

There are a number of prophylactic drugs that are associated with improved outcomes for headaches, including β-blockers (atenolol, metoprolol, propranolol), anticonvulsants (gabapentin, topiramate, valproate), the calcium channel blocker flunarizine, and tricyclic antidepressants (amitriptyline and clomipramine). The reported range of efficacy for these drugs varies from modest (effect size, 0.5-0.8) for most drugs (atenolol, metoprolol, propranolol, clomipramine, topiramate, and flunarizine) to large (effect size, >0.8) for amitriptyline and valproate. The effect sizes in our review are smaller than reported values in other reviews, suggesting that botulinum toxin A may be associated with less benefit than other common prophylactic medications for migraine headaches. However, the paucity of direct comparisons makes definitive conclusions difficult.

Although single trials found no differences between botulinum toxin A and amitriptyline55 or topiramate57 for chronic migraine headaches and no differences between botulinum toxin A and valproate58 for chronic tension-type headaches, none of these trials were designed as equivalence trials and all were underpowered to show even modest differences (amitriptyline power = 0.61, topiramate power = 0.28, and valproate power = 0.27). The trials of topiramate and valproate had significant loss to follow-up (topiramate, 18%; valproate, 45%) and the maximum doses of the 3 comparison medications were low, using only 50% of standard migraine prophylactic treatment doses (amitriptyline, 50 mg; topiramate, 100 mg; and valproate, 500 mg). Porta56 reported that botulinum toxin A was associated with better outcomes than methylprednisolone for chronic tension-type headaches. Given that our analyses demonstrated no association of botulinum toxin A with improved outcomes for chronic tension-type headaches, that corticosteroids are not generally used as a prophylactic medication for headaches, and that there are no trials of corticosteroids for use in prophylactic treatment of headaches, it is unclear how useful this comparison is clinically.

Our systematic review has limitations. First, for nearly all the headache types, there were relatively few studies and many of the studies were quite small. Our results could be spurious, particularly given that the meta-analysis is based on assumptions of normality for tests of significance. Analysis of the data using nonnormal approaches, approximate predictive distribution of a future trial, based on the extent of heterogeneity as suggested by Higgins et al25 or Bayesian methods26 suggests that botulinum toxin A may not be associated with benefit for any headache types. More trials are needed.

A second limitation is that we had only aggregate data. Many of the outcomes had considerable heterogeneity and the lack of patient-level data precluded fully exploring potential sources of differences between the studies. This makes it difficult to explore why botulinum toxin A is not associated with benefit for chronic tension-type headaches, even though it is associated with improved outcomes for chronic daily headaches. Third, headache is a chronic problem and all the trials were relatively short. At least 1 systematic review85 found that prophylactic treatment becomes more effective over time. Fourth, none of the studies evaluated more than 3 injections, 90 days apart. It is unclear whether a higher dosing strategy over time may be associated with greater benefit. Fifth, there are few comparisons between botulinum toxin A and other prophylactic medications, and these are underpowered or have other limitations that may prevent the ability to demonstrate benefit of botulinum toxin A. Although the reported SMD of benefit that has been associated with other prophylactic agents appears to be larger than the SMD we found for botulinum toxin A, the best way to make this determination is with direct comparative trials. In addition, we only included events from these randomized controlled trials. Observational studies and Food and Drug Administration adverse event reports likely include additional harms, particularly rare ones that may be missed in short-term, relatively small studies. We may have underestimated adverse effects of botulinum toxin A.

In conclusion, botulinum toxin A is not associated with greater benefit than placebo in prophylactic treatment of episodic migraine or chronic tension-type headaches. Botulinum toxin A may be associated with benefit in prophylaxis of chronic daily headaches and chronic migraine headaches. This beneficial association appears limited to patients with chronic migraine headaches and the absolute reduction in the number of headaches is only 2 to 3 days a month.

Corresponding Author: Jeffrey L. Jackson, MD, MPH, Department of Medicine, Medical College of Wisconsin, 5000 W National Ave, Milwaukee, WI 53295 (jjackson@mcw.edu).

Author Contributions: Dr Jackson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jackson, Kuriyama, Hayashino.

Acquisition of data: Jackson, Kuriyama, Hayashino.

Analysis and interpretation of data: Jackson.

Drafting of the manuscript: Jackson.

Critical revision of the manuscript for important intellectual content: Jackson, Kuriyama, Hayashino.

Statistical analysis: Jackson.

Study supervision: Hayashino.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Neither Dr Jackson nor Dr Kuriyama has any conflicts to disclose. Although Dr Hayashino has accepted speaker fees from a number of pharmaceutical firms, none of these manufacture botulinum toxin A.

Disclaimer: All opinions in this article are those of the authors and should not be construed to reflect in any way those of the US Department of Veterans Affairs.

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PubMed   |  Link to Article
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Sharp S. Meta-analysis regression.  Stata Tech Bull. 1998;42:16-22
Anand KS, Prasad A, Singh MM, Sharma S, Bala K. Botulinum toxin type A in prophylactic treatment of migraine.  Am J Ther. 2006;13(3):183-187
PubMed   |  Link to Article
Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM.BOTOX North American Episodic Migraine Study Group.  Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study.  Headache. 2007;47(4):486-499
PubMed
Cady R, Schreiber C. Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues.  Headache. 2008;48(6):900-913
PubMed   |  Link to Article
Chankrachang S, Arayawichanont A, Poungvarin N,  et al.  Prophylactic botulinum type A toxin complex (Dysport) for migraine without aura.  Headache. 2011;51(1):52-63
PubMed   |  Link to Article
Elkind AH, O’Carroll P, Blumenfeld A, DeGryse R, Dimitrova R.BoNTA-024-026-036 Study Group.  A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.  J Pain. 2006;7(10):688-696
PubMed   |  Link to Article
Evers S, Vollmer-Haase J, Schwaag S, Rahmann A, Husstedt IW, Frese A. Botulinum toxin A in the prophylactic treatment of migraine: a randomized, double-blind, placebo-controlled study.  Cephalalgia. 2004;24(10):838-843
PubMed   |  Link to Article
Freitag FG, Diamond S, Diamond M, Urban G. Botulinum toxin type A in the treatment of chronic migraine without medication overuse.  Headache. 2008;48(2):201-209
PubMed
Hamdy SM, Samir H, El-Sayed M, Adel N, Hasan R. Botulinum toxin: could it be an effective treatment for chronic tension-type headache?  J Headache Pain. 2009;10(1):27-34
PubMed   |  Link to Article
Harden RN, Cottrill J, Gagnon CM,  et al.  Botulinum toxin A in the treatment of chronic tension-type headache with cervical myofascial trigger points: a randomized, double-blind, placebo-controlled pilot study.  Headache. 2009;49(5):732-743
PubMed   |  Link to Article
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(4):293-307
PubMed   |  Link to Article
Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study.  Cephalalgia. 2004;24(1):60-65
PubMed   |  Link to Article
Padberg M, de Bruijn SF, de Haan RJ, Tavy DL. Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial.  Cephalalgia. 2004;24(8):675-680
PubMed   |  Link to Article
Petri S, Tölle T, Straube A, Pfaffenrath V, Stefenelli U, Ceballos-Baumann A.Dysport Migraine Study Group.  Botulinum toxin as preventive treatment for migraine: a randomized double-blind study.  Eur Neurol. 2009;62(4):204-211
PubMed   |  Link to Article
Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C.European BoNTA Headache Study Group.  A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches.  Cephalalgia. 2007;27(6):492-503
PubMed   |  Link to Article
Rollnik JD, Tanneberger 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(4):300-305
PubMed   |  Link to Article
Rollnik JD, Karst M, Fink M, Dengler R. Botulinum toxin type A and EMG: a key to the understanding of chronic tension-type headaches?  Headache. 2001;41(10):985-989
PubMed   |  Link to Article
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(4):427-433
PubMed   |  Link to Article
Saper JR, Mathew NT, Loder EW, DeGryse R, VanDenburgh AM.BoNTA-009 Study Group.  A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine.  Pain Med. 2007;8(6):478-485
PubMed   |  Link to Article
Schmitt WJ, Slowey E, Fravi N, Weber S, Burgunder JM. Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial.  Headache. 2001;41(7):658-664
PubMed   |  Link to Article
Schulte-Mattler WJ, Krack P.BoNTTH Study Group.  Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study.  Pain. 2004;109(1-2):110-114
PubMed   |  Link to Article
Silberstein S, Mathew N, Saper J, Jenkins S.For the BOTOX Migraine Clinical Research Group.  Botulinum toxin type A as a migraine preventive treatment.  Headache. 2000;40(6):445-450
PubMed   |  Link to Article
Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC.BoNTA-039 Study Group.  Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial.  Mayo Clin Proc. 2005;80(9):1126-1137
PubMed   |  Link to Article
Silberstein SD, Göbel H, Jensen R,  et al.  Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study.  Cephalalgia. 2006;26(7):790-800
PubMed   |  Link to Article
Straube A, Empl M, Ceballos-Baumann A, Tölle T, Stefenelli U, Pfaffenrath V.Dysport Tension-Type Headache Study Group.  Pericranial injection of botulinum toxin type A (Dysport) for tension-type headache: a multicentre, double-blind, randomized, placebo-controlled study.  Eur J Neurol. 2008;15(3):205-213
PubMed   |  Link to Article
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(5):(suppl)  B113-B118
PubMed
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(6):463-466
PubMed   |  Link to Article
Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache.  Curr Rev Pain. 2000;4(1):31-35
PubMed   |  Link to Article
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(1):21-32
PubMed   |  Link to Article
Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.  Headache. 2008;48(2):210-220
PubMed   |  Link to Article
Mathew NT, Kailasam J, Meadors L. Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache.  Headache. 2008;48(2):194-200
PubMed
Behmand RA, Tucker T, Guyuron B. Single-site botulinum toxin type A injection for elimination of migraine trigger points.  Headache. 2003;43(10):1085-1089
PubMed   |  Link to Article
Binder WJ, Brin MF, Blitzer A, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine.  Dis Mon. 2002;48(5):323-335
PubMed   |  Link to Article
Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders.  Headache. 2003;43(8):853-860
PubMed   |  Link to Article
Burstein R, Dodick D, Silberstein S. Migraine prophylaxis with botulinum toxin A is associated with perception of headache.  Toxicon. 2009;54(5):624-627
PubMed   |  Link to Article
Calandre EP, Hidalgo J, García-Leiva JM, Rico-Villademoros F. Trigger point evaluation in migraine patients: an indication of peripheral sensitization linked to migraine predisposition?  Eur J Neurol. 2006;13(3):244-249
PubMed   |  Link to Article
Chan VW, McCabe EJ, MacGregor DL. Botox treatment for migraine and chronic daily headache in adolescents.  J Neurosci Nurs. 2009;41(5):235-243
PubMed   |  Link to Article
Christie SN, Giammarco R, Gawel M, Mackie G, Gladstone J, Becker WJ. Botulinum toxin type A and acute drug costs in migraine with triptan overuse.  Can J Neurol Sci. 2010;37(5):588-594
PubMed
Dowson AJ, Kilminster SG, Salt R. Clinical profile of botulinum toxin A in patients with chronic headaches and cervical dystonia: a prospective, open-label, longitudinal study conducted in a naturalistic clinical practice setting.  Drugs R D. 2008;9(3):147-158
PubMed   |  Link to Article
Erdemoglu AK, Varlibas A. The long-term efficacy and safety of botulinum toxin in refractory chronic tension-type headache.  J Headache Pain. 2007;8(5):294-300
PubMed   |  Link to Article
Eross EJ, Gladstone JP, Lewis S, Rogers R, Dodick DW. Duration of migraine is a predictor for response to botulinum toxin type A.  Headache. 2005;45(4):308-314
PubMed   |  Link to Article
Harrison AR, Erickson JP, Anderson JS, Lee MS. Pain relief in patients receiving periocular botulinum toxin A.  Ophthal Plast Reconstr Surg. 2008;24(2):113-116
PubMed   |  Link to Article
Kapural L, Stillman M, Kapural M, McIntyre P, Guirgius M, Mekhail N. Botulinum toxin occipital nerve block for the treatment of severe occipital neuralgia: a case series.  Pain Pract. 2007;7(4):337-340
PubMed   |  Link to Article
Liu YC, Fuh JL, Chen RC, Lin KP, Wang SJ. Botulinum toxin type A in the prophylactic treatment of transformed migraine in Taiwanese patients: a review of 30 consecutive cases.  J Chin Med Assoc. 2007;70(12):535-540
PubMed   |  Link to Article
Menezes C, Rodrigues B, Magalhães E, Melo A. Botulinum toxin type A in refractory chronic migraine: an open-label trial.  Arq Neuropsiquiatr. 2007;65(3A):596-598
PubMed   |  Link to Article
Smuts JA, Schultz D, Barnard A. Mechanism of action of botulinum toxin type A in migraine prevention: a pilot study.  Headache. 2004;44(8):801-805
PubMed   |  Link to Article
Sostak P, Krause P, Förderreuther S, Reinisch V, Straube A. Botulinum toxin type-A therapy in cluster headache: an open study.  J Headache Pain. 2007;8(4):236-241
PubMed   |  Link to Article
Suzuki K, Iizuka T, Sakai F. Botulinum toxin type A for migraine prophylaxis in the Japanese population: an open-label prospective trial.  Intern Med. 2007;46(13):959-963
PubMed   |  Link to Article
Taylor M, Silva S, Cottrell C. Botulinum toxin type-A (BOTOX) in the treatment of occipital neuralgia: a pilot study.  Headache. 2008;48(10):1476-1481
PubMed   |  Link to Article
Tepper SJ, Bigal ME, Sheftell FD, Rapoport AM. Botulinum neurotoxin type A in the preventive treatment of refractory headache: a review of 100 consecutive cases.  Headache. 2004;44(8):794-800
PubMed   |  Link to Article
Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia.  Clin Neuropharmacol. 2005;28(4):161-162
PubMed   |  Link to Article
Solomon S. Botulinum toxin for the treatment of chronic migraine: the placebo effect.  Headache. 2011;51(6):980-984
PubMed   |  Link to Article
Lu CL, Chang FY. Placebo effect in patients with irritable bowel syndrome.  J Gastroenterol Hepatol. 2011;26:(suppl 3)  116-118
PubMed   |  Link to Article
Mangera A, Chapple CR, Kopp ZS, Plested M. The placebo effect in overactive bladder syndrome.  Nat Rev Urol. 2011;8(9):495-503
PubMed   |  Link to Article
Puhl AA, Reinhart CJ, Rok ER, Injeyan HS. An examination of the observed placebo effect associated with the treatment of low back pain: a systematic review.  Pain Res Manag. 2011;16(1):45-52
PubMed
Gallahan WC, Case D, Bloomfeld RS. An analysis of the placebo effect in Crohn's disease over time.  Aliment Pharmacol Ther. 2010;31(1):102-107
PubMed   |  Link to Article
Jackson JL, Shimeall W, Sessums L,  et al.  Tricyclic antidepressants and headaches: systematic review and meta-analysis.  BMJ. 2010;341:c5222
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Change in Number of Monthly Headaches Among Adults in Randomized Controlled Trials of Botulinum Toxin A vs Placebo
Graphic Jump Location

Size of data markers is proportional to study weight.

Place holder to copy figure label and caption
Figure 2. Relative Risk of 50% Reduction in Number of Headaches per Month Among Adults in Randomized Controlled Trials of Botulinum Toxin A vs Placebo
Graphic Jump Location

Size of data markers is proportional to study weight.

Tables

Table Graphic Jump LocationTable 1. Randomized Controlled Trials of Botulinum Toxin A and Association With Migraine and Chronic Daily Headachesa
Table Graphic Jump LocationTable 2. Randomized Controlled Trials of Botulinum Toxin A and Association With Chronic Tension-Type Headachesa
Table Graphic Jump LocationTable 3. Adverse Effects of the Randomized Controlled Trials

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Anand KS, Prasad A, Singh MM, Sharma S, Bala K. Botulinum toxin type A in prophylactic treatment of migraine.  Am J Ther. 2006;13(3):183-187
PubMed   |  Link to Article
Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM.BOTOX North American Episodic Migraine Study Group.  Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study.  Headache. 2007;47(4):486-499
PubMed
Cady R, Schreiber C. Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues.  Headache. 2008;48(6):900-913
PubMed   |  Link to Article
Chankrachang S, Arayawichanont A, Poungvarin N,  et al.  Prophylactic botulinum type A toxin complex (Dysport) for migraine without aura.  Headache. 2011;51(1):52-63
PubMed   |  Link to Article
Elkind AH, O’Carroll P, Blumenfeld A, DeGryse R, Dimitrova R.BoNTA-024-026-036 Study Group.  A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.  J Pain. 2006;7(10):688-696
PubMed   |  Link to Article
Evers S, Vollmer-Haase J, Schwaag S, Rahmann A, Husstedt IW, Frese A. Botulinum toxin A in the prophylactic treatment of migraine: a randomized, double-blind, placebo-controlled study.  Cephalalgia. 2004;24(10):838-843
PubMed   |  Link to Article
Freitag FG, Diamond S, Diamond M, Urban G. Botulinum toxin type A in the treatment of chronic migraine without medication overuse.  Headache. 2008;48(2):201-209
PubMed
Hamdy SM, Samir H, El-Sayed M, Adel N, Hasan R. Botulinum toxin: could it be an effective treatment for chronic tension-type headache?  J Headache Pain. 2009;10(1):27-34
PubMed   |  Link to Article
Harden RN, Cottrill J, Gagnon CM,  et al.  Botulinum toxin A in the treatment of chronic tension-type headache with cervical myofascial trigger points: a randomized, double-blind, placebo-controlled pilot study.  Headache. 2009;49(5):732-743
PubMed   |  Link to Article
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(4):293-307
PubMed   |  Link to Article
Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study.  Cephalalgia. 2004;24(1):60-65
PubMed   |  Link to Article
Padberg M, de Bruijn SF, de Haan RJ, Tavy DL. Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial.  Cephalalgia. 2004;24(8):675-680
PubMed   |  Link to Article
Petri S, Tölle T, Straube A, Pfaffenrath V, Stefenelli U, Ceballos-Baumann A.Dysport Migraine Study Group.  Botulinum toxin as preventive treatment for migraine: a randomized double-blind study.  Eur Neurol. 2009;62(4):204-211
PubMed   |  Link to Article
Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C.European BoNTA Headache Study Group.  A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches.  Cephalalgia. 2007;27(6):492-503
PubMed   |  Link to Article
Rollnik JD, Tanneberger 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(4):300-305
PubMed   |  Link to Article
Rollnik JD, Karst M, Fink M, Dengler R. Botulinum toxin type A and EMG: a key to the understanding of chronic tension-type headaches?  Headache. 2001;41(10):985-989
PubMed   |  Link to Article
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(4):427-433
PubMed   |  Link to Article
Saper JR, Mathew NT, Loder EW, DeGryse R, VanDenburgh AM.BoNTA-009 Study Group.  A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine.  Pain Med. 2007;8(6):478-485
PubMed   |  Link to Article
Schmitt WJ, Slowey E, Fravi N, Weber S, Burgunder JM. Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial.  Headache. 2001;41(7):658-664
PubMed   |  Link to Article
Schulte-Mattler WJ, Krack P.BoNTTH Study Group.  Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study.  Pain. 2004;109(1-2):110-114
PubMed   |  Link to Article
Silberstein S, Mathew N, Saper J, Jenkins S.For the BOTOX Migraine Clinical Research Group.  Botulinum toxin type A as a migraine preventive treatment.  Headache. 2000;40(6):445-450
PubMed   |  Link to Article
Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC.BoNTA-039 Study Group.  Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial.  Mayo Clin Proc. 2005;80(9):1126-1137
PubMed   |  Link to Article
Silberstein SD, Göbel H, Jensen R,  et al.  Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study.  Cephalalgia. 2006;26(7):790-800
PubMed   |  Link to Article
Straube A, Empl M, Ceballos-Baumann A, Tölle T, Stefenelli U, Pfaffenrath V.Dysport Tension-Type Headache Study Group.  Pericranial injection of botulinum toxin type A (Dysport) for tension-type headache: a multicentre, double-blind, randomized, placebo-controlled study.  Eur J Neurol. 2008;15(3):205-213
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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(5):(suppl)  B113-B118
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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(6):463-466
PubMed   |  Link to Article
Porta M. A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache.  Curr Rev Pain. 2000;4(1):31-35
PubMed   |  Link to Article
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(1):21-32
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Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine.  Headache. 2008;48(2):210-220
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Mathew NT, Kailasam J, Meadors L. Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache.  Headache. 2008;48(2):194-200
PubMed
Behmand RA, Tucker T, Guyuron B. Single-site botulinum toxin type A injection for elimination of migraine trigger points.  Headache. 2003;43(10):1085-1089
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Binder WJ, Brin MF, Blitzer A, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine.  Dis Mon. 2002;48(5):323-335
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Blumenfeld A. Botulinum toxin type A as an effective prophylactic treatment in primary headache disorders.  Headache. 2003;43(8):853-860
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Burstein R, Dodick D, Silberstein S. Migraine prophylaxis with botulinum toxin A is associated with perception of headache.  Toxicon. 2009;54(5):624-627
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Calandre EP, Hidalgo J, García-Leiva JM, Rico-Villademoros F. Trigger point evaluation in migraine patients: an indication of peripheral sensitization linked to migraine predisposition?  Eur J Neurol. 2006;13(3):244-249
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Chan VW, McCabe EJ, MacGregor DL. Botox treatment for migraine and chronic daily headache in adolescents.  J Neurosci Nurs. 2009;41(5):235-243
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Christie SN, Giammarco R, Gawel M, Mackie G, Gladstone J, Becker WJ. Botulinum toxin type A and acute drug costs in migraine with triptan overuse.  Can J Neurol Sci. 2010;37(5):588-594
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Dowson AJ, Kilminster SG, Salt R. Clinical profile of botulinum toxin A in patients with chronic headaches and cervical dystonia: a prospective, open-label, longitudinal study conducted in a naturalistic clinical practice setting.  Drugs R D. 2008;9(3):147-158
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Erdemoglu AK, Varlibas A. The long-term efficacy and safety of botulinum toxin in refractory chronic tension-type headache.  J Headache Pain. 2007;8(5):294-300
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Eross EJ, Gladstone JP, Lewis S, Rogers R, Dodick DW. Duration of migraine is a predictor for response to botulinum toxin type A.  Headache. 2005;45(4):308-314
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Harrison AR, Erickson JP, Anderson JS, Lee MS. Pain relief in patients receiving periocular botulinum toxin A.  Ophthal Plast Reconstr Surg. 2008;24(2):113-116
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Kapural L, Stillman M, Kapural M, McIntyre P, Guirgius M, Mekhail N. Botulinum toxin occipital nerve block for the treatment of severe occipital neuralgia: a case series.  Pain Pract. 2007;7(4):337-340
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Liu YC, Fuh JL, Chen RC, Lin KP, Wang SJ. Botulinum toxin type A in the prophylactic treatment of transformed migraine in Taiwanese patients: a review of 30 consecutive cases.  J Chin Med Assoc. 2007;70(12):535-540
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Menezes C, Rodrigues B, Magalhães E, Melo A. Botulinum toxin type A in refractory chronic migraine: an open-label trial.  Arq Neuropsiquiatr. 2007;65(3A):596-598
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Smuts JA, Schultz D, Barnard A. Mechanism of action of botulinum toxin type A in migraine prevention: a pilot study.  Headache. 2004;44(8):801-805
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Sostak P, Krause P, Förderreuther S, Reinisch V, Straube A. Botulinum toxin type-A therapy in cluster headache: an open study.  J Headache Pain. 2007;8(4):236-241
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Suzuki K, Iizuka T, Sakai F. Botulinum toxin type A for migraine prophylaxis in the Japanese population: an open-label prospective trial.  Intern Med. 2007;46(13):959-963
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Taylor M, Silva S, Cottrell C. Botulinum toxin type-A (BOTOX) in the treatment of occipital neuralgia: a pilot study.  Headache. 2008;48(10):1476-1481
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Tepper SJ, Bigal ME, Sheftell FD, Rapoport AM. Botulinum neurotoxin type A in the preventive treatment of refractory headache: a review of 100 consecutive cases.  Headache. 2004;44(8):794-800
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Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia.  Clin Neuropharmacol. 2005;28(4):161-162
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Solomon S. Botulinum toxin for the treatment of chronic migraine: the placebo effect.  Headache. 2011;51(6):980-984
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Lu CL, Chang FY. Placebo effect in patients with irritable bowel syndrome.  J Gastroenterol Hepatol. 2011;26:(suppl 3)  116-118
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Mangera A, Chapple CR, Kopp ZS, Plested M. The placebo effect in overactive bladder syndrome.  Nat Rev Urol. 2011;8(9):495-503
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Puhl AA, Reinhart CJ, Rok ER, Injeyan HS. An examination of the observed placebo effect associated with the treatment of low back pain: a systematic review.  Pain Res Manag. 2011;16(1):45-52
PubMed
Gallahan WC, Case D, Bloomfeld RS. An analysis of the placebo effect in Crohn's disease over time.  Aliment Pharmacol Ther. 2010;31(1):102-107
PubMed   |  Link to Article
Jackson JL, Shimeall W, Sessums L,  et al.  Tricyclic antidepressants and headaches: systematic review and meta-analysis.  BMJ. 2010;341:c5222
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