Safety Profile of Botulinum Toxin for Migraine Headache Prophylaxis: A Systematic Review and Meta-analysis

authors:

avatar Mohaddeseh Azadvari ORCID 1 , 2 , avatar Maryam Hosseini ORCID 1 , avatar Seyede Zahra Emami Razavi ORCID 1 , 3 , * , avatar Mahsa Ghajarzadeh 4 , avatar Saeed Vaheb 5

Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
Joint Reconstruction Research Center, Tehran University of Medical Sciences, Tehran, Iran
Universal Council of Epidemiology (UCE), Universal Scientific Education and Research Network (USERN), Tehran, Iran
Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

how to cite: Azadvari M, Hosseini M, Emami Razavi S Z, Ghajarzadeh M, Vaheb S. Safety Profile of Botulinum Toxin for Migraine Headache Prophylaxis: A Systematic Review and Meta-analysis. Ann Mil Health Sci Res. 2023;21(3):e139223. https://doi.org/10.5812/amh-139223.

Abstract

Context:

Nowadays, botulinum toxin is used for migraine prophylaxis, and a wide range of adverse effects (AEs) are reported after administration.

Objectives:

The present study was conducted to evaluate the safety profile of botulinum toxin for migraine headache prophylaxis.

Methods:

Migraine Disorder, Disorder AND Migraine, Headache AND Sick, Headache AND Migraine, Migraine, Migrainosus, Migraine Headache, Migraines, Sick Headaches, Botulinum, Toxins AND Botulinum, Botulinum AND Neurotoxins, Toxins AND Clostridium Botulinum Neurotoxins, Botulinum Toxin, Botulinum Neurotoxin, Clostridium Botulinum Toxins, and Botulin were searched in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar databases, and gray literature, including references of the studies published before April 2023.

Results:

We found 3081 articles by literature search; after deleting duplicates, 1711 remained. Thirty-five articles remained for meta-analysis. The pooled prevalence of musculoskeletal weakness in the head and neck regions was 4% (95% CI: 2-5%) (I2 = 92.2%, P < 0.001). The pooled prevalence of neck pain was 6% (95% CI: 4-7%) (I2 = 95.8%, P < 0.001). The pooled prevalence of blepharoptosis was 2% (95% CI: 2-3%) (I2 = 91.1%, P < 0.001). The pooled prevalence of facial paralysis was 2% (95% CI: 1-4%) (I2 = 94.1%, P < 0.001). The pooled prevalence of injection site pain was 4% (95% CI: 2-5%) (I2 = 93.5%, P < 0.001).

Conclusions:

The results of this systematic review and meta-analysis show that the most common AEs following botulinum toxin injection for migraine headache prophylaxis are neck pain, followed by musculoskeletal weakness and injection site pain.

1. Context

The first cause of living with a disability in individuals under 50 is migraine, which is the second cause of disability all over the world (1, 2). Globally, nearly 1.04 billion people suffer from migraines (3). One of the main issues regarding migraine is its chronicity and severity, affecting the quality of life and interfering with daily activities (4). Nearly 40% of migraineurs need preventive agents, while only 13% receive these medications (5). Beta-blockers, antiepileptic drugs, topiramate, calcium channel blockers, antidepressants, botulinum toxin, and calcitonin gene-related peptide (CGRPs) monoclonal antibodies are used as preventive agents (6). Up to one-third of patients are not responsive to prophylactic medications (7).

2. Objectives

In October 2010, the United States Food and Drug Administration (FDA) approved botulinum toxin type A (BT-A) for migraine prevention (8). Now, it is used in different populations for migraine prevention, while the rates of adverse effects (AEs) vary.

We designed this systematic review and meta-analysis to estimate the pooled safety of botulinum toxin injection in migraineurs.

3. Methods

3.1. Data Sources

The search terms were Migraine Disorder, Disorder AND Migraine, Headache AND Sick, Headache AND Migraine, Migraine, Migrainosus, Migraine Headache, Migraines, Sick Headaches, Botulinum, Toxins AND Botulinum, Botulinum AND Neurotoxins, Toxins AND Clostridium Botulinum Neurotoxins, Botulinum Toxin, Botulinum Neurotoxin, Clostridium Botulinum Toxins, and Botulin.

We searched PubMed, Scopus, EMBASE, Web of Science, Google Scholar databases, and gray literature, including references of the studies published before April 2023.

3.2. Study Selection

The inclusion criteria included trials reporting the efficacy of botulinum toxin in treating headache attacks in migraineurs. The exclusion criteria included letters to the editor, case-controls, case reports, and cross-sectional/cohort studies. We extracted data regarding the total number of participants, the first author, the year of publication, the country of origin, the mean age, and the AEs of botulinum toxin in migraineurs.

3.3. Risk of Bias Assessment

We evaluated the risk of bias in randomized trials using the Cochrane Collaboration’s tool (9).

3.4.. Data Extraction

All statistical analyses were performed using STATA (Version 14.0; Stata Corp LP, College Station, TX, USA). We used random effects to determine heterogeneity. Inconsistency (10) was also calculated.

4. Results

We found 3081 articles by literature search; after deleting duplicates, 1711 remained. Thirty-five articles remained for meta-analysis (Figure 1).

The flow diagram summarizing the selection of eligible studies
The flow diagram summarizing the selection of eligible studies

Thirty-five articles were included. Totally, 10271 patients received botulinum toxin.

The basic characteristics of the included studies are shown in Table 1.

Table 1.

Data Extracted from Studies

Ref.YearCountryNo. of Patients in Botox GroupNo. of ControlsDose of Botox or Type of ControlAgeaDisease DurationaAge at OnsetaDuration of Taking BotolinumMuscular WeaknessNeck PainBlepharoptosisMyalgiaSkin TightnessInjection PainHeadacheMusculo- skeletal PainNauseaDizzinessMigraineFacial ParalysisMusculo- skeletal StiffnessInfluenza- Like
(11)3042.2U14.9 (7.2)36132
2009USA30Topiramate20.0 (9.2)
(12)2010USA29200U313
30Topiramate6
(10)2020USA45155U15.1 (1.4)4.1 (2.9)10.7 (3.0)33131
4374U15.0 (1.5)4.2 (2.7)10.4 (2.9)5303
37Placebo15.2 (1.5)4.5 (3.4)10.3 (3.8)0011
(13)2009Germany31210U42 (12)23 (14)382
2980U49 (11)29 (13)
62Placebo47 (11)27 (12)1
(14)1999USA4225 U42.823.4364
4075 U42.416.975
41Placebo46.827.401
(15)2014Brazil20100U44.8 (12.6)362
18Placebo45.8 (14.2)21
(16)2013China6025U40.255.7421
(17)2016USA359155U45.1 (13.2)123355143
(18)2018USA716155U43.0 (11.3)27172918107141279
(19)2019USA641155U43.112.832.32710281761410367173
(20)2019USA140200U40.2 (11.7)810166
142Topiramate39.4 (12.6)319182
(21)2004Germany20100U37 (14)21 (14)33220
2016U41 (9)23 (11)1422
20Placebo37 (9)22 (2)5011
(22)2019USA30185U16.5 (1.83)12-241
(23)2015Spain132155-195U46.3 (12.3)10.5 (8.4)1267
(24)2019USA716155U43.0 (11.3)27102918714127917
(25)2018USA716155U43.0 (11.3)10.6 (11.0)32.5 (13.7)27102918714127917
(22)2018India30185U16.5 (1.8)31
(26)2014USA513195U41.4 (10.2)19.6 (12.4)68221011
492Placebo42.3 (10.7)19.3 (12.6)
(27) 2010USA688155U41.163846281822201516
696Placebo41.521522141155
(28)2010USA341155U41.220.362020
338Placebo42.520.6
(29)2016Greece81155U43.5 (9.8)9553
(30)2004USA30200U46.3 (9.4)61
30Placebo47.7 (12.7)
(31)2014Germany1384163U42.1 (10.34)20.1 (12.55)21.0 (11.09)61271916343681115133531099935
1052Placebo42.3 (10.89)19.8 (12.89)21.6 (11.79)32553285829172511431
(32)2011Thailand43120U38.9 (9.8)4.3 (4.7)3200121
43240U38.1 (9.8)5.4 (6.3)020010
41Placebo38.7 (10.2)4.7 (6.6)101000
(33)2016Egypt15155-195U32.81 (7.64)5.12 (2.98)315
14RTMS31.98 (8.12)5.61 (3.20)
(34)2017UK688155U41.1 (10.4)19.4 (12.4)21.2 (11.0)63846231822201516
696Placebo41.5 (10.7)19.0 (12.7)21.9 (11.9)
(35)2015Italy24NR674
(36)2014Taiwan875U47.6 (13.6)8.1 (8.3)320
59100U33
27155U01
(37)2018USA716155U43 (11.3)2710031
(18)2018USA715155U43 (18-73)2729181417
(38)2010Taiwan688155U63860
696Placebo
(39)2008USA20100U42.2 (19-64)410
21Placebo42.4 (25-55)11
(40)2010Canada53*95-130 U46.5 (8.4)625
(41)2014UK254155U45.04 (19-91)1.4 (0.8-3)137283811
(42)2020Italy115155U50 (44.5-54)5.2 (2-12)151112

The pooled prevalence of musculoskeletal weakness in the head and neck regions was 4% (95% CI: 2-5%) (I2 = 92.2%, P < 0.001) (Figure 2).

The pooled prevalence of musculoskeletal weakness in the head and neck regions
The pooled prevalence of musculoskeletal weakness in the head and neck regions

The pooled prevalence of neck pain was 6% (95% CI: 4-7%) (I2 = 95.8%, P < 0.001) (Figure 3).

The pooled prevalence of blepharoptosis
The pooled prevalence of blepharoptosis

The pooled prevalence of blepharoptosis was 2% (95% CI: 2-3%) (I2 = 91.1%, P < 0.001) (Figure 4).

The pooled prevalence of blepharoptosis
The pooled prevalence of blepharoptosis

The pooled prevalence of facial paralysis was 2% (95% CI: 1-4%) (I2 = 94.1%, P < 0.001) (Figure 5).

The pooled prevalence of facial paralysis
The pooled prevalence of facial paralysis

The pooled prevalence of injection site pain was 4% (95% CI: 2-5%) (I2 = 93.5%, P < 0.001) (Figure 6).

The pooled prevalence of injection site pain
The pooled prevalence of injection site pain

The quality assessments of included studies are shown in Table 2.

Table 2.

The Quality Assessment of the Included Studies

First Author and YearRandom Sequence Generation (Selection Bias)Allocation Concealment (Selection Bias)Blinding of Outcome Assessment (Detection Bias)Incomplete Outcome Data (Attrition Bias)Selective Reporting (Reporting Bias)Other Potential Threats to Validity
Ninan T. Mathew (2009) (11)LRBLRBURBLRBURBLRB
Roger K. Cady (2011) (12)LRBLRBLRBURBLRBLRB
Paul K. Winner (2019) (24)LRBLRBLRBLRBLRBLRB
Susanne Petri (2009) (13)LRBLRBLRBLRBLRBLRB
Stephen Silberstein (2000) (14)LRBLRBLRBHRBLRBLRB
Luciano Hollanda (2014) (15)LRBLRBHRBURBLRBURB
Yu-Feng Shao (2013) (16)LRBHRBHRBURBLRBHRB
Kasra Maasumi (2015) (17)HRBHRBHRBHRBLRBHRB
Andrew M. Blumenfeld (2019) (18)HRBHRBHRBLRBLRBURB
William B. Young (2019) (19)HRBHRBHRBLRBLRBURB
John F. Rothrock (2019) (20)LRBHRBHRBLRBHRBURB
S. Evers (2004) (21)LRBLRBLRBURBURBURB
Sameer S. Ali (2019) (22)HRBHRBHRBLRBLRBURB
Eva Cernuda-Morollo´n (2015) (23)HRBHRBHRBLRBLRBHRB
Paul K. Winner (2019) (24)HRBHRBHRBLRBLRBLRB
Andrew M. Blumenfeld (2018) (25)HRBHRBHRBURBLRBLRB
Ali S. (2019) (22)HRBHRBHRBURBHRBHRB
S. K. Aurora (2014) (26)LRBLRBLRBURBLRBLRB
David W. Dodick (2010) (27)LRBLRBLRBLRBLRBLRB
SK Aurora (2010) (28)LRBLRBLRBLRBLRBLRB
Michail Vikelis (2016) (29)HRBHRBHRBLRBLRBHRB
W.G. Ondo (2004) (30)LRBLRBLRBURBLRBURB
H.C. Diener (2014) (31)LRBLRBLRBLRBLRBLRB
Siwaporn Chankrachang (2011) (32)LRBLRBLRBLRBLRBLRB
Hatem S. Shehata (2016) (33)LRBHRBHRBURBURBHRB
Manjit Matharu (2017) (34)LRBLRBLRBLRBLRBLRB
Russo M. (2015) (35)URBHRBHRBHRBLRBHRB
Kuan-Hsiang Lin (2014) (36)HRBHRBHRBURBLRBHRB
Mitchell F. Brin (2018) (37)HRBHRBHRBHRBLRBHRB
Andrew M. Blumenfeld (2018) (18)URBHRBHRBURBLRBHRB
Shih-Pin Chen (2010) (38)LRBLRBLRBURBLRBHRB
Frederick G. Freitag (2008) (39)LRBLRBLRBLRBLRBLRB
Suzanne N. Christie (2010) (40)HRBHRBHRBLRBLRBURB
Modar Khalil (2014) (41)HRBHRBHRBLRBLRBURB
Raffaele Ornello (2020) (42)HRBHRBHRBLRBLRBLRB

5. Discussion

To the best of our knowledge, this is the first systematic review and meta-analysis evaluating botulinum toxin safety administration in patients with migraine.

The results show that the most frequent AEs were neck pain, followed by musculoskeletal weakness in the head and neck regions, injection site pain, and blepharoptosis or eyelid ptosis.

Hollanda et al., who assigned patients with chronic migraines to botulinum toxin or placebo groups, reported pain in injection site points as the most common AEs (15).

In a 24-week double-blind study of Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT), Aurora et al. reported AEs in 59.7% of enrolled patients in the botulinum toxin group and 46.7% in the placebo group. Only 5.3% experienced severe AEs, and 13.2% discontinued treatment (28). On the other hand, in the first 24 weeks of PREEMPT 2, 65.1% of patients experienced AEs, while only 4.3% had severe AEs (43). The pooled PREEMPT 24-week analysis showed that 62.4% of onabotA-treated patients reported AEs, while only 4.8% experienced serious AEs. Most AEs were mild/moderate and self-limited, and the most common AEs were neck pain, muscle weakness, ptosis, and injection-site pain (28, 43). In another 32-week open-label trial, Aurora et al. reported AEs in 58.3%, while 25.4% discontinued the treatment based on AEs. Like previous studies, neck pain, muscle weakness, and eyelid ptosis were the most frequent AEs (44). Finally, in an over 56-week trial, AEs were found in 78.3% and 75.9% of cases who received 5 or 3 cycles of botulinum toxin treatment. Serious AEs were found in 7.8% and 4.9% of 5 or 3 treatment cycles. It was shown that the rate of AEs decreased after each treatment cycle (26).

Diener et al. pooled data from 4 trials by evaluating 1997 patients with migraines and found that AEs happened in 73%, and almost all were mild/moderate (31). It was also demonstrated that patients who received 150-200 units per cycle experienced fewer AEs than those receiving more than 200 units per cycle of botulinum toxin. Most AEs were mild, lasted for one week, and were resolved between 8 to 9 weeks.

By enrolling 254 patients with chronic migraines in the Hull Migraine Clinic, Khalil et al. found injection-site pain, neck stiffness, ptosis, headache exacerbation, and dysphagia as common AEs after onabotA injection, respectively (41).

Dominguez et al. followed up on 725 patients with chronic migraine up to one year after administration of onabotA and showed AE incidence in 12.3% after the first dose, while 82.3% were mild/moderate and only 0.7% discontinued onabotA due to AEs (45).

Matharu et al. followed up on 1160 patients with chronic migraines from 58 European centers, 41.2% of which reported AEs, 5.3% were serious, and 4.4% discontinued treatment (46).

The present study had some strengths and limitations. First, we included most of all trials in this field. Second, we analyzed all related AEs.

The limitation was the difference in the dose of botulinum toxin in different studies.

5.1. Conclusions

The results of this systematic review and meta-analysis show that the most common AEs following botulinum toxin injection for migraine headache prophylaxis are neck pain followed by musculoskeletal weakness and injection site pain.

References

  • 1.

    G. B. D. Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: A Systematic Analysis For The Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(11):954-76. [PubMed ID: 30353868]. [PubMed Central ID: PMC6191530]. https://doi.org/10.1016/S1474-4422(18)30322-3.

  • 2.

    Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: Will health politicians now take notice? J Headache Pain. 2018;19(1):17. [PubMed ID: 29468450]. [PubMed Central ID: PMC5821623]. https://doi.org/10.1186/s10194-018-0846-2.

  • 3.

    G. B. D. Disease, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: A systematic analysis for the global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-59. [PubMed ID: 28919117]. [PubMed Central ID: PMC5605509]. https://doi.org/10.1016/S0140-6736(17)32154-2.

  • 4.

    Szok D, Csati A, Vecsei L, Tajti J. Treatment of chronic migraine with onabotulinumtoxina: Mode of action, efficacy and safety. Toxins (Basel). 2015;7(7):2659-73. [PubMed ID: 26193319]. [PubMed Central ID: PMC4516935]. https://doi.org/10.3390/toxins7072659.

  • 5.

    Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-9. [PubMed ID: 17261680]. https://doi.org/10.1212/01.wnl.0000252808.97649.21.

  • 6.

    Lai TH, Huang TC. Update in migraine preventive treatment. Prog Brain Res. 2020;255:1-27. [PubMed ID: 33008503]. https://doi.org/10.1016/bs.pbr.2020.05.017.

  • 7.

    Schulman EA, Brahin EJ. Refractory headache: Historical perspective, need, and purposes for an operational definition. Headache. 2008;48(6):770-7. [PubMed ID: 18479419]. https://doi.org/10.1111/j.1526-4610.2008.01135.x.

  • 8.

    G S. FDA approves Botox to treat chronic migraines. J Pharmacol Pharmacotherapeutics. 2022;2(3):216. https://doi.org/10.1177/0976500x20110303.

  • 9.

    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [PubMed ID: 22008217]. [PubMed Central ID: PMC3196245]. https://doi.org/10.1136/bmj.d5928.

  • 10.

    Winner PK, Kabbouche M, Yonker M, Wangsadipura V, Lum A, Brin MF. A randomized trial to evaluate onabotulinumtoxina for prevention of headaches in adolescents with chronic migraine. Headache. 2020;60(3):564-75. [PubMed ID: 32037549]. [PubMed Central ID: PMC7065250]. https://doi.org/10.1111/head.13754.

  • 11.

    Mathew NT, Jaffri SF. A double-blind comparison of onabotulinumtoxina (BOTOX) and topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine: A pilot study. Headache. 2009;49(10):1466-78. [PubMed ID: 19912346]. https://doi.org/10.1111/j.1526-4610.2009.01566.x.

  • 12.

    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 ID: 21070228]. https://doi.org/10.1111/j.1526-4610.2010.01796.x.

  • 13.

    Petri S, Tolle T, Straube A, Pfaffenrath V, Stefenelli U, Ceballos-Baumann A, et al. Botulinum toxin as preventive treatment for migraine: A randomized double-blind study. Eur Neurol. 2009;62(4):204-11. [PubMed ID: 19622887]. https://doi.org/10.1159/000228987.

  • 14.

    Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. For the BOTOX migraine clinical research group. Headache. 2000;40(6):445-50. [PubMed ID: 10849039]. https://doi.org/10.1046/j.1526-4610.2000.00066.x.

  • 15.

    Hollanda L, Monteiro L, Melo A. Botulinum toxin type a for cephalic cutaneous allodynia in chronic migraine: A randomized, double-blinded, placebo-controlled trial. Neurol Int. 2014;6(4):5133. [PubMed ID: 25568735]. [PubMed Central ID: PMC4274405]. https://doi.org/10.4081/ni.2014.5133.

  • 16.

    Shao YF, Zhang Y, Zhao P, Yan WJ, Kong XP, Fan LL, et al. Botulinum toxin type a therapy in migraine: Preclinical and clinical trials. Iran Red Crescent Med J. 2013;15(10). e7704. [PubMed ID: 24693369]. [PubMed Central ID: PMC3950781]. https://doi.org/10.5812/ircmj.7704.

  • 17.

    Maasumi K, Thompson NR, Kriegler JS, Tepper SJ. Effect of onabotulinumtoxina injection on depression in chronic migraine. Headache. 2015;55(9):1218-24. [PubMed ID: 26381856]. https://doi.org/10.1111/head.12657.

  • 18.

    Blumenfeld AM, Tepper SJ, Robbins LD, Manack Adams A, Buse DC, Orejudos A, et al. Effects of onabotulinumtoxinA treatment for chronic migraine on common comorbidities including depression and anxiety. J Neurol Neurosurg Psychiatry. 2019;90(3):353-60. [PubMed ID: 30630956]. [PubMed Central ID: PMC6518474]. https://doi.org/10.1136/jnnp-2018-319290.

  • 19.

    Young WB, Ivan Lopez J, Rothrock JF, Orejudos A, Manack Adams A, Lipton RB, et al. Effects of onabotulinumtoxinA treatment in chronic migraine patients with and without daily headache at baseline: Results from the COMPEL Study. The Journal of Headache and Pain. 2019;20:1-10.

  • 20.

    Rothrock JF, Adams AM, Lipton RB, Silberstein SD, Jo E, Zhao X, et al. FORWARD study: Evaluating the comparative effectiveness of onabotulinumtoxina and topiramate for headache prevention in adults with chronic migraine. Headache. 2019;59(10):1700-13. [PubMed ID: 31559634]. [PubMed Central ID: PMC6899480]. https://doi.org/10.1111/head.13653.

  • 21.

    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):838-43. [PubMed ID: 15377314]. https://doi.org/10.1111/j.1468-2982.2004.00754.x.

  • 22.

    Ali SS, Bragin I, Rende E, Mejico L, Werner KE. Further evidence that onabotulinum toxin is a viable treatment option for pediatric chronic migraine patients. Cureus. 2019. https://doi.org/10.7759/cureus.4343.

  • 23.

    Cernuda-Morollon E, Ramon C, Larrosa D, Alvarez R, Riesco N, Pascual J. Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: What happens after one year? Cephalalgia. 2015;35(10):864-8. [PubMed ID: 25431141]. https://doi.org/10.1177/0333102414561873.

  • 24.

    Winner PK, Blumenfeld AM, Eross EJ, Orejudos AC, Mirjah DL, Adams AM, et al. Long-term safety and tolerability of onabotulinumtoxina treatment in patients with chronic migraine: Results of the COMPEL Study. Drug Saf. 2019;42(8):1013-24. [PubMed ID: 31102144]. [PubMed Central ID: PMC6647876]. https://doi.org/10.1007/s40264-019-00824-3.

  • 25.

    Blumenfeld AM, Stark RJ, Freeman MC, Orejudos A, Manack Adams A. Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. J Headache Pain. 2018;19(1):13. [PubMed ID: 29404713]. [PubMed Central ID: PMC5799088]. https://doi.org/10.1186/s10194-018-0840-8.

  • 26.

    Aurora SK, Dodick DW, Diener HC, DeGryse RE, Turkel CC, Lipton RB, et al. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129(1):61-70. [PubMed ID: 24107267]. [PubMed Central ID: PMC4033567]. https://doi.org/10.1111/ane.12171.

  • 27.

    Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-36. [PubMed ID: 20487038]. https://doi.org/10.1111/j.1526-4610.2010.01678.x.

  • 28.

    Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793-803. [PubMed ID: 20647170]. https://doi.org/10.1177/0333102410364676.

  • 29.

    Vikelis M, Argyriou AA, Dermitzakis EV, Spingos KC, Mitsikostas DD. Onabotulinumtoxin-A treatment in Greek patients with chronic migraine. J Headache Pain. 2016;17(1):84. [PubMed ID: 27640152]. [PubMed Central ID: PMC5026980]. https://doi.org/10.1186/s10194-016-0676-z.

  • 30.

    Ondo WG, Vuong KD, Derman HS. Botulinum toxin A for chronic daily headache: A randomized, placebo-controlled, parallel design study. Cephalalgia. 2004;24(1):60-5. [PubMed ID: 14687015]. https://doi.org/10.1111/j.1468-2982.2004.00641.x.

  • 31.

    Diener HC, Dodick DW, Turkel CC, Demos G, Degryse RE, Earl NL, et al. Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine. Eur J Neurol. 2014;21(6):851-9. [PubMed ID: 24628923]. [PubMed Central ID: PMC4233954]. https://doi.org/10.1111/ene.12393.

  • 32.

    Chankrachang S, Arayawichanont A, Poungvarin N, Nidhinandana S, Boonkongchuen P, Towanabut S, et al. Prophylactic botulinum type A toxin complex (Dysport(R)) for migraine without aura. Headache. 2011;51(1):52-63. [PubMed ID: 21083558]. https://doi.org/10.1111/j.1526-4610.2010.01807.x.

  • 33.

    Shehata HS, Esmail EH, Abdelalim A, El-Jaafary S, Elmazny A, Sabbah A, et al. Repetitive transcranial magnetic stimulation versus botulinum toxin injection in chronic migraine prophylaxis: A pilot randomized trial. J Pain Res. 2016;9:771-7. [PubMed ID: 27785091]. [PubMed Central ID: PMC5063492]. https://doi.org/10.2147/JPR.S116671.

  • 34.

    Matharu M, Halker R, Pozo-Rosich P, DeGryse R, Manack Adams A, Aurora SK. The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis. J Headache Pain. 2017;18(1):78. [PubMed ID: 28766236]. [PubMed Central ID: PMC5539058]. https://doi.org/10.1186/s10194-017-0784-4.

  • 35.

    Mazza MR, Salvino D, Trimboli M, Curcio M, Vescio B, Quattrone A, et al. Predictor factors influencing the response to botulinum toxin type a bonta) in chronic migraine: A new therapeutic strategy. Neurol Sci. 2015;36(1):S173-9.

  • 36.

    Lin KH, Chen SP, Fuh JL, Wang YF, Wang SJ. Efficacy, safety, and predictors of response to botulinum toxin type A in refractory chronic migraine: a retrospective study. J Chin Med Assoc. 2014;77(1):10-5. [PubMed ID: 24269600]. https://doi.org/10.1016/j.jcma.2013.09.006.

  • 37.

    Brin MF, Winner P, Blumenfeld AM, Eross EJ, Orejudos A, Adams AM. Long-Term Safety and Tolerability of OnabotulinumtoxinA Treatment in Chronic Migraine Patients: COMPEL Analysis by Treatment Cycle. Neurology. 2018;90(15 Supplement):P4. 123.

  • 38.

    Chen SP, Fuh JL, Wang SJ. OnabotulinumtoxinA: preventive treatment for chronic migraine. Curr Pain Headache Rep. 2011;15(1):4-7. [PubMed ID: 20882371]. https://doi.org/10.1007/s11916-010-0150-6.

  • 39.

    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):201-9. [PubMed ID: 18042229]. https://doi.org/10.1111/j.1526-4610.2007.00963.x.

  • 40.

    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):588-94. [PubMed ID: 21059503]. https://doi.org/10.1017/s031716710001074x.

  • 41.

    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(1):54. [PubMed ID: 25178393]. [PubMed Central ID: PMC4166400]. https://doi.org/10.1186/1129-2377-15-54.

  • 42.

    Ornello R, Guerzoni S, Baraldi C, Evangelista L, Frattale I, Marini C, et al. Sustained response to onabotulinumtoxin A in patients with chronic migraine: real-life data. The Journal of Headache and Pain. 2020;21(1). https://doi.org/10.1186/s10194-020-01113-6.

  • 43.

    Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804-14. [PubMed ID: 20647171]. https://doi.org/10.1177/0333102410364677.

  • 44.

    Aurora SK, Winner P, Freeman MC, Spierings EL, Heiring JO, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program. Headache. 2011;51(9):1358-73. [PubMed ID: 21883197]. https://doi.org/10.1111/j.1526-4610.2011.01990.x.

  • 45.

    Dominguez C, Pozo-Rosich P, Torres-Ferrus M, Hernandez-Beltran N, Jurado-Cobo C, Gonzalez-Oria C, et al. OnabotulinumtoxinA in chronic migraine: predictors of response. A prospective multicentre descriptive study. Eur J Neurol. 2018;25(2):411-6. [PubMed ID: 29171146]. https://doi.org/10.1111/ene.13523.

  • 46.

    Matharu M, Pascual J, Nilsson Remahl I, Straube A, Lum A, Davar G, et al. Utilization and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine from an observational study in Europe. Cephalalgia. 2017;37(14):1384-97. [PubMed ID: 28758415]. [PubMed Central ID: PMC5734384]. https://doi.org/10.1177/0333102417724150.