For contributions to JHRR, contact at email: editor@jhrlmc.

com
Original Article
Comparison of Efficacy of Botulinum Toxin Injection and
Conventional Oral Drugs for Treatment of Refractory Migraine
Anusha Pervaiz1*, Wasim Alamgir1, Babar Khan1, Khurram Haq Nawaz1, Imran Ahmad1, Saima Shafait2, Fawad Ahmad1
1Pak-Emirates Military Hospital, Rawalpindi
2FaujiFoundation Hospital, Lahore
*Corresponding Author: Anusha Pervaiz; Email: [email protected]

Conflict of Interest: None.

Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

ABSTRACT
Background: Migraine, a debilitating neurological condition, significantly impacts quality of life. Despite various treatments, some
cases remain refractory to conventional therapies. This study explores the efficacy of Botulinum Toxin Type A (BOTOX) injections
compared to Conventional Oral Drugs (CODs) in treating refractory migraines, offering potential advancements in migraine
management.

Objectives: This single-center retrospective cohort study compared the efficacy and safety of Botulinum toxin (BOTOX) injection and
Conventional Oral Drugs (COD) for treating the refractory migraine.

Methods: Between May and August of 2023, 78 adults with refractory migraine were enrolled at tertiary care center in Islamabad.
Their demographic data revealed the mean age of 46.5 years (SD=10.09), gender distribution of 28 males (35.90%) and 50 females
(64.10%), and distribution of 27 employed (34.61%) and 51 unemployed (65.30%).

Results: Average duration of refractory migraines was 9.72 years and average number of migraines per month was 22. The number
of headache days per month decreased from 22 at baseline to 19 after two months and to 12 after three months (p=0.239) as the
primary outcome measure (p>0.05). The VAS scores decreased substantially from 7.6 to 5.5 (p=0.049), indicating decrease in
headache severity (p<0.05). Scores on Migraine-Specific Quality of Life (MSQ) increased from 43 to 73% (p>0.05). The Migraine
Disability Assessment (MIDAS) scores decreased from 66 to 48 (p=0.047) and Headache Impact Test (HIT-6) scores decreased from
69 to 40 (p=0.025), indicating an improvement in disability and quality of life (p<0.05). Injection site pain (n=35), nausea (n=25),
dizziness (n=15), fatigue (n=12), parched mouth (n=5), and muscle weakness (n=5) were reported as adverse effects.

Conclusion: While BOTOX treatment significantly improved measures of headache severity, disability, and quality of life, patient
tolerability and potential distress must be considered when selecting this treatment.

Keywords: BOTOX; Headache; Migraine; NSAIDs; OnabotulinumtoxinA, Refractory migraine

INTRODUCTION
Refractory migraine, a complex neurological disorder resistant to standard treatment modalities, has a devastating impact on
affected health and comfort. These are resistant, necessitating the use of more specialized and frequently intensive treatment
methods (1-2). Despite comprehensive, appropriate intervention, these migraines persist in frequency and intensity and typically
manifest on 15 or more days per month for at least three months (3).
There are two primary manifestations of this condition: Refractory Chronic Migraine (RCM) and Refractory Episodic Migraine (REM).
With the pathogenesis that is complex and not entirely understood, both types can cause significant pain and impairment (4).
Researchers believe that family predisposition, environmental factors, and concomitant medical and psychiatric conditions all play a
role in their development (5).
Given the resistance of refractory migraines to conventional therapeutic approaches, their management presents a formidable
challenge. As a result, the discipline has shifted its focus to innovative, multidisciplinary approaches to treat this condition. Current
research seeks to develop more effective treatments and discover the enigmatic causes and mechanisms underlying migraines that
are resistant to treatment (6).

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 921
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

Life with refractory migraine is fraught with challenges, including chronic pain, disturbed sleep, impaired physical abilities, and
diminished capacity for daily activities. Equally profound are the societal ramifications of this condition, as it generates considerable
economic strain through rising healthcare costs and decreased productivity. Awareness and comprehension of refractory migraines
are essential for both patients and healthcare providers responsible for their care (7).
The administration of BoNT-A injections and use of conventional oral medications have emerged as the two most effective
treatments for refractory migraines at present. Although BoNT-A was initially recognized for its cosmetic applications, it has shown
promise in the treatment of intractable migraines (8-9). Numerous studies attest to its efficacy and safety, resulting in FDA approval
for the treatment of chronic migraines. Despite its demonstrated efficacy, precise mechanism of BoNT-A in migraine prophylaxis is
still a subject of active investigation (10). Conventional oral medications, a broad category that includes triptans, nonsteroidal anti-
inflammatory drugs (NSAIDs), beta-blockers, antiepileptic drugs, and antidepressants, primarily seek to prevent migraines or reduce
their severity. Although essential to the treatment of refractory migraines and effective in most patients, a significant proportion do
not respond or cannot tolerate adverse effects, necessitating the investigation of alternative therapies (11).
Comparative investigations of BoNT-A injections and conventional oral medications have produced contradictory findings. Some
claim that BoNT-A is preferable in managing migraines by reducing their frequency and severity, others indicate that two methods
are equally effective. However, factors such as adverse effect profiles, patient preferences, cost, and accessibility frequently influence
the selection of a treatment (12-13).
The lifestyle of the patient, their personal preferences, and economic implications of treatment also play the crucial role (14). While
progress has been made in understanding and treating refractory migraine, this investigation between BoNT-A injections and
conventional oral medications would provide healthcare professionals with clearer guidelines, enabling them to make more
informed judgments regarding optimal treatment options, thereby enhancing the overall management of this challenging condition.

MATERIAL AND METHODS

The study was a single-center retrospective cohort investigation conducted at the Neurology Outpatient Department of a tertiary
care center in Islamabad, Pakistan. It enrolled 78 adult participants aged between 18 and 65 years who were diagnosed with
refractory migraine according to the International Classification of Headache Disorders (ICHD-3) criteria. This enrolment occurred
from May to August 2023.
Participants in the study, all of whom had refractory migraine that did not respond to Conventional Oral Drugs (CODs), were chosen
based on the ICHD-3 criteria. The refractoriness of their condition was determined in line with the European Headache Federation's
guidelines for refractory migraine. The study employed OnabotulinumtoxinA injections (BoNT-A/BOTOX) as per the protocol outlined
in the PREEMPT study. These injections were administered at multiple sites using the "FDFS" and "FTP" injection paradigms, with a
dosage of 195 U across 39 sites. The injections were scheduled at the start (day 0) and then at three-month intervals (plus or minus
one week). The efficacy of the treatment was evaluated through the frequency of headaches, number of migraine days, and acute
pain medication intake. Baseline data were captured using patients' headache diaries from the month prior to the initiation of
OnabotulinumtoxinA treatment. Follow-up evaluations were conducted every three months in conjunction with each injection
session. Additionally, the Headache Impact Test (HIT-6) was completed by patients after three months to further assess efficacy. The
outcomes were then juxtaposed with the initial scores. During this three-month period, all adverse effects associated with the
treatment were meticulously recorded, serving as indicators of safety (15).
The study's primary aim was to ascertain whether the BOTOX dosage had a differential impact on efficacy and tolerability compared
to COD. To this end, the outcomes were compared with the baseline scores of the investigated population. The clinical evaluation
regimen for these patients was rigorously adhered to throughout the study period.
The primary outcome measure was the change from baseline in the number of headache days per month, assessed after three
months. Secondary outcome measures included changes in headache severity, measured using the Visual Analogue Scale (VAS);
disability, determined by the Migraine Disability Assessment (MIDAS) questionnaire; and quality of life, evaluated through the
Migraine-Specific Quality of Life Questionnaire (MSQ).
For the statistical evaluation, the data were analyzed with the intent-to-treat approach, using the ANOVA test for categorical data. A
p-value of 0.05 or less was considered statistically significant. All analyses were performed using version 26.0 of the SPSS Statistics
software.
To account for potential confounding variables, factors such as age, sex, employment status, duration of migraine history, headache
frequency and types, and the presence of comorbidities were recorded at baseline and controlled for during the statistical analysis.
Adverse events were closely monitored and recorded throughout the study to ensure a comprehensive safety assessment.

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 922
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

RESULTS
Comprehensive overview of baseline characteristics and demographic data for the BOTOX group indicated that the participants'
average age was 46.5 years, with a standard deviation (SD) of 10.09 years (p>0.05). In terms of gender, this cohort consisted of 28
men (35.90%) and 50 women (64.10%). The gender distribution within the group did not manifest a statistically significant difference
(p>0.05). It was also determined that 27 participants (34.61%) were employed while 51 participants (65.39%) were unemployed
(p>0.05), indicating that the employment status distribution within the sample was not statistically significant. Mean duration of
refractory migraines among the study's participants was 9.72 years (standard deviation = 2.40 years) (p>0.05). The average number
of migraine days per month for participants was 22 (standard deviation = 2), and there was no statistically significant variation within
the group (F- value = 0.0007, p-value = 0.97). The participants' average (HIT-6) score was 69.35 (SD = 3.01) (p>0.05). In terms of
these demographic characteristics and baseline characteristics, BOTOX group was statistically indistinguishable among the
participants (Table 1).
There were 32 participants (41.02%) who reported experiencing imploding migraines. Statistical analysis demonstrated that the
incidence of imploding headaches within the group does not differ substantially (p>0.05). Twenty-one participants (or 26.92%)
reported experiencing exploding migraines (p>0.05). Twelve participants (15.38%) of the cohort, reported having equal-type
headaches (p>0.05). 13 participants (16.66%) reported ocular migraines as a final symptom. The variance in the incidence of ocular
migraines within the group was not statistically significant, as indicated by an F-value of 2.165 and a p-value of 0.141. None of the
four headache types – imploding, explosive, equal, and ocular – showed the statistically significant difference in their incidence
within the group, indicating a heterogeneous distribution of headache types among the participants (Table 2).
The outcomes of treatment modalities of the participants were keenly recorded and throughout the treatment duration, participants
reported fewer headaches per month. Initially, at baseline, participants experienced 22 migraines per month on average. This
average decreased to 19 headaches per month after two months, and further decreased to 12 headaches per month after three
months of treatment. Nevertheless, this decrease in headache frequency over time was not statistically significant with p-value of
0.239. In contrast, the VAS scores for headache intensity decreased significantly over the course of treatment (p<0.05). At the
beginning of this research, average VAS score of the participants was 7.6. This average score decreased to 6.8 after two months and
to 5.5 by the conclusion of the three-month period with a p-value of 0.049, the decline in VAS scores during the treatment period
was statistically significant (p<0.05). The participants' MSQ scores increased from 43% at baseline to 56% after two months and then
to 73% after three months (p>0.05). Scores on MIDAS and HIT-6 also improved significantly (p<0.05). The MIDAS scores decreased
from 66 at baseline to 58 after two months and to 48 after three months (F-value = 4.041, p-value = 0.047). Similarly, the HIT-6
scores decreased from 69 at baseline to 59 after two months and from 59 to 40 after three months (F-value = 4.348, p-value =
0.025). Over the duration of three months, BOTOX treatment significantly improved VAS scores for headache intensity, MIDAS, and
HIT-6 scores, indicating its potential efficacy in managing refractory migraine. Despite being observed, the decrease in the number
of migraines per month and the improvement in MSQ scores were not statistically significant (Table 3). The presented data provided
an overview of the adverse effects participants experienced after receiving BOTOX treatment for refractory migraines. 35 participants
reported experiencing discomfort at the injection site as the most common adverse effect. This was followed by nausea, which was
reported by 25 people. 15 participants reported dizziness, and 12 participants reported fatigue, indicating that these were
uncommon but evident side effects of the treatment. Five participants reported dry mouth and muscle weakness as the adverse
effects that occurred the least frequently. While the evidence suggested the potential efficacy of BOTOX in treating the refractory
migraines, these side effects emphasized the importance of considering patient tolerability and potential discomfort when choosing
this treatment option (Figure 1).

Table 1 Baseline characteristics and demographic features of randomized trial participants

S. No Characteristics BOTOX group (n=78) F-value p-value

1 Age (Mean + SD) years 46.5+10.09 0.0005 0.9826

2 Gender n(%) Male
Female 28 (35.90) 0.5027 0.4783
50 (64.10) 0.1567 0.6922

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 923
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

S. No Characteristics BOTOX group (n=78) F-value p-value

3 Working status n(%) Employed

Unemployed 27 (34.61) 0.5038 0.4778
51 (65.39) 0.2720 0.6020
4 Duration of refractory migraine (years) 9.72+2.34 0.0029 0.9568
5 Monthly migraine days (n) 22+2 0.0007 0.9793
6 Mean HIT-6 scores 69.35+3.01 0.0004 0.9831

Table 2 Types of headaches in participating individuals

S. No Type of headache BOTOX group (n=78) F-value p-value

1 Imploding 32 (41.02) 0.025 0.874

2 Exploding 21 (26.92) 0.375 0.540

3 Equal 12 (15.38) 1.610 0.204

4 Ocular 13 (16.66) 2.165 0.141

Table 3 Outcome of treatment modalities

S. No Outcome measures BOTOX group (n=78) F-value p-value

1 No. of headache per month Baseline 22 1.389 0.239

months 19
months 12
2 VAS score for headache Baseline 7.6 4.281 0.049*
months 6.8
months 5.5
3 MSQ score (%) Baseline 43 1.234 0.267
months 56
months 73
4 MIDAS 66 4.041 0.047*
Baseline 2 months 58
3 months 48
5 HIT-6 Scores Baseline 69 4.348 0.037*
months 59
months 40
*indicated that the value is significant at p<0.05

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 924
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

Adverse effects associated with the DISCUSSION

The objective of this
40 treatments
retrospective cohort study was
to compare the efficacy of
30 botulinum toxin injection
(BOTOX) and CODs for treating
refractory migraine. Significant
20 improvements in headache
severity, migraine-related
disability, and quality of life
10
were observed in 78
participants non-responsive to
0 CODs after receiving BOTOX
Injection site pain Fatigue Muscle Dizzines Dry injections for three months. A
Naus weakness s mouth
BOTO crucial finding was the
Figure 1 Recorded adverse events during the trial Column2 significant decrease in VAS
scores for headache intensity
from 7.6 at baseline to 5.5 after three months (p<0.05), suggesting that BOTOX injections may effectively treat patients with
refractory migraine attacks.
Moreover, MIDAS and HIT-6 scores improved significantly after three months of BOTOX treatment (p<0.05), indicating an
enhancement in the quality of life by decreasing migraine-related disability. Our research revealed a diverse distribution of
imploding, exploding, equal, and ocular migraines. Adverse effects associated with BOTOX use included pain at the injection site and
vertigo, while dizziness, fatigue, dry mouth, and muscle weakness were less frequent. Despite these effects, the health
improvements in participants were notable. Supporting our findings, a retrospective analysis of 33 patients receiving Botox®
injections every three months according to the PRE-EMPT protocol for up to 33 months showed a significant decrease in HIT-6 scores
(mean reduction = -5.45, p = 0.000920), with 21% of patients exhibiting a sustained decrease to below 60 (16). This indicated the
effectiveness of Botox® therapy for chronic migraines resistant to relief.
Although limited randomized, double-blind, placebo-controlled studies exist, our study aligns with previous research suggesting the
efficacy of Botulinum toxin A in migraine prevention. In one study, 30% of patients in both botulinum toxin A treatment groups
experienced a 50% or greater reduction in migraine frequency in the third month relative to baseline, compared to 25% in the
placebo group (P = 0.921) (17).
Our findings also align with a study evaluating headache days, migraine days, acute pain medication ingestion days, and HIT-6 score
reductions in 172 patients treated with OnabotulinumtoxinA 195 U over two years. This study demonstrated the efficacy, safety, and
tolerability of OnabotulinumtoxinA 195 in treating chronic migraine patients (15). Our investigation concurred with a report stating
BoNT-A injections significantly reduced headache frequency and migraine disability assessment scores in Refractory Chronic
Migraine patients. Approximately 40% of patients experienced at least a 30% reduction in headache frequency twelve weeks after
injection. Patients with ocular-type headaches had a higher response rate, suggesting a predictor of favorable treatment outcomes.
Despite some adverse events like lateral eyebrow elevation and neck discomfort, these were mostly transient and manageable,
confirming the safety of BoNT-A in migraine treatment. These results underscore the potential of BoNT-A as a viable treatment
option for Refractory Chronic Migraine, especially in patients with ocular-type migraines (18, 20).

CONCLUSION
This study provided compelling evidence for efficacy of BOTOX injections in the treatment of refractory migraine. Over a three-
month period, BOTOX injections significantly decreased headache severity and improved migraine-related disability and health of
patients. Even though the reduction in headache days per month was not statistically significant, the overall improvement of patients
who did not respond to conventional oral medications was remarkable. However, potential adverse effects such as injection site pain
and nausea have been reported, highlighting the importance of considering patient tolerance and potential discomfort when
deciding on this treatment. This study added to the increasing body of evidence supporting BOTOX as a potential treatment for
refractory migraine; however, additional research is required to confirm these findings and investigate their long-term effects.

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 925
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

ETHICAL APPROVAL
Before enrolment, informed consent was obtained from all participants. Institutional ethics committee endorsed the study protocol,
and it was conducted in accordance with the Declaration of Helsinki.

REFERENCES
1. D'Antona L, Matharu M. Identifying and managing refractory migraine: barriers and opportunities? J Headache Pain. 2019
Aug 23;20(1):89. doi: 10.1186/s10194-019-1040- x.
2. Gupta J, Gaurkar SS. Migraine: An Underestimated Neurological Condition Affecting Billions. Cureus. 2022 Aug
24;14(8):e28347. doi: 10.7759/cureus.28347.
3. Eigenbrodt AK, Ashina H, Khan S, Diener HC, Mitsikostas DD, Sinclair AJ, Pozo-Rosich P, Martelletti P, Ducros A, Lantéri-Minet
M, Braschinsky M, Del Rio MS, Daniel O, Özge A, Mammadbayli A, Arons M, Skorobogatykh K, Romanenko V, Terwindt GM,
Paemeleire K, Sacco S, Reuter U, Lampl C, Schytz HW, Katsarava Z, Steiner TJ, Ashina
4. M. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021 Aug;17(8):501-514. doi: 10.1038/s41582-
021-00509-5.
5. Mungoven TJ, Henderson LA, Meylakh N. Chronic Migraine Pathophysiology and Treatment: A Review of Current
Perspectives. Front Pain Res (Lausanne). 2021 Aug 25;2:705276. doi: 10.3389/fpain.2021.705276.
6. Martelletti P, Katsarava Z, Lampl C, Magis D, Bendtsen L, Negro A, Russell MB, Mitsikostas DD, Jensen RH. Refractory chronic
migraine: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain. 2014 Aug
28;15(1):47. doi: 10.1186/1129-2377-15-47.
7. Bussone G. Clinical considerations on chronic migraine, pharmacoresistance and refractoriness. Neurol Sci. 2010 Jun;31
Suppl 1:S83-5. doi: 10.1007/s10072-010-0294-5.
8. Shimizu T, Sakai F, Miyake H, Sone T, Sato M, Tanabe S, Azuma Y, Dodick DW. Disability, quality of life, productivity impairment
and employer costs of migraine in the workplace. J Headache Pain. 2021 Apr 21;22(1):29. doi: 10.1186/s10194-021-01243-5.
9. Kępczyńska K, Domitrz I. Botulinum Toxin-A Current Place in the Treatment of Chronic Migraine and Other Primary
Headaches. Toxins (Basel). 2022 Sep 5;14(9):619. doi: 10.3390/toxins14090619.
10. Sebastianelli G, Casillo F, Di Renzo A, Abagnale C, Cioffi E, Parisi V, Di Lorenzo C, Serrao M, Pierelli F, Schoenen J, et al. Effects
of Botulinum Toxin Type A on the Nociceptive and Lemniscal Somatosensory Systems in Chronic Migraine: An Electrophysiological
Study. Toxins. 2023; 15(1):76. https://doi.org/10.3390/ toxins15010076
11. Martinelli D, Pocora MM, De Icco R, Allena M, Vaghi G, Sances G, Castellazzi G, Tassorelli C. Searching for the Predictors of
Response to BoNT-A in Migraine Using Machine Learning Approaches. Toxins. 2023; 15(6):364. https://doi.org/10.3390/
toxins15060364
12. Demaagd G. The pharmacological management of migraine, part 1: overview and abortive therapy. P T. 2008 Jul;33(7):404-
16. PMID: 19750119; PMCID: PMC2740949.
13. Ramachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014
Sep;171(18):4177-92. doi: 10.1111/ bph.12763.
14. Becker WJ. Botulinum Toxin in the Treatment of Headache. Toxins (Basel). 2020 Dec 17;12(12):803. doi:
10.3390/toxins12120803.
15. Frampton JE, Silberstein S. OnabotulinumtoxinA: A Review in the Prevention of Chronic Migraine. Drugs. 2018
Apr;78(5):589-600. doi: 10.1007/s40265-018-0894-6.
16. 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. doi: 10.1186/s10194-016-0591-3.
17. Atraszkiewicz D, Ito R, Bahra A. The efficacy of botulinum toxin type-A for intractable chronic migraine patients with no
pain-free time. Br J Pain. 2022 Feb;16(1):41-49. doi: 10.1177/20494637211014544.
18. 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 Oct; 24 ( 10 ): 838 - 43 . doi: 10 . 1111 / j.1468-
2982.2004.00754.x.
19. 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 Jan;77(1):10-5. doi: 10.1016/j.jcma.2013.09.006.

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 926
Botulinum Toxin vs. Oral Drugs in Migraine Treatment
Pervaiz A., et al. (2023). 3(2): DOI: https://doi.org/10.61919/jhrr.v3i2.241

20. Shaterian N, Shaterian N, Ghanaatpisheh A, Abbasi F, Daniali S, Jalali Jahromi M, Sanie MS, Abdoli A. Botox
(OnabotulinumtoxinA) for Treatment of Migraine Symptoms: A Systematic Review. Pain Res Manag. 2022 Mar 31;2022:3284446.
doi: 10.1155/2022/3284446. eCollection 2022. PMID: 35401888; PMCID: PMC8989603.

© 2023 et al. Open access under Creative Commons by License. Free use and distribution with proper citation. Page 927