Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox) And Anti CGRP In Migraine Prevention: A Systematic Review

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This systematic review aims to evaluate the comparative efficacy, safety profiles, cost-effectiveness, and additional dimensions of two prominent chronic migraine (CM) prophylactics: OnabotulinumtoxinA (BoNT-A) and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Methods Using specific keywords related to onabotulinumtoxinA and anti-CGRP treatments for migraines, we conducted a comprehensive search of electronic databases, including PubMed and the Cochrane Library, spanning from 2015 to 2024. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Our analysis included 13 publications that revealed notable decreases in migraine frequency and severity with both treatment modalities. While CGRP mAbs demonstrated significant reductions in migraine days with minimal adverse effects, BoNT-A emerged as a superior option due to its cost-efficiency and higher patient satisfaction. Both treatments exhibited mild short-term side effects; however, CGRP mAbs were occasionally associated with extended periods of constipation. The simplicity of adherence, with either monthly self-administered injections of CGRP mAbs or quarterly physician-administered BoNT-A injections, further distinguished these treatments. BoNT-A, in particular, was recognized for enhancing overall quality of life and performance metrics. Conclusions BoNT-A stands out as a low-cost intervention effective across various migraine categories, including chronic, episodic, unilateral, and vestibular types, significantly alleviating pain severity and reducing migraine episode frequency. The findings underscore that both CGRP mAbs and BoNT-A are comparably effective for CM prophylaxis. However, BoNT-A is especially beneficial for patients ineligible for CGRP mAb therapy or those requiring localized treatment with minimal systemic exposure risk. For patients resistant or refractory to BoNT-A, combining it with CGRP mAbs may maximize therapeutic benefits due to their distinct modes of action. The efficacy, safety, and cost-benefit analyses of these medications may help clinicians make more informed treatment decisions based on the study's findings. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-665", "name": "Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox)..." } } ] } Home Browse Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox)... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Gaviria E and Eltayeb Hamid AH. Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox) And Anti CGRP In Migraine Prevention: A Systematic Review [version 1; peer review: awaiting peer review] . F1000Research 2024, 13 :665 ( https://doi.org/10.12688/f1000research.151605.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox) And Anti CGRP In Migraine Prevention: A Systematic Review [version 1; peer review: awaiting peer review] Elizabeth Gaviria https://orcid.org/0000-0001-8046-1445 1 , Awab Hamid Eltayeb Hamid https://orcid.org/0009-0001-2729-530X 2 Elizabeth Gaviria https://orcid.org/0000-0001-8046-1445 1 , Awab Hamid Eltayeb Hamid https://orcid.org/0009-0001-2729-530X 2 PUBLISHED 20 Jun 2024 Author details Author details 1 University of California Santa Barbara, Santa Barbara, California, 050021, USA 2 Nile University Sudan, Khartoum, Khartoum, 11111, Sudan Elizabeth Gaviria Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Awab Hamid Eltayeb Hamid Roles: Methodology, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW REVIEWER STATUS AWAITING PEER REVIEW Abstract Background Every year, 15% of the global population suffers from migraines, making it a substantial social burden with a significant negative impact on quality of life. This systematic review aims to evaluate the comparative efficacy, safety profiles, cost-effectiveness, and additional dimensions of two prominent chronic migraine (CM) prophylactics: OnabotulinumtoxinA (BoNT-A) and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs). Methods Using specific keywords related to onabotulinumtoxinA and anti-CGRP treatments for migraines, we conducted a comprehensive search of electronic databases, including PubMed and the Cochrane Library, spanning from 2015 to 2024. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Our analysis included 13 publications that revealed notable decreases in migraine frequency and severity with both treatment modalities. While CGRP mAbs demonstrated significant reductions in migraine days with minimal adverse effects, BoNT-A emerged as a superior option due to its cost-efficiency and higher patient satisfaction. Both treatments exhibited mild short-term side effects; however, CGRP mAbs were occasionally associated with extended periods of constipation. The simplicity of adherence, with either monthly self-administered injections of CGRP mAbs or quarterly physician-administered BoNT-A injections, further distinguished these treatments. BoNT-A, in particular, was recognized for enhancing overall quality of life and performance metrics. Conclusions BoNT-A stands out as a low-cost intervention effective across various migraine categories, including chronic, episodic, unilateral, and vestibular types, significantly alleviating pain severity and reducing migraine episode frequency. The findings underscore that both CGRP mAbs and BoNT-A are comparably effective for CM prophylaxis. However, BoNT-A is especially beneficial for patients ineligible for CGRP mAb therapy or those requiring localized treatment with minimal systemic exposure risk. For patients resistant or refractory to BoNT-A, combining it with CGRP mAbs may maximize therapeutic benefits due to their distinct modes of action. The efficacy, safety, and cost-benefit analyses of these medications may help clinicians make more informed treatment decisions based on the study's findings. READ ALL READ LESS Keywords Anti-CGRP monoclonal antibodies, OnabotulinumtoxinA, migraine Corresponding Author(s) Awab Hamid Eltayeb Hamid ( [email protected] ) Close Corresponding author: Awab Hamid Eltayeb Hamid Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Gaviria E and Eltayeb Hamid AH. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Gaviria E and Eltayeb Hamid AH. Comparative Long-Term Effectiveness Of OnabotulinumtoxinA (Botox) And Anti CGRP In Migraine Prevention: A Systematic Review [version 1; peer review: awaiting peer review] . F1000Research 2024, 13 :665 ( https://doi.org/10.12688/f1000research.151605.1 ) First published: 20 Jun 2024, 13 :665 ( https://doi.org/10.12688/f1000research.151605.1 ) Latest published: 20 Jun 2024, 13 :665 ( https://doi.org/10.12688/f1000research.151605.1 ) Introduction Headache is a primary condition that is extremely debilitating and impacts 2% of the general population. 6% of men and 15%–17% of women experience migraines through their lifetimes and is among the main causes of medical consults. 1 – 3 Characterized as a neurological disorder, migraines manifest through symptoms such as sensory overload, vomiting, dizziness, and pulsatile headaches, accompanied by an increased sensitivity to light, sound, and smell. Triggers for this condition can vary widely, encompassing alcohol, certain foods, scents, hormonal changes, stress, and even weather changes. According to recent rankings, migraine is identified among the top 10 disabling diseases globally, 2 , 4 illustrating its considerable impact on individuals' lives. A typical migraine headache is recognized by its unilateral, moderate to severe pulsating pain, which is often accompanied by photophobia, nausea, and vomiting. 5 Migraines can be broadly categorized into two primary types: migraine without aura, affecting vision, and migraine with aura, characterized by sensory disturbances. 5 Among the spectrum of migraine-related conditions, Chronic Migraine (CM) stands out as one of the gravest, severely diminishing patients' quality of life and posing a significant social challenge worldwide. 6 , 7 Furthermore, statistics reveal a striking gender disparity in CM prevalence, with women being 2.5–6.5 times more likely than men to suffer from this condition, 8 underscoring the need for gender-specific research and interventions in the field of migraine studies. With an annual frequency of around 15% of the population, migraine is among the second most prevalent cause of neurological problems after tension headaches. Iran-based research indicates that in 2016, around 14% of the population had been diagnosed with the condition. 9 , 10 People who get migraines may experience various issues, including missed work or school due to illness and decreased productivity at home and work. As a result, the disorder significantly strains society. 11 Given the variety of variables influencing migraine, the disease's pathophysiology is controversial despite having a hereditary basis. Certain elements significantly influence this respect, including genes, immune cells, cytokines, tumor necrosis factor α (TNFα), and environmental characteristics. As a result, each of the characteristics above is the focus of several therapeutic methods. 12 – 14 By preventing migraine attacks in anticipation and treating them prophylactically, CM treatments aim to lessen the frequency, intensity, and accompanying impairment of headaches as well as the requirement for immediate treatment, which may be a factor in subsequent drug overuse headaches. 3 Several pharmacological and non-pharmacological preventative medications are on the market, but not all are supported by clinically solid effectiveness data. 4 Many treatments nowadays prevent severe migraines. 15 , 16 These include β-blockers, antiepileptic medications, calcium antagonists, antidepressants, CGRP, and onabotulinumtoxinA (BoNT-A). The anaerobic, Gram-positive bacteria Clostridium botulinum produces the complex protein known as BoNT-A. 17 The mechanism by which this toxin relieves pain was first proposed to be related to muscular relaxation and the resulting hypotension. 18 Merely around 33 percent of migraineurs obtain appropriate preventative migraine therapy, such as antidepressants or antiepileptic medications. 19 , 20 – 22 BoNT-A fixed-site or fixed-dose (155 to 195 U) intramuscular injections were authorized by the Food and Drug Administration (FDA) in October 2010 as a preventative therapy for CM. 23 BoNT-A is thought to work in the trigeminovascular system by inhibiting the production of substances P and CGRP. 24 , 25 It has been suggested that the BoNT-A effect reduces peripheral and cerebral sensitization by blocking sensory pain impulses from reaching the central nervous system. BoNT-A's safety and effectiveness were further examined and analyzed. 9 – 14 Before the latest authorization of CGRP monoclonal antibodies (mAbs) for CM prevention in the European Union, BoNT-A was the sole therapy approved for this purpose. 3 , 7 , 26 As the first preventative therapies created especially for migraine, anti-CGRP monoclonal antibodies (mAbs) inhibit the CGRP pathway and have a generally favorable safety record. 27 – 30 These findings were validated by other research, and they proved beneficial for patients who were not responding to therapy. 31 – 33 Recent experimental research shows BoNT-A may impact the brain and spinal cord. The BoNT-A was first prescribed to cure blepharospasm as well as dystonia; however, carefully monitored research studies determined that this medication could additionally reduce migraines. 34 These investigations, referred to as the Phase III Research Evaluating Migraine Prophylaxis treatment (PREEMPT), revealed that the injection of BoNT-A reduced the frequency and intensity of migraine attacks as well as their associated symptoms when compared to a placebo. The most frequent adverse effects following the injection were discomfort at the injection site, weakening of the muscles, and neck pain. It was demonstrated by repeating this therapy that BoNT-A was effective and well tolerated for CM. 35 Before beginning BoNT-A medication, patients should ideally attempt some other migraine prevention techniques. 36 However, the cost-effectiveness of BoNT-A therapy is a crucial consideration for the general public and the patient. The National Institute for Health and Care Excellence (NICE) determined this approach is economical. 37 Given that migraine is linked to disability and has a very high prevalence, the purpose of this systematic review was to assess how BoNT-A is affected and beneficial for migraine attacks. Methods The Recommended Reported Standards to the Conduct of Systematic Reviews and Meta-Analysis (PRISMA) 2020 were followed during this research project. Search methods The databases and search engines utilized for this analysis included The Cochrane Library, Medline, and PubMed. Our search targeted studies published from 2015 to 2024, aiming to provide a comprehensive review of the literature. Despite the presence of numerous systematic studies in the field, our research brings updated insights into the effectiveness of anti-CGRP monoclonal antibodies (mAbs) and Botulinum toxin type A (BoNT-A) for migraine prevention. To integrate relevant concepts with specific keywords, we used Boolean operators “AND” and “OR,” as outlined in Table 2 . In our meticulous selection process, we included publications in various languages, and abstract-only papers were also considered, adhering to the “Human studies only” screening criterion to ensure a broad and inclusive review of the available evidence. Ethics approval was not required for this systematic review. Inclusion criteria The criteria used to select the research studies included are as follows: 1. Observational studies, clinical trials, randomized control trials, and research that assessed the safety and efficacy of BoNT-A and Anti-CGRP mAbs in CM. 2. To increase knowledge of the efficacy, safety, and tolerance of combining a CGRP mAb with BoNT-A therapy for the prophylactic management of CM. Exclusion criteria Papers that did not discuss the BoNT-A and CGRP mAbs in CM were excluded. Articles published in languages other than English must be removed due to the difficulties in translating them. Publications that contained passages from the original papers but did not fully relate to the review's subject matter were also disregarded. Every article in the review discussed how CGRP mAbs and BoNT-A in CM affect a patient's risk assessment during physical therapy. Evaluation of quality The Critical Appraisal Skills Programme or CASP checklist, 38 was used to evaluate the dependability and competence of the selected research projects. CASP is one of the most useful evaluation methods since the reviewers have chosen the research papers for the systematic reviews. A high, low, or unknown category was assigned to each of the possible causes of bias: poor assessments, measurement mistakes, selective clinical effectiveness, and schedule setting. The primary objective of the quality evaluation process was to use evidence to support quality assessment. The systematic review was assessed using a 10-item checklist (see Table 1 ). Several considerations were made, including the method's validity, the findings' efficacy, and the dependability of the research designs. Several elements with low accuracy are eliminated in the assessment of external validity, which also considers the small sample size and precision of the results. The following is a list of the checklist's score criteria. Table 1. Critical Appraisal Skills Program (CASP) Checklist of included Qualitative studies (n: 13). Number Author/Year of publication Was there a clear statement of the aims of the research? Is the qualitative methodology appropriate? Was the research design appropriate to address the aims of the research? Was the recruitment strategy appropriate to the aims of the research? Was the data collected in a way that addressed the research issue? Has the relationship between researcher and participants been adequately considered? Have ethical issues been taken into consideration? Was the data analysis sufficiently rigorous? Is there a clear statement of findings? Is the research valuable? Total [1] Grazzi et al., 2024 41 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [2] Pallapothu et al., 2023 42 Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes 9 [3] Shaterian et al., 2023 43 Yes Yes Yes Yes Yes Yes Yes Unclear Yes Unclear 8 [4] Corasaniti et al., 2023 44 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [5] Mechtler & Adams, 2022 45 Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear 9 [6] Argyriou et al., 2022 46 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [7] Argyriou et al., 2021 47 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [8] Cheng & Ahmed, 2021 48 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [9] Siddiqui et al., 2021 49 Yes Yes Yes Yes Yes Yes Yes Unclear Yes Unclear 8 [10] Lu et al., 2021 50 Yes Yes Yes Yes Yes Yes Yes Yes Yes Unclear 9 [11] Blumenfeld et al., 2021 51 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [12] Chen & Zheng, 2021 4 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 [13] Szok et al., 2015 52 Yes Yes Yes Yes Yes Yes Yes Yes No Yes 10 Table 2. Search strategy used to find relevant articles. Search Number Search phrases and keywords Outcomes #1 Efficacy [Title/Abstract] AND safety of CGRP † monoclonal antibody [Title/Abstract] OR botulinum toxin in the prophylactic treatment of chronic migraine [Title/Abstract]. 80 #2 OnabotulinumtoxinA [MeSH Term] 4 #3 (effect of OnabotulinumtoxinA in migraine) AND (efficacy of anti-CGRP in migraine) 17 † Calcitonin gene-related peptide (CGRP). Data extraction First, eligible publications were reviewed according to the Center for Reviews and Dissemination standards for title and abstract. 39 After being verified, duplicate articles were eliminated. The whole text of the qualifying records was obtained after duplicates were eliminated, and two experienced investigators assessed the articles' eligibility. Subsequently, one investigator extracted the necessary data, and two more verified it; disagreements or opinions were settled by discussion and agreement with the principal investigator. Evidence from each publication was obtained before the research projects were released as papers. Data items • Author of study • Study type Information sources 1. PubMed or Medline (2015-2024) 2. Cochrane reviews (2015-2024) Results Figure 1 illustrates the total number of publications found using the previously recommended phrase combination for searches. 40 Duplicate articles were removed after they were determined to be eligible. Thirteen articles were selected for inclusion in this review after screening (see Table 3 ). Figure 1. Diagram of the data search process. Table 3. Comparative long-term effectiveness of Botox and Anti CGRP in migraine prevention. No Author’s Name and Year Study design Objectives Conclusion 1 Grazzi et al., 2024 41 Observational and retrospective study To assess the safety and efficacy of BoNT-A † and Anti-CGRP ‡ monoclonal antibodies in chronic migraine. For patients with CM § , BoNT-A is still a useful and appropriate treatment preference. Furthermore, to maximize the beneficial effects of BoNT-A for patients who are resistant or refractory, it may be possible to combine anti-CGRP monoclonal antibodies with it due to their distinct modes of action. The efficacy, safety, and cost-benefit analyses of these medications may help clinicians make more informed treatment decisions based on the study's findings. 2 Pallapothu et al., 2023 42 Review To evaluate how well anti-CGRP and BoNT-A function as treatments for migraine The review of several trials examined the two medications' mechanisms of action, side effects, adherence, cost-effectiveness, and ability to treat migraines. Many research studies discovered that Botox was more compliant than anti-CGRP since it was given by a physician every three months and had less adverse effects than anti-CGRP, which can be self-administered every month. Based on analysis of the available data, Botox is thought to be the most successful treatment. Even though both treatments are effective, this paper compared both to identify the more effective management approach. 3 Shaterian et al., 2023 43 Systematic Review To assess how BoNT-A affects migraine episodes. BoNT-A therapy is a low-cost approach for treating both episodic as well as CM type disorders. BoNT-A can lessen the intensity of discomfort and lower the monthly frequency of migraine attacks. 4 Corasaniti et al., 2023 44 Review To evaluate and investigate BoNT-A effectiveness and safety in CM. As compared to 1.4% of patients who did not get antithrombotic medication, the data show that patients undergoing antithrombotic therapy following BoNT-A treatment. Consequently, findings validate the safety of BoNT-A when used in conjunction with antithrombotic treatment. 5 Mechtler & Adams, (2022) 45 A retrospective study The objective of this study was to understand better the assurance, tolerability, and efficacy of combining a CGRP monoclonal antibody with BoNT-A therapy for the preventative treatment of CM. BoNT-A was successful in lowering CM, and for patients who continued the combination medication, the addition of a CGRP monoclonal antibodies was safe, well-tolerated, and linked to progressive and clinically significant decreases in CM. Prospective controlled studies in real-life settings are required to assess the safety and possible advantages of this combination therapy approach. 6 Argyriou et al., 2022 46 Review To evaluate the efficacy of adding anti-CGRP mabs to BoNT-A therapy in patients with CM who are not responding to treatment. The findings supported the theory that dual treatment works well and needs to be considered for patients with CM who are challenging to treat and have not responded to any existing monotherapies. 7 Argyriou et al., 2021 47 Review To find out how BoNT-A works in treating various main headache issues For people who don't react to standard preventive care, BoNTA could be an effective treatment. BoNTA may be taken into consideration in cases with trigeminal pain accompanied with autonomic symptoms, main stabbing headache, central area and pain during sleep and when a person wakes up and persistent headache that is challenging to treat, according to limited data that is currently available. 8 Cheng & Ahmed, 2021 48 Review To evaluate and investigate BoNT-A's safety and effectiveness in adult CM prevention For CM, OnabotA is a safe, effective, and well-tolerated medication. When taken with overuse of medications and other oral preventatives, OnabotA shows good safety and effectiveness. Studies that are now available show that onabotA is safer and more tolerable than oral preventatives. 9 Siddiqui et al., 2021 49 Review To compare anti-CGRP mAbs with Botox in terms of effectiveness, side effects, cost-efficiency, and other aspects. According to the analyzed publications, Botox is a more effective migraine preventive measure. Both Botox and CGRP mAbs are efficient and tolerated; however, Botox has been around for longer, is less expensive, has fewer side effects, and is simpler to administer. 10 Lu et al., 2021 50 Review to evaluate the safety and effectiveness of BoNT-A toxin and CGRP monoclonal antibody in the preventative therapy of CM. In terms of safety and effectiveness, CGRP monoclonal antibody proved to be marginally superior to botulinum toxin for individuals suffering from persistent migraines. Head-to-head trials would be preferable in the future to assess the safety and effectiveness of various drugs in the prevention of CM. 11 Blumenfeld et al., 2021 51 Review The goal is to assess the safety and effectiveness of anti-CGRP mAb and BoNT-A combination therapy for the prevention of migraines. The research study found that onabotulinumtoxinA and CGRP mAb combination therapy was well tolerated, did not reveal any new safety signals, and had extra benefits that were clinically significant. To further evaluate the safety and possible advantages of combination therapy, further controlled and real-world trials had to be taken into account. 12 Chen & Zheng, (2021) 4 Review To investigate the impacts of BoNT-A and CGRPmAbs in conjunction with any uncertainties regarding the safety and efficacy of CM medications. BoNT-A and CGRP mAbs both demonstrated comparable effects when used as a preventative measure for CM. BoNT-A's cost-effectiveness characteristics may lead to its favoured selection. 13 Szok et al., 2015 52 Review To ascertain BoNT-A's method of action as well as its effectiveness, safety, and tolerability in treating CM. It is determined that OBOT-A is a well-tolerated, safe, and efficacious preventive therapy for CM. At present, it is the only preventative medicine for CMurs that has received FDA approval. † OnabotulinumtoxinA. ‡ Calcitonin gene-related peptide (CGRP). § Chronic Migraine. Discussion Migraine pathophysiology The premonitory phase, starting three days before the headache phase, is distinguished by an intricate interaction between many cortical and subcortical of the brain, such as the brainstem nuclei and hypothalamus, which regulate nociceptive transmission. The headache episode involves the trigeminovascular system being activated. 53 Chronic headache is defined as 15 or more days of cerebral discomfort per month for three months or more, with migraine spikes occurring at least eight days per month, according to the International Classification of Headache Disorders, third edition (ICHD-3). 54 Several brainstem levels, including the hypothalamus and basal ganglia nuclei, receive signals from the Trigeminocervical complex (TCC) via ascending pathways. Nuclei project to different cortical locations, processing nociceptive impulses and resulting in symptoms including light sensitivity, loud noises, smell, touch, and neurocognitive disorder. Effectiveness of botox They are a widely recognized example of neurotoxins with several FDA-approved therapeutic applications, such as managing spastic bladder, preventing cerebral discomfort, and effectively relaxing cervical dystonia. 55 Even though the effects are temporary, they may be altered by altering the organization's sum and recurrence. Botox, one of the worst naturally occurring risks, was just made available for medical use, but not before it caused many accidental deaths. It was initially used in medicine to treat strabismus in 1980. Strabismus is a condition when neither eye lines up in the same way. Although the cosmetic benefits of Botox for wrinkles were first identified in 1989, it wasn't until 2002 that the treatment gained widespread recognition as a viable therapeutic option following FDA approval. 56 In 2014, Ali et al. discovered that Botox suppresses mechanical pain in peripheral trigeminovascular neurons. It is believed that meningeal and trigeminal nociceptors have a significant role in the development of severe migraines. According to Ali et al., BoNT-A reduces the onset of headaches by inhibiting high-threshold, mechanosensitive particle pathways implicated in mechanical pain from joining into the terminals of the nerve layer. 55 There are several advantages of Botox over additional preventive drugs. In 2018, a cohort study was conducted on 245 individuals who had persistent headaches and had received BoNT-A injections at varying periods. Eighty patients made it through the exploration, and 82.8% declared that Botox had helped them feel more in control of their migraines. 57 A more extensive, double-blind, randomized study with 1,384 participants was conducted in 2010; 688 patients received Botox treatments, while 696 patients received placebos. The frequency of migraine recurrence was significantly reduced in patients who received Botox. 35 Furthermore, compliance was considered more accessible because this approach is repeated every 12 weeks. The efficacy, safety, and cost-benefit analyses of these medications may help clinicians make more informed treatment decisions based on the study's findings. 41 There were no particularly notable long-term antagonistic effects except the standard Botox effects. In one research that included children, Botox was proven to be safe and effective in younger individuals. Because migraines can occur at any age, some people begin to experience headaches as early as childhood. According to the findings of a clinical experiment, a group of six individuals aged 14 to 18 who had not responded to prior migraine preventive treatments were given Botox during a clinical trial. Every sixth participant reported fewer headaches without significant side effects. 49 Anti-CGRP mechanism of action One significant neurotransmitter connected to migraines is CGRP. Monoclonal antibodies and anti-CGRP agonists are effective migraine preventives. The nociceptive neuron cell terminals emit a vasoactive neuropeptide called CGRP—hereditary variations in locus heterogeneity result in various CGRP isoforms. According to a survey regarding the effectiveness of monoclonal antibodies against CGRP, the medications were successful and maintained for several trials. People found it more straightforward to have many prescription medicines since mAbs are not compatible with other medications because they are transformed into amino acids and peptides. These monoclonal antibodies that fight against CGRP must be taken monthly, in contrast to the daily usage of many of the earlier preventive drugs. As a result, patients can follow their treatment regimens. 49 Botox versus anti-CGRP BoNT-A and CGRP monoclonal antibodies are used to treat CM. This section will examine the viability, side effects, cost-effectiveness, and other factors of CGRP mAbs and BoNT-A. 49 A total of 1,672 patients were randomly assigned to groups that received varying doses of galcanezumab and a placebo. A total of 1,672 individuals were randomized randomly to receive either galcanezumab at a dosage or a placebo. 60.9% of patients experienced a reduction of more than 50% in migraine occurrences when taking 240 mg. Without having any unfavorable side effects, it has been shown that CGRP mAb lessens migraines. 49 Table 4 summarizes the difference between the application of BoNT-A and anti-CGRP. Table 4. Comparison between BoNT-A and Anti-CGRP monoclonal antibodies. Anti-CGRP monoclonal antibodies Botox Administration Self-administered subcutaneous injection every month Physician-administered injections every 3 months Mechanism of action Blockade of CGRP † release leads to blocking of nociceptive sensation from the meninges of the brain and the trigeminovascular system Inhibition of acetylcholine release into the nerve terminal, resulting in decreased release of inflammatory and excitatory neurotransmitters Outcome Overall decrease in migraine episodes and pain reported Overall decrease in migraine episodes and pain reported † Calcitonin gene-related peptide. Additionally, they have no adverse hepatotoxic effects and are not associated with other medications. Compliance was advanced since it was handled once a month instead of regularly. In a retrospective analysis, all medical records from July 1, 1994, to December 1, 2017, were reviewed to see if patients had received migraines with aura at least a single session of Botox injections. They were following a review of the medical records of the remaining eleven patients (seven with a rare type of migraine, i.e., aura migraine, and four with an inherited subtype of migraine, the frequency and type of the patient's headaches before and following receiving Botox were documented. Nine of the eleven research participants reported decreased frequency, intensity, and duration of their auras following Botox administration. 58 About week nine or ten of the 12-week course, six out of the nine people with improved aura symptoms reported the effects of Botox and improvements occurring in the subsequent cycle. 58 In one study, researchers did a retrospective file evaluation of patients who had both Botox and a CGRP-mAb to ascertain whether additional treatment with CGRP-mAbs improves Botox treatment in CM sufferers. Patients who met the criteria for chronic headaches and were at least eighteen years old made their initial appointment at a single headache center. Individuals who had CGRP-mAb treatment for less than two months or who switched medications throughout the trial were not allowed to participate. The primary goal of the experiment was to determine whether the number of reported monthly headache days varied. The change in the severity of the pain was the secondary outcome. It is safe and beneficial to use CGRP-mAb medication as a supplemental preventive treatment in individuals with CM who have only partially responded to Botox. The researchers found that the CGRP-mAbs significantly reduced the number of days experiencing headaches and pain intensity and that the adverse event rates were similar to those observed in other trials with these medications. 59 It's noteworthy to note a lot of the triggers, such as hunger, lack of sleep, or bright light, that migraine patients point out could be premonitory indicators of a migraine attack that is actively in progress. This relationship explains why findings in clinical studies intended to identify and validate migraine trigger factors prospectively often diverge from findings in survey-based studies, where participants essentially describe their historical perspective of factors causing their migraine attacks. 60 Most medications on the market now that prevent migraines were developed to treat other conditions. This may help to explain some of the tolerability issues with some medications. First-line preventive drugs from the antidepressant medicine, anti-hypertensive, antiepileptic, and calcium channel blocker categories, among others, are still often used because clinical trials have shown them to be effective. 58 Even though these medicines assist up to 50% of migraineurs in reducing the total number of days they confront headache pain each month, none of the conventional oral preventive medications, which include beta-blockers, tricyclic antidepressants, serotonin antagonists, antidepressant medications, and anti-epileptic drugs were developed to treat headaches. Furthermore, there is often poor adherence to these drugs due to their poor tolerance. 61 Although Botox has been linked to notable clinical relief for those with CM, it usually isn't able to lower the frequency of headaches; therefore, other drugs are needed. 42 The guidelines' recommendations include a series of micro-injections between 31 and 39 used to administer Botox. These are injected into the muscular tissues of the neck, forehead, and region above the ears, either directly or beneath the skin. The physician is qualified to give Botox for the treatment of severe migraines. Injections are given every 12 weeks. Botox is usually used until three consecutive months of episodic migraine attacks or until quality-of-life surveys demonstrate a noticeable decrease in the level of impairment. The Botox treatment may be discontinued if it doesn't significantly lessen your migraines. 42 , 43 Migraine sufferers are treated with the same injections used by cosmetic surgeons and dermatologists to minimize wrinkles on the face. Qualified medical professionals treat migraines by injecting botulinum toxin into different parts of the head and neck; prophylactic medications are intended to reduce the incidence of migraine attacks. 42 A review of the most recent research on the function of CGRP in the digestive system suggests that the protein may reduce food intake, inhibit colon contractions in rats, and minimize stomach emptying. Some of these effects were local, while others were indirect, using neuronal CGRP receptors. The purpose of this study was to advance the understanding of a crucial gastrointestinal target for CGRP, which could be helpful in the understanding of constipation caused by anti-CGRP therapy and perhaps provide a medication choice for those experiencing constipation. 62 As a result, the majority of migraine specialists consider these drugs to impact CGRP outside of the CNS, maybe in the meninges, which are the membranes covering the brain and skull, which is where migraine pain may initially arise. 63 Botox and CGRP monoclonal antibodies have advantages over one another when managing migraines but also disadvantages. CGRP mAbs need monthly self-injections from patients, and adverse symptoms, such as redness and itching at the site of injection, have been documented. Additionally, some patients may find it less accessible because it is an expensive medication that may run up to $600 dollars a month without insurance. 60 Even though CGRP mAb and Botox infusions have different mechanisms of action, they appear t to work similarly in blocking the sensations of pain channels that cause headaches. Reduced acetylcholine release at neuromuscular connections is how Botox functions; meanwhile, it is believed that CGRP mAbs suppress pain perception by irritating an obvious burning marker like CGRP. Subsequent searches that examined the effectiveness of anti-CGRP and included significant test measures showed that such drugs were effective headache preventives. Various studies have demonstrated the benefits of Botox throughout the last ten years. Regarding adverse effects, BoNT-A and anti-CGRP have direct, temporary antagonistic effects; overall, an adverse long-standing impact unique to CGRP mAb users was at a standstill. 61 The CGRP mAb infusions are also significantly more painful than Botox injections. When analyzing BoNT-A and anti-CGRP, cost-effectiveness should be taken into account. Even while some insurance plans cover both medications entirely or partly, those without assurance may not be able to purchase any of these prescriptions. BoNT-A is typically the less expensive medication over the long term, so that it might be a sensible option for people on a tight budget. According to the reviewed papers, Botox may be a better option for treating migraines than CGRP mAbs because it is easier, less expensive, and more effective. 49 Conclusions A painful disorder that affects a large number of individuals worldwide is migraine. Botox and anti-CGRP are the two main treatments utilized in the present management approaches for CM. One can employ these two methods for preventative purposes or long-term treatment. The exotoxin known as Botox is synthesized by Clostridium botulinum and inhibits the release of acetylcholine from nerve terminals. On the other hand, anti-CGRP reduces pain perception by blocking the inflammatory receptor. Anti-CGRP adverse effects include tiredness and itching, but the most common ones are constipation and infections in the upper respiratory tract. A condition called ptosis or prolapse, neck discomfort, and muscle weakness are among the other adverse effects of Botox. Additionally, there is a cost difference between anti-CGRP and Botox, where Botox is the first one being more affordable over time. Insurance companies may or may not pay for the procedure, although Botox is generally preferable. Anti-CGRP is more effective when combined with Botox since it causes fewer adverse effects and better patient benefits. Furthermore, to improve the therapeutic potential of BoNT-A for patients resistant to treatment, the potential combination of Anti-CGRP mAbs with BoNT-A may be considered due to their distinct modes of action. These medications' efficacy, safety, and cost-benefit analyses may help clinicians make more informed treatment decisions based on the study's findings. Additional research is required to validate our results. Limitations Even though the researcher used the available platform to conduct an extensive evaluation, the researcher must consider the possibility that the researcher overlooked significant research. Because the researcher only included papers from a limited number of databases and did not have full access to publications. All the research examined for this study was selected only written in English. A limited number of study publications compared anti-CGRP with Botox. However, this assumption is unsubstantiated because most of the included studies did not include any information on ethnicity. Secondly, not enough trials were included, affecting the accuracy of the effect estimations. The researcher needs to make an effort to conduct a more thorough investigation to compare these two appropriately. Ethics and consent Ethical approval and consent were not required Author contributions Elizabeth Gaviria: Conceptualization; Methodology; Writing original draft; Visualization. Awab Hamid: Writing original draft; writing, reviewing, and editing. Transparency statement The lead author, Elizabeth Gaviria, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and if relevant, registered) have been explained. Data availability statement No data associated with this article. Extended data Figshare: PRISMA checklist and flow chart for “Comparative long-term effectiveness of OnabotulinumtoxinA (Botox) and Anti CGRP in migraine prevention: A systematic review”. https://doi.org/10.6084/m9.figshare.25928722.v2 . 40 This project contains the following extended data: • PRISMA_2020_checklist.docx (checklist of the PRISMA guidelines applied). • Flowchart.jpg (diagram of the data search process). • Tables.docx (tables presenting detailed data results). Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Reporting guidelines Figshare: PRISMA checklist and flow chart for “Comparative long-term effectiveness of OnabotulinumtoxinA (Botox) and Anti CGRP in migraine prevention: A systematic review”. https://doi.org/10.6084/m9.figshare.25928722.v2 . 40 Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). References 1. Natoli JL, Manack A, Dean B, et al. : Global prevalence of chronic migraine: a systematic review. Cephalalgia: an international journal of headache. 2010; 30 (5): 599–609. PubMed Abstract | Publisher Full Text 2. Robbins MS: Diagnosis and Management of Headache: A Review. JAMA. 2021; 325 (18): 1874–1885. Publisher Full Text 3. Agostoni EC, Barbanti P, Calabresi P, et al. : Current and emerging evidence-based treatment options in chronic migraine: a narrative review. J. Headache Pain. 2019; 20 (1): 92. PubMed Abstract | Publisher Full Text | Free Full Text 4. 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Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });