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Botulinum Toxin and Migraine: Goals and Perspectives

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 20061

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Special Issue Editor

Dr. Maria Pia Prudenzano

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Guest Editor

Headache Center, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
Interests: clinical neurology; adult neurology; headache; botulinum toxins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Migraine is a type of disabling primary headache and is widespread in the general population. Migraine-related disability increases proportionally with headache frequency and reaches its highest levels in chronic migraine, which is often comorbid with psycho and somatic pathologies as well as symptomatic drug overuse.

On 15 October 2010, the U.S. Food and Drug Administration approved onabotulinumtoxinA to prevent headaches in adult patients with chronic migraine. After more than a decade, it is time to take stock of this successful therapeutic option. Many of its aspects deserve in-depth study. For example, what is its precise peripheral antimigraine mechanism of action and how does it exert its possible effects on the central nervous system? Additionally, what is the best paradigm of injection? Can long-term treatment modify the natural history of migraine, and is this therapy useful for episodic migraine or other forms of headaches? Other no less interesting aspects to consider are the possibility of a shorter administration interval to counter the phenomenon of the dose wearing off or the association of the botulinum toxin with antiCGRP antibody therapy in resistant forms. The possibility of extending the indications to migraine patients in adolescence and or of developmental age or for particular conditions such as migraine during pregnancy represent further research topics. Both review and research articles on animal models, clinical studies, case reports, or off-label indications are welcome contributions to this Special Issue, “Botulinum Toxin and Migraine: Goals and Perspectives”.

Dr. Maria Pia Prudenzano
Guest Editor

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Keywords

onabotulinumtoxinA
chronic migraine
injection paradigm
mechanism of action
animal models
clinical study
case report
off-label use
new indications

Published Papers (11 papers)

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Research

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10 pages, 1725 KiB

Open AccessCommunication

Onabotulinumtoxin-A: Previous Prophylactic Treatment Might Improve Subsequent Anti-CGRP Monoclonal Antibodies Response in Patients with Chronic Migraine

by Giulia Ceccardi, Francesca Schiano di Cola, Salvatore Caratozzolo, Michele Di Pasquale, Marco Bolchini, Alessandro Padovani and Renata Rao

Toxins 2023, 15(12), 677; https://doi.org/10.3390/toxins15120677 - 30 Nov 2023

Viewed by 1400

Abstract

The aim of the present study was to evaluate whether previous preventive treatment with onabotulinumtoxin-A might influence subsequent clinical response following a switch to anti-CGRP monoclonal antibodies (mAbs). The present retrospective study was conducted at the Headache Centre—Neurology Clinic at the Spedali Civili Hospital of Brescia between November 2018 and May 2023. The primary objective was to assess clinical outcome (monthly headache days (MHDs), monthly migraine days (MMDs), mean analgesics consumption, and clinical disability according to Migraine Disability Assessment (MIDAS)) following three months (T3) of preventive treatment with anti-CGRP mAbs comparing patients who did and those who did not previously receive treatment with Onabotulinumtoxin-A. Moreover, we aimed to evaluate whether the clinical response to anti-CGRP mAbs was affected by the number of previous Onabotulinumtoxin-A administrations. At T3, compared to Onabotulinumtoxin-A naïve patients, patients who previously received Onabotulinumtoxin-A documented fewer MMDs (3.3 ± 3.7 versus 5.2 ± 5.0; p = 0.017) and a lower MIDAS score (23.2 ± 20.9 versus 37.4 ± 39.6; p = 0.013). Patients who received at least 3 onabotulinumtoxin-A administrations documented, at T3, lower MMDs compared to those who received fewer cycles (respectively, 2.1 ± 2.7 vs. 6.5 ± 4.4; p = 0.024). In conclusion, according to our data, previous treatment with onabotulinumtoxin-A might improve subsequent response to anti-CGRP mAbs preventive treatment. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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12 pages, 903 KiB

Open AccessArticle

Effects of a Single Session of OnabotulinumtoxinA Therapy on Sleep Quality and Psychological Measures: Preliminary Findings in a Population of Chronic Migraineurs

by Angelo Torrente, Paolo Alonge, Laura Pilati, Andrea Gagliardo, Lavinia Vassallo, Vincenzo Di Stefano, Antonino Lupica, Irene Quartana, Giovanna Viticchi, Mauro Silvestrini, Marco Bartolini, Cecilia Camarda and Filippo Brighina

Toxins 2023, 15(9), 527; https://doi.org/10.3390/toxins15090527 - 27 Aug 2023

Cited by 2 | Viewed by 814

Abstract

Chronic migraine is a burdensome condition, and onabotulinumtoxinA is revealed to be an effective therapy. Migraine shows a bidirectional relationship with sleep, but the effects of preventive therapies on sleep quality are poorly studied. This study aims to evaluate the effects of a single session of onabotulinumtoxinA on patients’ sleep quality and correlates the results with measures of comorbid anxiety/depression. Patients completed self-administrable questionnaires about sleep quality (Pittsburgh Sleep Quality Index—PSQI) and psychological symptoms (Beck Depression Inventory, 2nd edition—BDI-II—and Hospital Anxiety and Depression Scale—HADS—subscales “a” and “d” for anxiety and depression, respectively), and reported migraine frequency at baseline and after 12 weeks. The 42 included patients showed a significant reduction in migraine days (from 20.6 ± 6.0 to 13.6 ± 6.2, p < 0.001), while no changes were observed in sleep quality (PSQI score from 11.0 ± 5.0 to 9.8 ± 4.6, p = 0.277) or psychological measures (BDI-II from 16.7 ± 10.2 to 15.7 ± 10.3, p = 0.678; HADS-a from 10.3 ± 4.8 to 9.3 ± 5.5, p = 0.492; and HADS-d from 7.2 ± 3.9 to 7.1 ± 5.0, p = 0.901). On the other hand, a strong correlation among PSQI, BDI-II, HADS-a, and HADS-d scores (p < 0.001, rho > 0.7) was found. Despite its efficacy in migraine prevention, a single session of onabotulinumtoxinA was not able to affect patients’ sleep quality or their psychological symptoms. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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14 pages, 656 KiB

Open AccessArticle

Searching for the Predictors of Response to BoNT-A in Migraine Using Machine Learning Approaches

by Daniele Martinelli, Maria Magdalena Pocora, Roberto De Icco, Marta Allena, Gloria Vaghi, Grazia Sances, Gloria Castellazzi and Cristina Tassorelli

Toxins 2023, 15(6), 364; https://doi.org/10.3390/toxins15060364 - 29 May 2023

Cited by 1 | Viewed by 1321

Abstract

OnabotulinumtoxinA (BonT-A) reduces migraine frequency in a considerable portion of patients with migraine. So far, predictive characteristics of response are lacking. Here, we applied machine learning (ML) algorithms to identify clinical characteristics able to predict treatment response. We collected demographic and clinical data of patients with chronic migraine (CM) or high-frequency episodic migraine (HFEM) treated with BoNT-A at our clinic in the last 5 years. Patients received BoNT-A according to the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) paradigm and were classified according to the monthly migraine days reduction in the 12 weeks after the fourth BoNT-A cycle, as compared to baseline. Data were used as input features to run ML algorithms. Of the 212 patients enrolled, 35 qualified as excellent responders to BoNT-A administration and 38 as nonresponders. None of the anamnestic characteristics were able to discriminate responders from nonresponders in the CM group. Nevertheless, a pattern of four features (age at onset of migraine, opioid use, anxiety subscore at the hospital anxiety and depression scale (HADS-a) and Migraine Disability Assessment (MIDAS) score correctly predicted response in HFEM. Our findings suggest that routine anamnestic features acquired in real-life settings cannot accurately predict BoNT-A response in migraine and call for a more complex modality of patient profiling. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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10 pages, 1328 KiB

Open AccessArticle

Regional Targeted Subcutaneous Injection of Botulinum Neurotoxin Type A in Refractory Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study

by Francesco Bono, Maria Rosaria Mazza, Giuseppe Magro, Giorgio Spano, Giovanni Idone, Vincenzo Laterza, Denise Tedeschi, Francesco Pucci, Antonio Gambardella and Alessia Sarica

Toxins 2023, 15(5), 324; https://doi.org/10.3390/toxins15050324 - 9 May 2023

Cited by 1 | Viewed by 1780

Abstract

In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (−13.2 versus −1.2; p < 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the “follow the origin of maximum pain” approach using SjBoT injection paradigm. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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12 pages, 1938 KiB

Open AccessEditor’s ChoiceArticle

Quantitative and Qualitative Pain Evaluation in Response to OnabotulinumtoxinA for Chronic Migraine: An Observational Real-Life Study

by Claudia Altamura, Nicoletta Brunelli, Giovanna Viticchi, Sergio Salvemini, Gianluca Cecchi, Marilena Marcosano, Luisa Fofi, Mauro Silvestrini and Fabrizio Vernieri

Toxins 2023, 15(4), 284; https://doi.org/10.3390/toxins15040284 - 15 Apr 2023

Cited by 2 | Viewed by 1492

Abstract

(1) Background: Randomized controlled trials and real-life studies demonstrated the efficacy of OnabotulinumtoxinA (OBT-A) for CM prevention. However, no studies specifically addressed its effect on pain’s quantitative intensity and qualitative characteristics. (2) Methods: This is an ambispective study: a post-hoc retrospective analysis of real-life prospectively collected data from two Italian headache centers on CM patients treated with OBT-A over one year (i.e., Cy1-4). The primary endpoint was the changes in pain intensity (Numeric Rating Scale, NRS; the Present Pain Intensity (PPI) scale, the 6-point Behavioral Rating Scale (BRS-6)) and quality scale (the short-form McGill Pain Questionnaire (SF-MPQ)) scores. We also assessed the relationship between changes in intensity and quality of pain and disability scale (MIDAS; HIT-6) scores, monthly headache days (MHDs), and monthly acute medication intake (MAMI) (3) Results: We retrieved 152 cases (51.5 years SD 11.3, 80.3% females). From baseline to Cy-4, MHDs, MAMI, NRS, PPI, and BRS-6 scores decreased (consistently p < 0.001). Only the throbbing (p = 0.004), splitting (p = 0.018), and sickening (p = 0.017) qualities of pain collected in the SF-MPQ were reduced. Score variations in MIDAS related to those in PPI scales (p = 0.035), in the BRS-6 (p = 0.001), and in the NRS (p = 0.003). Similarly, HIT-6 score changes related to PPI score modifications (p = 0.027), in BRS-6 (p = 0.001) and NRS (p = 0.006). Conversely, MAMI variation was not associated with qualitative or quantitative pain score modifications except BRS-6 (p = 0.018). (4) Conclusions: Our study shows that OBT-A alleviates migraine by reducing its impact on multiple aspects, such as frequency, disability, and pain intensity. The beneficial effect on pain intensity seems specific to pain characteristics related to C-fiber transmission and is associated with a reduction in migraine-related disability. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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12 pages, 323 KiB

Open AccessArticle

A Single-Group Study on the Effect of OnabotulinumtoxinA in Patients with Chronic Migraine Associated with Medication Overuse Headache: Pain Catastrophizing Plays a Role

by Licia Grazzi, Danilo Antonio Montisano, Paul Rizzoli, Erika Guastafierro, Alessia Marcassoli, Arianna Fornari and Alberto Raggi

Toxins 2023, 15(2), 86; https://doi.org/10.3390/toxins15020086 - 17 Jan 2023

Cited by 3 | Viewed by 1482

Abstract

Pain catastrophizing and cutaneous allodynia are commonly altered in patients with chronic migraine associated with medication overuse headache (CM-MOH) and tend to improve in parallel with clinical improvement. The relation between pain catastrophizing and cutaneous allodynia is poorly understood in patients with CM-MOH receiving OnabotulinumtoxinA therapy. In this single-arm open-label longitudinal observational study, patients with CM-MOH were assigned to structured withdrawal and then administered OnabotulinumtoxinA (5 sessions on a three-month basis, 195 UI per 31 sites). Headache frequency, medication intake, disability, impact, cutaneous allodynia and pain catastrophizing were evaluated with specific questionnaires. In total, 96 patients were enrolled and 79 completed the 12-month follow-up. With the exclusion of cutaneous allodynia and the magnification subscale of the pain catastrophizing questionnaire, all variables showed significant improvement by the sixth month, which was maintained at 12 months. Reduction of pain catastrophizing, and particularly of its helplessness subscale, was a significant predictor of reduction in headache frequency and medication intake. Pain catastrophizing is often implicated in the clinical improvement in patients with CM-MOH receiving behavioral treatments, but, in this study, also showed a role in patients receiving OnabotulinumtoxinA; combining OnabotulinumtoxinA and behavioral treatments specifically addressing pain catastrophizing might further enhance patients’ clinical outcome. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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Graphical abstract

16 pages, 1050 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Effects of Botulinum Toxin Type A on the Nociceptive and Lemniscal Somatosensory Systems in Chronic Migraine: An Electrophysiological Study

by Gabriele Sebastianelli, Francesco Casillo, Antonio Di Renzo, Chiara Abagnale, Ettore Cioffi, Vincenzo Parisi, Cherubino Di Lorenzo, Mariano Serrao, Francesco Pierelli, Jean Schoenen and Gianluca Coppola

Toxins 2023, 15(1), 76; https://doi.org/10.3390/toxins15010076 - 14 Jan 2023

Cited by 6 | Viewed by 3363

Abstract

(1) Background: OnabotulinumtoxinA (BoNT-A) is a commonly used prophylactic treatment for chronic migraine (CM). Although randomized placebo studies have shown its clinical efficacy, the mechanisms by which it exerts its therapeutic effect are still incompletely understood and debated. (2) Methods: We studied in 15 CM patients the cephalic and extracephalic nociceptive and lemniscal sensory systems using electrophysiological techniques before and 1 and 3 months after one session of pericranial BoNT-A injections according to the PREEMPT protocol. We recorded the nociceptive blink reflex (nBR), the trigemino-cervical reflex (nTCR), the pain-related cortical evoked potential (PREP), and the upper limb somatosensory evoked potential (SSEP). (3) Results: Three months after a single session of prophylactic therapy with BoNT-A in CM patients, we found (a) an increase in the homolateral and contralateral nBR AUC, (b) an enhancement of the contralateral nBR AUC habituation slope and the nTCR habituation slope, (c) a decrease in PREP N-P 1st and 2nd amplitude block, and (d) no effect on SSEPs. (4) Conclusions: Our study provides electrophysiological evidence for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level of trigeminal system through a reduction in input from meningeal and other trigeminovascular nociceptors. Moreover, by reducing activity in cortical pain processing areas, BoNT-A restores normal functioning of the descending pain modulation systems. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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Graphical abstract

9 pages, 734 KiB

Open AccessArticle

Sustained Efficacy, Safety and High Adherence Rate of Onabotulinum Toxin Type A in Chronic Migraine Patients: A Multicentric Prospective Real-Life Study

by Ilenia Corbelli, Angela Verzina, Ilaria Leone De Magistris, Gioacchino De Vanna, Paolo Eusebi, Giorgia Mataluni, Antonio Pisani, Addolorata Maria Pia Prudenzano, Maria Trojano, Marianna Delussi, Marina De Tommaso, Antonio Russo, Marcello Silvestro, Gioacchino Tedeschi, Paolo Calabresi and Paola Sarchielli

Toxins 2023, 15(1), 34; https://doi.org/10.3390/toxins15010034 - 31 Dec 2022

Cited by 4 | Viewed by 1631

Abstract

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into “responders” (R), “partially responders” (PR) and “non-responders” (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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12 pages, 2464 KiB

Open AccessFeature PaperArticle

OnabotulinumtoxinA Treatment in Chronic Migraine: Investigation of Its Effects on Disability, Headache and Neck Pain Intensity

by Dilara Onan, Enrico Bentivegna and Paolo Martelletti

Toxins 2023, 15(1), 29; https://doi.org/10.3390/toxins15010029 - 30 Dec 2022

Cited by 2 | Viewed by 1632

Abstract

Neck disability and pain are frequently encountered problems in patients with chronic migraine (CM). The long-term stimuli of neurons in the trigeminocervical junction may explain this situation. OnabotulinumtoxinA (ONA) treatment is one of the proven treatments for CM; however, there is no study data on the efficacy of ONA treatment on neck disability and pain in CM patients. Therefore, we aimed to investigate the effect of ONA treatment on disability, neck pain and headache intensity in CM patients. One hundred thirty-four patients who met the inclusion criteria were included in the study. ONA treatment was administered at a dose of 195 U to 39 sites in total as per Follow-the-Pain PREEMPT protocol. The disability was evaluated with the Neck Disability Index and the Migraine Disability Assessment; pain intensity was evaluated with the Visual Analogue Scale; the monthly number of headache days were recorded; quality of life was evaluated with the Headache Impact Test. All assessments were recorded at baseline and 3 months after treatment. After the treatment, neck–migraine disabilities decreased from severe to mild for neck and moderate for migraine (p < 0.001). Neck pain and headache intensities decreased by almost half (p < 0.001). The median number of monthly headache days decreased from 20 days to 6 days (p < 0.000). The quality-of-life level decreased significantly from severe to substantial level (p < 0.001). According to our results, ONA treatment was effective in reducing neck-related problems in CM patients. Long-term follow-up results may provide researchers with more comprehensive results in terms of the treatment of chronic migraine–neck-related problems. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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10 pages, 1188 KiB

Open AccessArticle

OnabotulinumtoxinA Modulates Visual Cortical Excitability in Chronic Migraine: Effects of 12-Week Treatment

by Angelo Torrente, Laura Pilati, Salvatore Di Marco, Simona Maccora, Paolo Alonge, Lavinia Vassallo, Antonino Lupica, Serena Coppola, Cecilia Camarda, Nadia Bolognini and Filippo Brighina

Toxins 2023, 15(1), 23; https://doi.org/10.3390/toxins15010023 - 29 Dec 2022

Cited by 3 | Viewed by 1242

Abstract

Chronic migraine is a burdensome disease presenting with episodic pain and several symptoms that may persist even among headache attacks. Multisensory integration is modified in migraine, as assessed by the level of the perception of sound-induced flash illusions, a simple paradigm reflecting changes in cortical excitability which reveals to be altered in migraineurs. OnabotulinumtoxinA is an effective preventive therapy for chronic migraineurs, reducing peripheral and central sensitization, and may influence cortical excitability. Patients affected by chronic migraine who started onabotulinumtoxinA preventive therapy were included. Clinical effects (headache diaries and migraine related questionnaires) were assessed at the beginning of the therapy and after 12 weeks. Contextually, patients underwent the evaluation of multisensory perception by means of the sound-induced flash illusions. OnabotulinumtoxinA showed effectiveness both in migraine prevention and in reducing headache burden. Even one session of therapy was able to restore, at least partially, multisensory processing, as shown by patients’ susceptibility to the sound-induced flash illusion. OnabotulinumtoxinA could influence migraineurs cortical excitability concurrently to the beneficial effects in headache prevention. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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Review

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28 pages, 697 KiB

Open AccessReview

OnabotulinumtoxinA: Still the Present for Chronic Migraine

by Carlo Baraldi, Flavia Lo Castro, Raffaele Ornello, Simona Sacco, Luca Pani and Simona Guerzoni

Toxins 2023, 15(1), 59; https://doi.org/10.3390/toxins15010059 - 10 Jan 2023

Cited by 4 | Viewed by 3127

Abstract

OnabotulinumtoxinA (BT-A) is one of the few drugs approved for the preventive treatment of chronic migraine (CM). Despite this, some aspects of its mechanism of action are still a matter of debate, and the precise magnitude of BT-A effects needs to be completely elucidated. BT-A acts primarily upon trigeminal and cervical nerve endings, by inhibiting the release of inflammatory mediators such as calcitonin gene-related peptide, as well as reducing the insertion of ionotropic and metabotropic receptors into the neuronal membrane. These actions increase the depolarization threshold of trigeminal and cervical nerve fibers, thus reducing their activation. The central actions of BT-A are still a matter of debate: a retrograde axonal transport has been postulated, but not clearly assessed in humans. Clinically, the efficacy of BT-A in CM has been assessed by large, randomized placebo-controlled trials, such as the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Those results were also confirmed in a wide range of open-label studies, even for long-term periods. Recently, novel findings have led to a better understanding of its pharmacological actions and clinical usefulness in migraine prevention. This narrative review summarizes, updates and critically revises the available data on BT-A and its possible implementation in chronic migraine. Moreover, the current role of BT-A in CM treatment has been discussed. Full article

(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)

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