The Use of Botulinum Toxin in the Management of Headache Disorders.

In chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo treatment. Non-serious adverse events were probably experienced by 60/100 participants in the treated group compared with 47/100 in the placebo group. For people with episodic migraine, we remain uncertain whether or not this treatment is effective because the quality of this limited evidence is very low. Better reporting of outcome measures in published trials would provide a more complete evidence base on which to draw conclusions.

Introduction: Migraine is a chronic neurological disorder marked by recurrent moderate to severe headaches with symptoms such as nausea, photophobia, and phonophobia. Chronic migraine, occurring on 15 or more days per month for over three months, significantly impairs daily functioning and creates a substantial health burden. Botulinum toxin type A (BoNT-A) is an effective preventive option for patients who do not respond to standard treatments. Aim of the study: The aim of this review is to summarize current evidence on the mechanism of action, clinical efficacy, safety profile, and practical use of botulinum toxin type A in the prevention of chronic migraine. Materials and methods: A literature search was mostly performed in PubMed and Google Scholar for studies published between 2015 and 2025, using the keywords: migraine, chronic migraine, botulinum toxin, onabotulinumtoxinA, PREEMPT trials, CGRP. Priority was given to randomized controlled trials, long-term observational studies, clinical guidelines, and mechanistic research. Discussion: OnabotulinumtoxinA (BoNT-A) is a well-established preventive treatment for chronic migraine supported by evidence from the PREEMPT trials and long-term studies such as COMPEL. BoNT-A significantly reduces headaches, improves quality of life and decreases disability with benefits sustained over multiple treatment cycles. Its mechanism blocking the release of CGRP, substance P, and glutamate from sensory nerves and modulating nociceptive receptors targets both peripheral and central sensitization, which distinguishes it from traditional oral medication. Injection protocols vary worldwide. The PREEMPT paradigm is evidence-based and standardized, while alternative approaches, such as the Saudi 5/20/100 protocol, offer lower doses and fewer injections but lack of large-scale validation. The safety profile is generally positive. Following recommended dosing intervals minimizes the risk of neutralizing antibodies. Emerging CGRP-targeting therapies provide additional options, and early data suggest potential benefits of combination therapy for refractory cases. Economic analyses indicate that despite higher upfront costs, BoNT-A reduces healthcare use and disability, making it cost-effective in the long term. Future research should focus on identifying predictors of response, optimizing injection protocols, and evaluating combination strategies with biologics. Results: Evidence from large randomized trials (PREEMPT 1 and 2) demonstrates that BoNT-A significantly reduces the number of headache days, improves quality of life, and decreases disability in patients with chronic migraine. Long-term studies show sustained benefits over multiple treatment cycles with a favorable safety profile. BoNT-A reduces peripheral and central sensitization by inhibiting the release of pain-related neuropeptides and modulating sensory nerve activity. Conclusion: OnabotulinumtoxinA is an effective and well-tolerated preventive treatment for chronic migraine. Standardized injection protocols and appropriate patient selection optimize therapeutic outcomes. Further research is needed to identify predictors of treatment response and to explore the potential of combination therapy with CGRP (calcitonin gene-related peptide)-targeting agents.

Background Chronic migraine, defined as ≥15 headache days/month with ≥8 migraine days, is a disabling condition with limited effective treatment options. Greater occipital nerve block (GONB) and botulinum toxin type A (BoNTA) are used in chronic migraine management, yet data from certain regions remain scarce. Objective The objective of this study was to demonstrate the safety and efficacyof GONB and BoNTA treatments in patients with chronic migraine. Methods This prospective, observational, non-blinded exploratory pilot study included 20 adult patients with chronic migraine at a tertiary hospital in India (March 2020-October 2021). Patients were offered either GONB or BoNTA via a cafeteria approach. GONB was administered under ultrasound guidance using lidocaine and methylprednisolone, while BoNTA was injected following the PREEMPT (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) protocol. Headache diaries tracked frequency, severity (via visual analogue scale (VAS)), and medication use for four weeks post intervention. Results Sixteen patients (80%) chose GONB, while four (20%) opted for BoNTA. Mean baseline headache days were 22.63 ± 5.1 (GONB) and 26 ± 4.0 (BoNTA). At four weeks, headache days decreased to 10.81 (GONB) and 12.0 (BoNTA). Mean headache-free days post intervention were 17.19 (GONB) and 15.75 (BoNTA). VAS severity scores improved in both groups, with a marked reduction in high-intensity headache days. No serious adverse events occurred; minor local site pain and transient fatigue were the only reported side effects. Conclusion Both GONB and BoNTA significantly reduced headache frequency and severity in chronic migraine patients with favorable short-term safety profiles. GONB, being more accessible and cost-effective, may offer a viable alternative in resource-limited settings. Both GONB and BoNTA are effective and safe in chronic migraine, with GONB offering a cost-effective, practical option for resource-limited settings.

Background: Chronic Migraine (CM) is a disabling neurological disorder classified as a complication of migraine. Patients with CM experience headaches on 15 or more days per month in at least three consecutive months. Despites the range of therapeutic treatments, in some cases current treatments often have limited efficacy and intolerable adverse events, highlighting gaps in prophylactic treatment options. OnabotulinumtoxinA (BoNT-A), a purified protein that blocks acetylcholine release from presynaptic neurons and inhibits muscle contractions, has shown pain relief in various conditions, including migraine. Clinical trials suggest that BoNT-A may be an effective and safe prophylactic medication for treating migraines and other headache disorders. Objective: To evaluate the efficacy and safety of BT-A in the treatment of chronic migraine through a systematic review and meta-analysis. Methods: The literature search was performed using PubMed, Scopus, and Web of Science databases. The inclusion criteria consisted of randomized controlled trials that evaluated the use of BoNT-A in patients diagnosed with chronic migraine, comparing it to a placebo group. Studies were screened and selected based on relevance, and data were extracted by independent reviewers. The primary outcomes were the reduction in the number of headache days and the incidence of adverse events. All statistical analyses were performed using the RStudio (version 4.3.2). Results: A total of 11 studies and 3.617 patients were included, with 2.092 (57.84%) receiving botulinum toxin type A (BoNT-A) and 1.525 (42.16%) in the placebo group. BT-A therapy was associated with a significant reduction in the number of headache days per month in the BoNT-A group (odds ratio: 0.89; 95% CI: 0.54 to 1.49; P<0.01; I²=72%), suggesting that BoNT-A is effective in reducing the frequency of chronic migraine episodes. Adverse events were reported more frequently in the BT-A group compared to the placebo group (odds ratio: 0.96; 95% CI: 0.37 to 2.48; P<0.01; I²=97%). Common adverse effects included neck pain, muscle weakness, and injection site pain. The high heterogeneity indicates variability in the reported adverse effects among different studies. Conclusion: The results of our study suggest that the therapy with BT-A is demonstrated a significant reduction in headache days per month compared to the placebo group. However, BT-A treatment was also associated with a higher incidence of adverse effects. Overall, BT-A appears to be a promising prophylactic treatment for chronic migraine, balancing its beneficial reduction in headache frequency against the consideration of its adverse effects.

Migraine

Botulinum toxin type A in the treatment of chronic migraine and chronic tension-type headache

Considerable evidence exists supporting the notion that botulinum toxin type A (BoNT/A) can exert a direct analgesic effect in addition to its myorelaxant effect. It is likely that the benefict of using BoNT/A as prophylactic treatment for chronic migraine is due to its ability to inhibit overactivity of motor neurons and hyperexcitability of sensory neurons, by involving the suppression of peripheral and central sensitization. In this study we aimed to evaluate the effects of BoNT/A on amplitude, latency and habituation of laser evoked potentials (LEPs) in patients with chronic migraine. We recruited 20 patients with a diagnosis of chronic migraine treated with type A botulinum toxin every 3 months. LEPs were recorded in basal, two hours and ten days after both BoNT/A and placebo injection. Headache frequency, allodynia and total tenderness score (TTS) were evaluated at basal condition and after one-year of treatment. We found N2 and P2 latency increased 10 days after toxin injection, while LEPs amplitude was not modified. Compared to placebo injection, the habituation of N2/P2 LEPs component obtained by stimulating supraorbital zone was significantly increased after BoNT/A infiltration. After ten days, habituation pattern in migraine patients was similar to that of normal subjects. In the one-year follow-up we observed a significant migraine frequency and allodynia improvement, but no effect on total tenderness score. Furthermore the habituation change correlated with the clinical effectiveness. Study results suggest a toxin modulating action on nociceptive afferents in patients with chronic migraine. The N2 and P2 latency increase obtained from hand laser stimulation suggests a possible systemic pain inhibiting effect. Although the botulinum toxin did not show an inhibitory effect on trigeminal nociceptive system, it seems to improve the reduced habituation pattern which promotes the central sensitization. The therapeutic effect of BoTN/A seemed to be related to the effect on trigeminal habituation obtained after 10 days from the first infiltration, which could be considered as a potential neurophysiological pattern to predict the non-responders. Results of this study confirm that the effect of botulinum toxin on chronic migraine may be related to a modulation and normalization of central sensitization mechanisms. The lack of effects on pericranial muscle tension precludes to suppose a modulating effect on trigeminal nociception by the inhibition of the neuromuscular synapse. Written informed consent to publish was obtained from the patient(s).

To measure the effect of botulinum toxin type A (Botox, Allergan, Inc, Irvine, CA) treatment in 271 patients diagnosed with headache in accordance with International Headache Society (IHS) criteria. Botulinum toxin type A has shown promise for the treatment of headache in several clinical trials, but uncertainty remains as to how botulinum toxin type A optimally should be used for treating headache and which patients are best suited for this treatment. This was a retrospective chart review of all patients who received botulinum toxin type A for the treatment of headache from January 1999 to February 2002. Patients were injected with an average dose of 63.2 U (SD, 14.5) of botulinum toxin type A on 2 or more visits, with treatments involving a "fixed-site" or a "follow-the-pain" (or a combination of both) approach. In the fixed-site approach, botulinum toxin type A was injected into the procerus, corrugator, frontalis, and temporalis muscles. In the follow-the-pain approach, botulinum toxin type A was injected into a combination of the procerus, corrugator, frontalis, temporalis, occipitalis, trapezius, and/or semispinalis capitis muscles. The primary outcomes for the trial were the reduction in headache days per month or headache intensity (0 to 3 scale) (or both) from baseline. Patients were diagnosed according to IHS criteria and subsequently classified into the following categories: chronic daily headache (more than 15 headache days per month), episodic tension-type headache, episodic migraine, and "mixed" HA (less than 15 headache days per month, combination of migraine and tension-type headache). Treatment period was an average of 8.6 months (SD, 6.4); patients received an average of 3.4 doses (SD, 1.6) 3 months apart. Of the 271 patients, 29 (10.7%) had episodic migraine, 17 (6.3%) had episodic tension-type headache, 71 (26.2%) had mixed headache, and 154 (56.8%) had chronic daily headache. Two-hundred fifty-six patients had data for the number of headache days per month, 117 had data for headache intensity, and all 271 had data for headache days or headache intensity. Botulinum toxin type A treatment significantly reduced the number of headache days per month from 18.9 (SD, 10.3) to 8.3 (SD, 8.9) (n=256, P<.001)--a 56% reduction. Headache intensity decreased from 2.4 points (SD, 0.6) to 1.8 points (SD, 0.8) (n=117, P<.001)--a 25% reduction. Of 263 patients surveyed, 225 (85.6%) reported improvement in headache frequency and intensity. There was no correlation of effect/lack of effect with reason for treatment, duration/number of treatments, injection technique, mean/total dose, age, gender, or comorbidity. Approximately 95% of patients did not experience medication side effects. These results suggest that botulinum toxin type A may be an effective and safe prophylactic treatment for a variety of moderate to severe chronic headache types.

To identify the clinical characteristics and/or injection parameters that predict a favorable response to botulinum toxin type A in patients with episodic and chronic migraine. There is emerging scientific and clinical evidence to support the utility of botulinum toxin type A (BoNT-A) in the prophylaxis of episodic and chronic migraine headache. However, the patient characteristics and injection strategies that predict a favorable treatment response are unknown. We conducted a prospective, open-label study on 74 patients from our clinic receiving BoNT-A for episodic or chronic migraine. For all patients, migraine-related disability (Migraine Disability Assesment [MIDAS]), headache frequency, and average headache intensity were obtained at baseline and at 3 months post-BoNT-A. Information regarding demographic characteristics and injection parameters was also collected. Sixty-one patients met the study criteria and were available for 3-month follow-up. At the 3-month follow-up visit, the mean MIDAS scores of the 61 qualified study patients had decreased from 102 at baseline to 49 (52% decrease, P<.001). The mean number of headache days was reduced from 60 to 39 (P<.001), and the mean headache intensity decreased from 7.6 at baseline to 5.9 (P<.001). Frequency of migraine attacks, presence of analgesic overuse, total BoNT-A dose, and presence of underlying muscle tenderness were not predictive of treatment response. Age and duration of migraine were the only clinical factors significantly predictive of treatment response. Age likely was a predictor only as a consequence of duration of illness as subjects with migraine duration greater than 30 years were significantly less likely to respond to treatment with BoNT-A. BoNT-A may be effective in decreasing headache frequency, headache intensity, and headache-related disability in episodic and chronic migraine patients. Duration of illness emerged as a predictor of treatment response. Randomized controlled studies should evaluate headache-related disability as a primary endpoint in patients with episodic and chronic headache.

IntroductionChronic migraine is particularly devastating. It affects school work, extracurricular activities, and quality of life, including relationships with other family members, and can also influence the mental health of both the migraineurs and family members. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), chronic migraine is defined as 15 or more headache days per month for greater than three months, where at least on eight days per month, there are features of migraine headache. Although botulinum toxin type A (BoNTA) has been proven effective for treating chronic migraine in adults, little literature exists about its use in children. Here, we present the treatment response in children with chronic migraines treated with BoNTA at our institutions Duke and State University of New York (SUNY) Upstate.MethodA retrospective analysis of 30 adolescent migraineurs who met ICHD-3 criteria for chronic migraine were treated with BoNTA injection according to the standardized adult protocol. Descriptive statistics and paired t-tests were performed. A total of 185 units of botulinum toxin were injected intramuscularly per patient, as in addition to the standard 31 sites for a total of 155 units, an additional 30 units were given in areas that were felt to provide further benefit.ResultsParticipants (n=30) were 16.5 ± 1.83 years old. The headaches were precipitated by trauma in seven cases. All had failed standard pharmacotherapy, including amitriptyline and topiramate. An average of 2.47 ± 1.6 BoNTA injection cycles was performed. Migraine severity decreased significantly from 7.47 ± 1.89 on a 10-point scale to 4.34 ± 3.02 (p<.001). Additionally, headache frequency improved from 24.4 ± 7.49 painful days per month to 14.8 ± 12.52 painful days per month (p<.001). One patient developed nausea related to injections; all others tolerated it well, with no side effects.DiscussionBoNTA injection was a safe and effective therapy for chronic migraine in our cohort of children recalcitrant to medical therapy. Further research with multi-centered, double-blinded, randomized, placebo-controlled trials is warranted to evaluate the long-term safety and efficacy in this population.

Which Preparation of Botulinum Toxin A Should Be Used, Where Should It Be Injected, and How Should Its Efficacy Be Assessed?

Introduction: Nowadays, botulinum toxin has found use in many disease entities such as chronic migraine, spasticity, bruxism and many others. Among serotypes A-E, type A is mainly used in treatment. For the therapeutic effect to be maintained, injections need to be repeated most often after 12 weeks. More frequent injections of the toxin may result in the production of neutralizing antibodies. Aim of the study: The aim was to collect and analyze publications of application of botulinum toxin type A (BT-A) in the treatment of chronic migraine, spasticity and bruxism. Methods and materials: We reviewed the literature available in the PubMed database using the key words: “botulinum toxin”; “migraine”; “spasticity”; “bruxism”. Results: The use of botulinum toxin type A in patients with chronic migraine reduces the frequency of pain episodes and alleviates the symptoms. BT-A therapy reduces increased muscle tension, resulting in improved function of the upper or lower limb, facilitating the rehabilitation process, reducing pain associated with spasticity and protecting against the development of muscle contractures and secondary joint deformities. BT-A treatment of patients with bruxism reduces the level of pain and the maximum generated bite force, resulting in an improved quality of life for patients. Conclusion: Intramuscular administration of botulinum toxin is a safe, effective and minimally invasive method of treating chronic migraine, spasticity and bruxism. The botulinum toxin type A is the most studied serotype used for therapeutic purposes. Future research on botulinum toxin will certainly allow wider use.

Botulinum toxin has been shown to effectively treat several types of pain associated with neurologic disorders. It has recently been evaluated for the treatment of various types of headaches. In studies of migraine headache, chronic daily headache (more than 15 days of headache per month), tension-type headache, and post-whiplash headache, patients have reported decreased pain after treatment with botulinum toxin type A. A more recently available preparation, botulinum toxin type B, has also been shown to provide relief to patients with transformed migraine headache and post-whiplash headache. Additional study is under way to determine the effectiveness of botulinum toxin for the treatment of chronic cluster headaches. Although the pathophysiology of headache is incompletely understood, muscle tension may trigger or aggravate migraine headaches. Botulinum toxin, which reduces muscle hyperactivity, may reduce headache pain by decreasing muscle tension. It may also provide peripheral and central neurogenic effects and reduce inflammation. Large, rigorously controlled trials of botulinum toxin are needed to better characterize its effects on various types of headaches and its role as a therapeutic agent. Current data suggest that botulinum toxin is safe and does not produce systemic effects associated with other types of headache treatments.

Botulinum toxin Type A (BoNTA) is a successful treatment for chronic migraine prophylaxis. We aimed to evaluate the monthly change of effectiveness of BoNTA treatment. A total of 80 patients (70 females and 10 males) with chronic migraine were included. In our study protocol, we applied to 155 U across 31 fixed-sites and if the patient had pain, 40 U dose injections were applied across 8 specific head/neck muscle areas. Headache days and analgesic intake were noted before the BoNTA injection and during the interviews at the first, second, and third months after the BoNTA injection. The mean age was 37.59 ± 7.60 and 87.5% of the patients were female. The mean number of headache days/month before BoNTA was 18.95±2.69, decreasing to 10.55±3.15 days/month in the first month (p<0.001), 9.31±2.43 days/month in the second month (p<0.001), and increased to 11.97±3.27 days/month in the third month (p<0.001). The mean analgesic intake before BoNTA was 11.48±4.68 tablets/month, while it decreased to 6.53±2.72 tablets/month in the first month (p<0.001) and 5.40±2.46 tablets/month in the second month (p<0.001). In the third month, it was 5.85±2.59 tablets/month (p<0.001). There was a significant increase in pain medication use from the second to the third month (p<0.001). In our study, there was a significant reduction in analgesic intake and headache days in the first and second months after BoNTA injection, and an increase was observed in the third month.

To evaluate predictors of response to botulinum toxin type A (BoNTA; BOTOX, Allergan Inc., Irvine, CA, USA) in patients with chronic daily headache (CDH). Chronic migraine (CM) and chronic tension-type headache (CTTH) form the majority of CDH disorders. Controlled trials indicate that BoNTAis effective in reducing the frequency of headache and number of headache days in patients with CDH disorders. A recent migraine study found that patients with imploding or ocular types of headaches were responders to BoNTA, whereas those with exploding headaches were not. To date, there are no data on factors that might predict response to BoNTA in patients with CDH. A total of 71 patients with CM and 11 patients with CTTH were treated with 100 units BoNTA. Every patient received at least 2 sets of injections at intervals of 12-15 weeks; fixed sites, fixed dose, and "follow-the-pain" approaches were used for the injections. A detailed medical history was taken for each patient in addition to recording Migraine Disability Assessment Scale (MIDAS) scores at baseline and every 3 months after each set of injections. Headache frequency was assessed throughout the study from baseline to weeks 24-27. Patients recorded the frequency, severity, and duration of headaches in Headache Diaries. Patients were divided into responders (> or = 50% reduction in both headache frequency and MIDAS scores compared with baseline) and nonresponders (< 50% reduction in either of the above variables). Variables analyzed for predictors of response include headache that is predominantly unilateral or bilateral in location, presence of cutaneous allodynia (scalp allodynia), and presence of pericranial muscle tenderness (also referred to as muscle allodynia). Chi-square analysis was used for parallel-group comparisons (proportion of CM responders vs proportion of CM nonresponders and proportion of CTTH responders vs proportion of CTTH nonresponders). In the CM group, 76.1% (54 /71) of patients were responders to BoNTA, of which 68.5% (37/54) had headache that was predominantly unilateral in location and the remaining 31.5% (17/54) had headache that was predominantly bilateral in location (both P < .01 vs CM nonresponders). Of the 23.9% (17/71) CM nonresponders, 76.5% (13/17) reported predominantly bilateral headache and in the remaining 23.5% (4/17) the headache was unilateral. In the CM responders group, 81.5% (44/54) had clinically detectable scalp allodynia, while pericranial muscle tenderness was present in 61.1% (33/54) (both P < .01 vs CM nonresponders). The presence of scalp allodynia and pericranial muscle tenderness in the CM nonresponders was 11.8% (2/17) and 17.6% (3/17), respectively. In the CTTH group where all patients (100%, 11/11) had bilateral headache, 36.4% (4/11) of patients were responders to BoNTA. All of those CTTH responders (100%, 4/4) had pericranial muscle tenderness (P < .05 vs CTTH nonresponders). None of the CTTH nonresponders had pericranial muscle tenderness. No clinically significant serious adverse events (AEs) were reported. Mild AEs, eg, injection-site pain that persisted for 1-9 days, were reported in 11 patients. One patient had transient brow ptosis. A greater percentage of patients with CM responded to BoNTA than patients with CTTH. Headaches that were predominantly unilateral in location, presence of scalp allodynia, and pericranial muscle tenderness appear to be predictors of response to BoNTA in CM, whereas in CTTH, pericranial muscle tenderness may be a predictor of response.