Insights from 25 years of onabotulinumtoxinA in migraine - mechanisms and management.

OnabotulinumtoxinA (BTX-A) was first linked to beneficial effects in migraine 25 years ago and was approved by the FDA for preventive treatment of chronic migraine in 2010. The treatment has since had a major impact on the well-being of people with chronic migraine. The clinical development programme for BTX-A and research since its approval have provided insights into the neuromodulatory sensory effect of BTX-A, how it can control chronic migraine despite its peripheral action, and the underlying biology of migraine as a disease. In this Review, we consider the impact that BTX-A has had on the management of chronic migraine and on the research field. We discuss the insights provided by clinical research, encompassing the clinical trials and subsequent real-world evidence, and the mechanistic insights provided by preclinical and translational research. We also provide an overview of future directions of research in the field BTX-A in migraine and the clinical translation of this research.

Sustained benefits of onabotulinumtoxinA treatment in chronic migraine: An analysis of the pooled Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) randomized controlled trials.

OBJECTIVE: To characterize the long-term (56-week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. BACKGROUND: There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. METHODS: The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24-week, randomized, double-blind, placebo-controlled phase and a 32-week open-label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double-blind phase (Weeks 21-24; any 12 consecutive weeks; Weeks 13-24) and the entire study (Weeks 53-56; any 12 consecutive weeks; any 4-week period). We assessed the long-term impact on mean monthly headache days and changes from baseline on the six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2.1). RESULTS: We analyzed 1384 participants with chronic migraine (double-blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open-label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56-week treatment period for onabotulinumtoxinA and placebo were 25.4% (n = 175) and 29.3% (n = 204), respectively. During Weeks 13-24 of the double-blind phase, significantly more onabotulinumtoxinA-treated (386/688 [56.1%]) than placebo-treated (342/696 [49.1%]) individuals had <15 headache days/month (p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25-56, 81.1% (558/688) at Weeks 53-56, and 79.4% (546/688) during any consecutive 12-week period. Mean changes from baseline on the HIT-6 and MSQv2.1 questionnaire surpassed within-group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA-treated participants who achieved <15 monthly headache days during Weeks 21-24 had a greater mean HIT-6 score reduction (-6.5 vs. -1.4) and greater mean MSQv2.1 Role-Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. CONCLUSIONS: Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache-related disability and migraine-specific quality of life compared with those who remained at or above the 15-monthly headache days threshold. Sustained benefits observed over 56 weeks support long-term onabotulinumtoxinA use for the prevention of CM.

Clinical factors associated with day-to-day peak pain severity in individuals with chronic migraine: A cohort study using daily prospective diary data.

OBJECTIVE: To describe the association between day-to-day peak pain severity and clinical factors in individuals with chronic migraine (CM). BACKGROUND: Little is known about how clinical factors relate to day-to-day pain severity in individuals with CM. METHODS: Adults with CM were enrolled into this observational prospective cohort study that collected daily data about headache, associated symptoms, and lifestyle factors using a digital health platform (N1-Headache™) for 90 days. "Migraine days" were defined as days in which a headache occurred that had features described by the International Classification of Headache Disorders criteria. On these days, peak pain severity was recorded on a 4-point scale; on non-headache days peak pain severity was imputed as "0/none". The associations between peak pain severity and 12 clinical factors were modeled and adjusted for sex, age, daily headache, presence of menstrual bleeding, day of the week, and disability. All numerical and Likert scale variables were standardized prior to analysis. RESULTS: Data were available for 392 participants (35,280 tracked days). The sample was predominantly female (90.6%), with a mean (standard deviation) age of 39.9 (12.8) years. In the final multivariable model with random intercept and slopes, higher than typical self-reported levels of standardized stress (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.11), standardized irritability (OR 1.05, 95% CI 1.02-1.08), standardized sadness (OR 1.05, 95% CI 1.02-1.07), fatigue (OR 1.25, 95% CI 1.15-1.36), eyestrain (OR 1.38, 95% CI 1.26-1.52), neck pain (OR 1.94, 95% CI 1.76-2.13), skin sensitivity (OR 1.61, 95% CI 1.44-1.80), and dehydration (OR 1.29, 95% CI 1.18-1.42) were associated with higher reported peak pain severity levels, while standardized sleep quality (OR 0.96, 95% CI 0.93-0.99) and standardized waking feeling refreshed (OR 0.84, 95% CI 0.81-0.88) were associated with lower reported peak pain severity levels. The inclusion of a random intercept and random slopes improved upon more parsimonious models and illustrated large differences in individuals' reporting of peak severity according to the levels of the associated clinical factors. CONCLUSION: Our data showed that the experience of CM, from a pain severity perspective, is complex, related to multiple clinical variables, and highly individualized. These results suggest that future work should aim to study a personalized approach to both medical and behavioral interventions for CM based on which clinical factors relate to the individual's experience of pain severity.

Developments in targeting calcitonin gene-related peptide.

INTRODUCTION: Calcitonin Gene-Related Peptide (CGRP)-targeted therapy has revolutionized migraine treatment since its first approval in 2018. CGRP-targeted therapy includes monoclonal antibodies (mAbs) and gepants, which modulate trigeminal nociceptive and inflammatory responses, alleviating pain sensitization involved in migraine pathogenesis. CGRP-targeted therapy is effective not only for migraine but also for other chronic headache disorders that share the CGRP pathway. AREAS COVERED: The authors review the latest developments and evidence for CGRP-targeted therapy for episodic migraine and chronic migraine. In addition, the authors discuss the emerging evidence on response prediction, menstrual migraine, vestibular migraine, idiopathic intracranial hypertension, post-traumatic headache, and the relationship between selected migraine comorbidities and CGRP. EXPERT OPINION: Since the launch of CGRP-targeted therapy, many practical issues have been raised. Generally, it's safe to combine CGRP-targeted mAbs and gepants; this is an excellent option for patients with partial response. When considering stopping CGRP-targeted therapy, although a disease-modifying effect is likely, the optimal time for discontinuation remains unknown. Finally, beyond migraine, CGRP-targeted therapy may be used for other chronic pain disorders and psychological comorbidities.

How early can we treat migraine attacks? A perspective based on prodrome.

Treating migraine attacks early at the onset of a headache is a common proven strategy. But does this strategy work before headache onset? In the PRODROME trial, Dodick et al. showed that ubrogepant taken during the prodrome can prevent headache attacks and reduce functional disability.1.

Evidence-based preventive treatment of migraine.

The evidence base for migraine prevention in both episodic and chronic migraine is outlined. The older oral preventatives, including antidepressants, antihypertensives, serotonin antagonists, antiepileptics, and calcium channel antagonists, and newer options including onabotulinumtoxinA and the CGRP monoclonal antibodies are covered. Many of the older oral preventatives were trialed before chronic migraine was defined, and they are used in chronic migraine based on the assumption that episodic migraine and chronic migraine are on a spectrum of the same condition. First- and second-line options are given, and a multicountry perspective is considered.

Drug-Free Noninvasive Thermal Nerve Block: Validation of Sham Devices.

Headache is a leading cause of disability and suffering. One major challenge in developing device treatments is demonstrating their efficacy given devices' often-high placebo rate. This paper reviews the importance of validating sham devices as part of finalizing the design for larger-scale prospective randomized controlled trials in patients with chronic headache as well as the results of a prospective, single-blind trial to validate two potential sham noninvasive thermal nerve block devices. Study participants were trained to self-administer thermal nerve block treatment using sham devices in an office visit. Two different sham systems with different temperature profiles were assessed. Devices were offered for patients to use daily at-home for one week to assess the durability of sham placebo effects before participants were given active treatment in a second office visit followed by another optional week of self-administered active treatment at-home use. Sham treatments reduced pain scores by an average of 31% from 6.0 ± 2.3 to 4.3 ± 3.3, including two participants who fell asleep during the in-office treatment and woke up with no pain, but whose pain recurred after returning home during at-home use of the sham system. In-office active treatments reduced pain scores by 52% from 6.7 ± 2.1 to 3.3 ± 2.9 with sustained pain relief during optional at-home use. Successful blinding for the study was confirmed with an ideal Bang's Blinding Index of 0 and an ideal James' Blinding Index of 1. Both the sham and active treatments were viewed by participants as highly credible, and credibility increased from the beginning to end of sham treatments on average.

Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study.

BACKGROUND: Dihydroergotamine (DHE), like triptans, is contraindicated in patients with ischemic heart disease or coronary vasospasm. Its true safety, tolerability, and efficacy in patients with cardiovascular risk without ischemic heart disease or coronary vasospasm remain unclear. OBJECTIVES: To assess the safety, tolerability, and effectiveness of repetitive intravenous DHE in patients with cardiovascular risk factors. METHODS: A single-center, retrospective cohort study was conducted at the Jefferson Headache Center inpatient unit for refractory chronic migraine patients treated with our intravenous DHE protocol between January 1, 2019, and October 15, 2019. We evaluated tolerability and effectiveness outcomes based on atherosclerotic cardiovascular disease 10-year calculated risk scores, stratified into low (<5.0%) and elevated (≥5.0%) risk. Data were presented in mean ± standard deviation or median (25th percentile, 75th percentile) if non-normally distributed. RESULTS: Among 347 patients (median age of 46 [36, 57], female n = 278 [80.1%]), who received inpatient intravenous DHE, 227 patients (age 53 [45, 60], female 81.1%) had calculable risk scores, 64 (28.2%) had elevated risk, and 38 (16.7%) had cardiology consultations. There were no clinically significant electrocardiogram abnormalities or cardiovascular adverse events. The median hospital length of stay was 6 (5, 7) days. Compared to the low-risk group, those with elevated risk had higher nausea (31.3% vs. 14.1%, p = 0.008), but similar initial DHE dose (0.5 [0.25, 0.5] vs. 0.5 [0.25, 0.5], p = 0.009), lower final DHE dose (0.75 [0.5, 1] vs. 1 [0.75, 1] p < 0.001), and lower pain reduction after admission (-3.8 [2.1, 6] vs. -5 [3, 7] p = 0.037). CONCLUSION: Patients receiving intravenous DHE by the Jefferson Headache Center inpatient headache protocol had significantly reduced pain severity at discharge. No clinically significant cardiac or electrocardiogram abnormalities were detected in patients with elevated (or low) atherosclerotic cardiovascular disease risk. Repetitive intravenous DHE used by our protocol was safe in refractory chronic migraine patients.

Multimodal Migraine Management and the Pursuit of Migraine Freedom: A Narrative Review.

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associated symptoms and others accepting the occasional migraine attack if it does not impact functioning. Therefore, migraine management should be optimized so that patients can have the best opportunity to achieve their optimal treatment goals. With migraine freedom as a goal and, given the complex pathophysiology of migraine and the high incidence of comorbidities among individuals with migraine, treatment with a single modality may be insufficient, as it may not achieve migraine freedom in those with more frequent or disabling attacks. In this clinical perspective article, we have identified four key, partially overlapping principles of multimodal migraine treatment: (1) manage common comorbidities; (2) control modifiable risk factors for progression by addressing medication and caffeine overuse; (3) diagnose and treat secondary causes of headache, if present; and (4) individualize acute and preventive treatments to minimize pain, functional disability, and allodynia. There are many barriers to pursuing migraine freedom, and strategies to overcome them should be optimized. Migraine freedom should be an aspirational goal both at the individual attack level and for the disease overall. We believe that a comprehensive and multimodal approach that addresses all barriers people with migraine face could move patients closer to migraine freedom.

A Novel Virtual-Based Comprehensive Clinical Approach to Headache Care.

One major innovation, a result of the coronavirus pandemic, has been the proliferation of telemedicine. Telehealth can help solve the access problems that plague headache medicine, allowing patients in areas with no headache expertise to consult and work with a headache specialist. This is a retrospective chart review of patients seen by Neura Health, a comprehensive app-based telehealth headache center. Patients are seen by a specialist and, in addition to any medical recommendations, are given care plans individualized to their condition and recommendations at the end of their clinical appointments. The primary outcome of this study is a decrease in monthly headache days after 90 days; secondary outcomes include disability as determined by MIDAS score, depression determined by PHQ-9, patients' utilization of emergency department or urgent care resources, as well as their global impression of improvement. The deidentified outcomes of consecutive patients of Neura Health were evaluated from March 2022-March 2023. Subjects were excluded if they did not complete all forms, or if they did not receive a clinical or coaching follow-up appointment within 90 days. A total of 186 consecutive patients at Neura Health were identified during the review period. The median decrease in monthly headache days was 55.0% after a 90 day period, headache severity was decreased by 16.7%, global impression of improvement increased by 60.9%, disability decreased by 38.7%, depression decreased by 12.5% and ER/urgent care visits were decreased by 66.1%. A comprehensive, telehealth-based virtual headache-care model significantly decreased migraine frequency, severity and disability, and is able to decrease ER or urgent care visits.

Treatment of chronic migraine with Botox (onabotulinumtoxinA): Development, insights, and impact.

Chronic migraine (CM) is a neurological disease characterized by frequent migraine attacks that prevent affected individuals from performing daily activities of living, significantly diminish quality of life, and increase familial burden. Before onabotulinumtoxinA was approved for CM, there were few treatment options for these seriously disabled patients and none had regulatory approval. The terminology and recognition of CM evolved in parallel with the onabotulinumtoxinA clinical development program. Because there were no globally accepted classification criteria for CM when onabotulinumtoxinA was in development, the patient populations for the trials conducted by Allergan were determined by the Allergan migraine team in collaboration with headache scientists and clinicians. These trials and collaborations ultimately led to improvements in CM classifications. In 2010, onabotulinumtoxinA became the first medication and first biologic approved specifically to prevent headaches in patients with CM. Approval was based on 2 similarly designed phase 3, double-blind, randomized, placebo-controlled, multicenter clinical studies. Both studies showed significantly greater improvements in mean change from baseline in headache-day frequency in patients with CM receiving onabotulinumtoxinA compared with those receiving placebo. The safety and effectiveness of onabotulinumtoxinA have been established globally in >5000 patients with CM with or without medication overuse treated in clinical and observational studies. Benefits also include improvements in quality of life, fewer psychiatric comorbidities, and reduced healthcare resource utilization. Across studies, onabotulinumtoxinA was well tolerated; adverse events tended to be mild or moderate in severity and to decline over subsequent treatment cycles.

Celecoxib Oral Solution and the Benefits of Self-Microemulsifying Drug Delivery Systems (SMEDDS) Technology: A Narrative Review.

INTRODUCTION: The oral route of drug delivery is the most widespread and preferred route of administration, but it has several limitations, including variable pharmacokinetics (PK), reduced dissolution and absorption, and gastrointestinal irritation. Further, many compounds have low aqueous solubility, which also limits intestinal absorption. METHODS: For this narrative review, we conducted a literature search of PubMed until August 2022, focusing on emulsions, microemulsions, nanoemulsions, and self-emulsifying drug delivery systems. RESULTS: The self-microemulsifying drug delivery system (SMEDDS) overcomes these limitations of hydrophobic compounds to enhance their bioavailability. A SMEDDS formulation is a clear, thermodynamically stable, oil-in-water emulsion of lipid, solubilized drug, and two surfactants, which spontaneously forms droplets < 100 nm in diameter. These components help deliver presolubilized drugs to the gastrointestinal tract, while protecting them from degradation in gastric acid or first-pass hepatic metabolism. SMEDDS formulations have improved oral drug delivery in the treatment of cancer (paclitaxel), viral infections (ritonavir), and migraine headache (ibuprofen and celecoxib oral solution). The American Headache Society recently updated their consensus statement for the acute treatment of migraine and included a selective cyclo-oxygenase-2 selective inhibitor formulated in SMEDDS, celecoxib oral solution. This SMEDDS formulation showed pronounced improvement in bioavailability compared with celecoxib capsules, allowing for a low dose of celecoxib in the oral solution to provide safe and effective acute migraine treatment. Here, we will focus on SMEDDS formulations, what differentiates them from other analogous emulsions as vehicles for poorly soluble drugs, and their clinical application in the acute treatment of migraine. CONCLUSIONS: Oral drugs reformulated in SMEDDS have shown accelerated times to peak plasma drug concentrations and increased maximum plasma concentrations, compared with capsules, tablets, or suspensions. SMEDDS technology increases both drug absorption and bioavailability of lipophilic drugs, compared with other formulations. Clinically, this allows the use of lower doses with improved PK profiles without compromising efficacy, as shown with celecoxib oral solution for the acute treatment of migraine.

Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis.

OBJECTIVE: Assess the long-term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. BACKGROUND: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. METHODS: This 52-week open-label extension study followed a 12-week double-blind placebo-controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once-monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. RESULTS: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was -9.3 (95% confidence interval: -10.4, -8.1 days) in the medication overuse subgroup versus -9.3 (-10.1, -8.5 days) in the non-medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine-specific medication, the mean change in monthly migraine-specific medication days at Week 52 was -7.4 (-8.3, -6.4 days) in the medication overuse subgroup versus -5.4 (-6.1, -4.7 days) in the non-medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non-overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. CONCLUSION: Long-term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse.

Current and emerging pharmacotherapy for menstrual migraine: a narrative review.

INTRODUCTION: In this article, we discuss menstrual migraine (MM), which can be categorized as menstrually related migraine (MRM) or pure menstrual migraine (PMM). MM attacks are often longer, more severe, and harder to treat than other migraine attacks. Appropriate treatment strategies include acute treatment, short term preventive treatment, and daily preventive treatment, depending on the patient's pattern of migraine and occurrence of migraine outside the menstrual period. AREAS COVERED: A PubMed, Cochrane Library, Medline, and Ovid search from inception to October 2022 provided articles relating to MM pathophysiology and treatment. EXPERT OPINION: In patients for whom standard acute therapy is inadequate, short term or daily preventive treatment should be considered. Patients with PMM may be adequately managed with short term preventive treatment started 2 days prior to the onset of migraine and continued for 5-6 days. Frovatriptan is the mainstay of short-term prevention. Patients who experience additional attacks outside the menstrual period may benefit from daily preventive treatment. Estrogen-containing contraceptive treatment may be effective in appropriately selected patients. Emerging research on the pathophysiology of MM indicates that oxytocin agonists and CGRP antagonists may prove to be effective treatment options.

Adverse Events Reported with Therapies Targeting the CGRP Pathway During the First 6 Months Post-launch: A Retrospective Analysis Using the FDA Adverse Events Reporting System.

INTRODUCTION: Through 2018, three calcitonin gene-related peptide pathway-targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab. METHODS: This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA Adverse Event Reporting System (FAERS) safety surveillance database during the first 6 months post-approval of erenumab (May 2018 to November 2018), fremanezumab (September 2018 to March 2019), and galcanezumab (September 2018 to March 2019). Reporting rates (RR) per 1000 exposed patients were calculated from number of reported events (when product classified as "primary suspect") in each AE category and estimated number of treated patients based on de-identified prescription data (IQVIA database) and were ranked on the basis of frequency for each product. RESULTS: RR per 1000 exposed patients for "migraine" (erenumab, 4.89; fremanezumab, 1.01; galcanezumab, 2.99), "headache" (3.32, 1.27, 3.07), and "drug ineffective" (3.68, 1.14, 1.69) were commonly reported for all three products, as were migraine-associated symptoms ("nausea": 2.94, 0.91, 1.09) and "injection-site" reactions ("pain": 2.94, 0.8, 4.9; "swelling": 0.56, 0.53, 1.25; "pruritus": 0.26, 0.63, 1.14; "erythema": 0.58, 0.71, 1.58). "Constipation" ranked second for erenumab (4.90) but did not make the top ten events for fremanezumab (0.46) or galcanezumab (0.76); cardiovascular events did not rank in the top ten AEs for any product. The frequency of serious outcomes was low, with ≤ 2% of AEs categorized as serious across the CGRP mAbs. CONCLUSION: These results aid in supporting the safety profile of CGRP mAbs in the real-world setting and may provide clinicians and patients with additional insight when considering migraine preventive treatments.

Guidelines of the International Headache Society for Clinic-Based Headache Registries, 1st edition.

Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache.

Petasites for Migraine Prevention: New Data on Mode of Action, Pharmacology and Safety. A Narrative Review.

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45-90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.

Lidocaine infusions for refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Patients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly 'break the cycle' of pain. Lidocaine infusions may be effective but evidence is limited. METHODS: The records of 832 hospital admissions involving continuous multiday lidocaine infusions for migraine were reviewed. All patients met criteria for refractory chronic migraine. During hospitalization, patients received additional migraine medications including ketorolac, magnesium, dihydroergotamine, methylprednisolone, and neuroleptics. The primary outcome was change in headache pain from baseline to hospital discharge. Secondary outcomes measured at the post-discharge office visit (25-65 days after treatment) included headache pain and the number of headache days, and percentage of sustained responders. Percentage of acute responders, plasma lidocaine levels, and adverse drug effects were also determined. RESULTS: In total, 609 patient admissions met criteria. The mean age was 46±14 years; 81.1% were female. Median pain rating decreased from baseline of 7.0 (5.0-8.0) to 1.0 (0.0-3.0) at end of hospitalization (p<0.001); 87.8% of patients were acute responders. Average pain (N=261) remained below baseline at office visit 1 (5.5 (4.0-7.0); p<0.001). Forty-three percent of patients were sustained responders at 1 month. Headache days (N=266) decreased from 26.8±3.9 at baseline to 22.5±8.3 at the post-discharge office visit (p<0.001). Nausea and vomiting were the most common adverse drug effects and all were mild. CONCLUSION: Lidocaine infusions may be associated with short-term and medium-term pain relief in refractory chronic migraine. Prospective studies should confirm these results.

The Arrival of Anti-CGRP Monoclonal Antibodies in Migraine.

Remarkable advancements have been made in the field of migraine pathophysiology and pharmacotherapy over the past decade. Understanding the molecular mechanism of calcitonin gene-related peptide (CGRP) has led to the discovery of a novel class of drugs, CGRP functional blocking monoclonal antibodies (mAbs), for migraine prevention. CGRP is a neuropeptide inherently involved in migraine physiology where its receptors are found dispersed throughout the central and peripheral nervous systems. CGRP-targeted mAbs are effective in the preventive treatment of both chronic and episodic migraine. The advantages of mAbs over oral migraine preventives are numerous. Favorable attributes of the mAbs include high affinity and selectivity for CGRP molecular targets, long-circulating plasma half-lives, and limited risk for nonspecific hepatic and renal toxicity. This pharmacological profile leads to fewer off-target (side) effects and drug-drug interactions rendering mAbs an attractive alternative to traditional small molecule therapies, especially for the preventive treatment of migraine. MAbs display minimal drug interaction thus are excellent for patients prescribed with multiple medications. However, the long-term safety of CGRP blockade is incompletely known, and CGRP mAbs use should be avoided during pregnancy. CGRP mAbs represent a radical shift in preventing chronic and episodic migraine.