Triptan use in elderly over 65 years and the risk of hospitalization for serious vascular events.

BACKGROUND: Several studies have focused on the use of triptan and the risk of acute vascular events but the existence of such association is still debated and has never been quantified in patients over 65 years. To assess whether triptan use among older is associated with an increased risk of hospitalization for acute vascular events. METHODS: A propensity score-matched cohort study was designed using the French national health insurance database linked to hospital stays. Patients aged ≥ 65 years, newly treated by triptans between 2011 and 2014, were included… The primary event was hospitalization for an acute ischemic vascular event within de 90 days following triptan initiation. Association with triptan exposure was investigated through cox regression model, considering exposure at inclusion, and with exposure as a time-varying variable A case-crossover (CCO) and a self-controlled case series (SCCS) analyses were also conducted to address potential residual confounding. RESULTS: The cohort included 24, 774 triptan users and 99 096 propensity matched controls (mean (SD) age: 71 years (5.9), 74% of women). Within 90 days after cohort entry, 163 events were observed in the triptan group, and 523 in the control group (0.66% vs. 0.53%, adjusted hazard ratio (aHR) exposed/not exposed 1.25 95%CI [1.05-1.49]; aHR time-varying 8.74 [5.21-14.66]). The association was significant (CCO) for all events (adjusted odds ratio (aOR1.63 [1.22-2.19]) with a more consistent association with cerebral events (aOR 2.14 [1.26-3.63]). The relative incidence (RI) for all events was 2.13 [1.76-2.58] in the SCCS, for cardiac (RI: 1.67 [1.23-2.27]) and for cerebral events (RI: 3.20, [2.30-4.45]). CONCLUSION: The incidence of acute vascular events was low among triptan users. We found that triptan use among older may be associated with a low increased risk for acute vascular events, which may be more marked for cerebral events such as stroke, than for cardiac events.

Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study.

BACKGROUND: Migraine is a disabling neurological disease adversely affecting many aspects of life. Most patients are still required to have failed several older oral preventive therapies before being reimbursed for a preventive, migraine-specific anti-calcitonin gene-related peptide treatment. In the 24-week placebo-controlled portion of DELIVER, eptinezumab was shown to reduce migraine frequency and resulted in higher migraine responder rates compared with placebo in patients with two to four previous preventive treatment failures. This subgroup analysis assessed if demographic or clinical characteristics were associated with differences in preventive benefits. METHODS: Migraine frequency reductions and responder rates (i.e., the proportion of patients reaching a ≥50% and ≥75% reduction in monthly migraine days relative to baseline) were determined in the total population and predefined subgroups by sex, age, migraine frequency (chronic migraine, episodic migraine, high-frequency episodic migraine, low-frequency episodic migraine), medication overuse, medication-overuse headache, and previous preventive treatment failures (2, >2). The primary endpoint was change from baseline in monthly migraine days over weeks 1-12. RESULTS: Eptinezumab 100 and 300 mg reduced monthly migraine days more than placebo over weeks 1-12 (-4.8 and -5.3 vs -2.1, respectively; p < 0.0001). In most subgroups, eptinezumab-treated patients demonstrated larger monthly migraine days reductions from baseline over weeks 1-12 than patients receiving placebo, with reductions maintained or increased over weeks 13-24. For ≥50% and ≥75% migraine responder rates, the odds ratios versus placebo all numerically favored eptinezumab. CONCLUSION: Eptinezumab had larger monthly migraine days reductions and higher responder rates than placebo across clinically relevant subgroups showing that, across different demographic populations and clinical characteristics, eptinezumab is effective in patients with migraine and prior preventive treatment failures.Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765).

Chronic Migraine Epidemiology and Outcomes - International (CaMEO-I) Study: Methods and multi-country baseline findings for diagnosis rates and care.

BACKGROUND: The Chronic Migraine Epidemiology and Outcomes-International study provides insight into people with migraine in multiple countries. METHODS: This cross-sectional, observational, web-based cohort study was conducted in Canada, France, Germany, Japan, United Kingdom, and United States. An initial Screening Module survey solicited general healthcare information from a representative sample and identified participants with migraine based on modified International Classification of Headache Disorders-3 criteria; those with migraine completed a detailed survey based on validated migraine-specific assessments. RESULTS: Among 90,613 people who correctly completed the screening surveys, 76,121 respondents did not meet the criteria for migraine, while 14,492 did. Among respondents with migraine, mean age ranged from 40 to 42 years. The median number of monthly headache days ranged from 2.33 to 3.33 across countries, while the proportion of respondents with moderate-to-severe disability (measured by Migraine Disability Assessment) ranged from 30% (Japan) to 52% (Germany). The proportion of respondents with ≥15 monthly headache days ranged from 5.4% (France) to 9.5% (Japan). Fewer than half of respondents with migraine in each country reported having received a migraine diagnosis. CONCLUSION: These results demonstrated high rates of migraine-related disability and underdiagnosis of migraine across six countries. This study will characterize country-level burden, treatment patterns, and geographical differences in care.

Occipital Nerve Stimulation for Recurrent Trigeminal Neuralgia Without Occipital Pain.

OBJECTIVES: Trigeminal neuralgia (TN) is a severe, debilitating pain condition causing physical and emotional distress. Although the management of TN is well codified with medical and then surgical treatments, 15% to 30% of patients will experience intractable pain. Neuromodulation techniques have been scarcely used for refractory TN, with only small case series and short-term follow-up. MATERIALS AND METHODS: We conducted a retrospective study of patients treated with occipital nerve stimulation (ONS) for medically and surgically resistant TN without painful trigeminal neuropathy. The effectiveness of the ONS was evaluated using the Barrow Neurological Institute (BNI) pain score and the pain relief (0%-100%) at best and at last follow-up. RESULTS: Seven patients who have refractory TN were included. The mean age at ONS was 49 years. The mean pain duration was 8.6 years. The mean number of medical and surgical treatments before ONS was six and five, respectively. A percutaneous trial was performed in five of seven patients; all responded (pain relief > 40%), and four of five patients experienced pain recurrence after explantation. Eventually, six patients had a permanent ONS implantation. The average BNI pain score before implantation was V. The mean follow-up after implantation was 59 months. All patients reported an improvement after implantation. The average BNI score and mean pain relief at best were IIIa and 86.7%, respectively. At last follow-up, the average BNI score and mean pain relief were IIIa and 58.0%, respectively, with three patients experiencing pain recurrence. Adverse events were reported for four patients who required surgical revision for lead breakage (1), erosion (1), migration (1), or hardware-related discomfort (1). One patient finally underwent explantation because of infection. CONCLUSIONS: Although ONS is not validated in this indication, these results suggest that it can induce an improvement in TN recurring after several surgical treatments, and the benefit of the stimulation can be sustained in the long term. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT01842763.

Pre- and post-headache phases of migraine: multi-country results from the CaMEO - International Study.

BACKGROUND: Individuals with migraine frequently experience pre- and post-headache symptoms. This analysis aimed to characterize the relative frequency and burden of pre- and post-headache symptoms in people with migraine using data collected through the Chronic Migraine Epidemiology and Outcomes - International Study. METHODS: This cross-sectional, observational, web-based survey was conducted in 2021-2022 in Canada, France, Germany, Japan, the United Kingdom, and the United States. Respondents who met modified International Classification of Headache Disorders, 3rd edition, criteria were offered the opportunity to participate. Information collected included migraine-related disability, depression/anxiety symptoms, cutaneous allodynia, activity limitations, and acute treatment optimization. Respondents indicated how often they had pre- or post-headache symptoms using a 5-point scale, ranging from 0 to 4, with a rating of 2 or higher classified as a pre- or post-headache symptom case. Modeling was used to examine relationships with monthly headache days (MHDs) and activity limitations during pre-headache and post-headache phases. RESULTS: Among a total of 14,492 respondents, pre-headache symptoms were reported by 66.9%, while post-headache symptoms were reported by 60.2%. Both pre-headache and post-headache symptoms were reported by 49.5% of respondents, only pre-headache by 17.4%, only post-headache by 10.7%, and neither pre- nor post-headache symptoms by 22.4%. Compared with respondents who experienced only pre- or post-headache symptoms, respondents who experienced both pre- and post-headache symptoms had the highest rates of 4-7, 8-14, and ≥ 15 monthly headache days (23.1%, 14.1%, and 10.9%, respectively). Of respondents with both pre- and post-headache symptoms, 58.5% reported moderate-to-severe disability, 47.7% reported clinically significant symptoms of depression, 49.0% reported clinically significant symptoms of anxiety, and 63.8% reported cutaneous allodynia with headache (ASC-12). Moderate-to-severe activity limitations were reported during the pre-headache (29.5%) and post-headache phases (27.2%). For all outcomes modeled, after controlling for covariates, having pre-headache symptoms, post-headache symptoms, or both were associated with worse outcomes than having neither. CONCLUSIONS: Pre- and post-headache phases of migraine are common, carry unrecognized burden, and may be a target for treatment.

Radiosurgery for classical trigeminal neuralgia: impact of the shot size on clinical outcome.

BACKGROUND: This study compares the outcome of patients suffering from medically refractory classical trigeminal neuralgia (TN) after treatment with radiosurgery using two different shot sizes (5- and 6-mm). METHODS: All patients included in this open, prospective, non-controlled study were treated in a single institution for TN (95 cases in 93 patients) with LINear ACcelerators (LINAC) single-dose radiosurgery using a 5-mm shot (43 cases) or 6-mm shot (52 cases). The target was positioned on the intracisternal part of the trigeminal nerve. RESULTS: The mean Dmax (D0.035) to the brainstem was higher in the 6-mm group: 12.6 vs 21.3 Gy (p < 0.001). Pain relief was significantly better in the 6-mm group: at 12 and 24 months in the 6-mm group the rate of pain-free patients was 90.2 and 87.8%, respectively vs. 73.6 and 73.6% in the 5-mm group (p = 0.045). At 12 and 24 months post-radiosurgical hypoesthesia was more frequent in the 6-mm group: 47.0 and 58% vs.11.3 and 30.8% in the 5-mm group (p = 0.002). To investigate the effect of cone diameter and the dose to the brainstem on outcomes, patients were stratified into three groups: group 1 = 5-mm shot, (all Dmax < 25 Gy, 43 cases), group 2 = 6-mm shot, Dmax < 25 Gy (32 cases), group 3 = 6-mm shot Dmax > 25 Gy (20 cases). At 12 months the rates of hypoesthesia were 11.3, 33.5 and 76.0%, respectively in groups 1, 2 and 3 (p < 0.001) and the rates of recurrence of pain were 26.4, 16.5 and 5%, respectively, (p = 0.11). CONCLUSION: LINAC treatment with a 6-mm shot provided excellent control of pain, but increased the rate of trigeminal nerve dysfunction, especially when the maximum dose to the brainstem was higher than 25 Gy.

Two-year efficacy and safety of erenumab in participants with episodic migraine and 2-4 prior preventive treatment failures: results from the LIBERTY study.

OBJECTIVE: To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed. METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability. RESULTS: Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain. CONCLUSIONS: Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. TRIAL REGISTRATION NUMBER: NCT03096834.

Effectiveness of onabotulinumtoxinA (BOTOX®) for the preventive treatment of chronic migraine: A meta-analysis on 10 years of real-world data.

BACKGROUND: This meta-analysis evaluated the real-world effectiveness of onabotulinumtoxinA (BOTOX®), the first preventive treatment FDA-approved specifically for chronic migraine in 2010. METHODS: We systematically reviewed onabotulinumtoxinA observational data in chronic migraine published between 1 January 2010 and 31 March 2021. Random-effects models evaluated available data for primary and secondary endpoints defined in onabotulinumtoxinA pivotal trials at approximately 24 weeks and 52 weeks. RESULTS: Of the 44 full-text eligible studies (29 prospective; 13 retrospective; 2 other), seven evaluated change from baseline (mean[confidence interval]) at ∼24 weeks and ∼52 weeks, respectively, for onabotulinumtoxinA in: number of headache days/month: (-10.64 [-12.31, -8.97]; -10.32 [-14.92, -5.73]); number of days of acute headache pain medication intake per month (-7.40 [-13.04, -1.77]; overlapping CIs at 52 weeks); total Headache Impact Test-6 score (-11.70 [-13.86, -9.54]); -11.80 [14.70, -8.90]); and Migraine-Specific Quality-of-Life v2.1 score (MSQ; 23.60 [CI: 21.56, 25.64]; 30.90 [CI: 28.29, 33.51]). At ∼24 weeks onabotulinumtoxinA showed total Migraine Disability Assessment score of 44.74 [28.50, 60.99] and ≥50% reduction in migraine days response rate of 46.57% [29.50%, 63.65%]. A sensitivity analysis at study-end suggested durability of onabotulinumtoxinA effectiveness on MSQ. CONCLUSION: The meta-analysis reflecting real-world practice broadly corroborated with evidence from pivotal and long-term open-label studies of onabotulinumtoxinA in chronic migraine preventive treatment.

Calcitonin gene-related peptide-targeting drugs and Raynaud's phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database.

BACKGROUND: Migraine is responsible for significant disability and societal burden. Recently, drugs targeting the calcitonin gene-related peptide (CGRP) pathway raised new hopes. CGRP, a potent vasodilator, plays a key role in the pathogenesis of migraine attacks. The deficiency of CGRP is involved in Raynaud's phenomenon, which consists of abnormal vasoconstriction of the digits. We aimed to assess the potential association of Raynaud's phenomenon with CGRP-targeting drugs, analyzing real-world data from the World Health Organization (VigiBase®). METHODS: We queried all reports of Raynaud's phenomenon involving a CGRP-targeting drug. We sought disproportionate reporting of Raynaud's phenomenon with these drugs. For this purpose, we relied on the calculation of the Information Component (IC). A positive lower end of the 95% confidence interval (CI) of the IC defines a statistically significant association. As migraine patients are prone to Raynaud's phenomenon, we also calculated the IC of Raynaud's phenomenon with CGRP-targeting drugs compared to 5HT1B/D agonists (triptans), and beta-blockers used in the treatment of migraine. RESULTS: Overall, 99 reports of Raynaud's phenomenon involving CGRP-targeting drugs have been yielded in VigiBase®. The most reported CGRP-targeting drug was erenumab, with 56 reports (56.6%). The median time to onset was 84 days. No fatality was notified, but one patient suffered from gangrene and extremity necrosis. As a whole, CGRP-targeting drugs were significantly associated with Raynaud's phenomenon, with an IC of 3.3 (95%CI: 3.0-3.5). There was a disproportionate reporting of Raynaud's phenomenon with CGRP-targeting drugs compared to triptans (IC 0.4; 95%CI: 0.1-0.6) and to beta-blockers (IC 0.5; 95%CI: 0.2-0.7) as well. CONCLUSIONS: There is a significant disproportionality signal of Raynaud's phenomenon with CGRP-targeting. This signal stands out when CGRP-targeting drugs are compared to other drugs used in patients with migraine. This study is limited by missing data in pharmacovigilance reports. CGRP-targeting drugs may be subject to Weber effect and reporting bias. Nonetheless, CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynaud's phenomenon. Pending further data regarding vascular safety of CGRP-targeting drugs, caution is warranted in these patients.

Effect of erenumab on functional outcomes in patients with episodic migraine in whom 2-4 preventives were not useful: results from the LIBERTY study.

OBJECTIVE: To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study. METHODS: As previously reported, 246 patients with EM with 2-4 prior failed preventives were randomised 1:1 to subcutaneous erenumab 140 mg or placebo every 4 weeks for 12 weeks. This analysis evaluated Migraine Physical Function Impact Diary (MPFID), Headache Impact Test (HIT-6) and Work Productivity and Activity Impairment (WPAI) scores at Week 12. P values were nominal without multiplicity adjustment. RESULTS: Erenumab significantly improved MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores versus placebo (treatment difference (TD) (95% CI) MPFID-PI: -3.5 (-5.7 to -1.2) (p=0.003); MPFID-EA: -3.9 (-6.1 to -1.7)) (p<0.001) at 12 weeks. Patients on erenumab were more likely to have a ≥5-point reduction in MPFID score (OR vs placebo (95% CI) MPFID-EA: 2.1 (1.2 to 3.6); MPFID-PI: 2.5 (1.4 to 4.5)). A similar trend was observed for HIT-6 (TD: -3.0; p<0.001); significantly higher proportions of patients on erenumab reported a ≥5-point reduction (OR (95% CI): 2.4 (1.4 to 4.1)). In three out of four WPAI domains, erenumab showed improvement versus placebo. CONCLUSION: At 12 weeks, erenumab was efficacious on functional outcomes in patients with EM in whom 2-4 preventives were not useful. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov identifier: NCT03096834.

Health technology assessment for the acute and preventive treatment of migraine: A position statement of the International Headache Society.

The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments.

Real-Life Management Pathways for Chronic Peripheral Neuropathic Pain at Tertiary Pain Clinics in France.

OBJECTIVE: Peripheral neuropathic pain (PNP) represents a major public health issue. Severe or refractory cases warrant tertiary multidisciplinary management, but little information is available about real-life care pathways. The primary objective of this cross-sectional, observational study was to investigate the pathways of patients with PNP consulting for the first time or followed for less than 1 year in French tertiary specialized pain clinics. METHODS: PNP was diagnosed with the NeuPSIG algorithm. Data collected included demographics, pain characteristics, and details of management before and after the study visit (e.g., drug and non-drug treatment, nature of medical visits), as well as time to referral to a pain clinic and time to a diagnosis of PNP. Factors associated with delayed referral or diagnosis were analyzed with multivariate analysis. RESULTS: A total of 404 patients with PNP (age 55.8 ± 15.6 years, 60.3% females, 78.3% retired or unemployed, pain duration 43.4 ± 68.9 months) were enrolled by 84 pain specialists. Pain affected mainly the lower limbs (53.5%) and was predominantly related to surgery or trauma (59.4%). Primary care management was characterized by a high proportion of conventional analgesics (60.7%). Time to referral to a pain clinic was 43.4 ± 68.9 months since pain onset and 20.1 ± 39.4 months since the diagnosis of PNP. Delayed referral to a pain clinic was independently predicted by the clinical specialty of the referring doctor and by male gender. CONCLUSIONS: This study highlights the need for accessible guidance for non-pain specialists to improve their diagnostic and management skills and for faster referral of patients with PNP to tertiary pain clinics.

Occipital Nerve Stimulation for Refractory Chronic Cluster Headache: A Cost-Effectiveness Study.

INTRODUCTION: Occipital nerve stimulation (ONS) is proposed to treat refractory chronic cluster headache (rCCH), but its cost-effectiveness has not been evaluated, limiting its diffusion and reimbursement. MATERIALS AND METHODS: We performed a before-and-after economic study, from data collected prospectively in a nation-wide registry. We compared the cost-effectiveness of ONS associated with conventional treatment (intervention and postintervention period) to conventional treatment alone (preintervention period) in the same patients. The analysis was conducted on 76 rCCH patients from the French healthcare perspective at three months, then one year by extrapolation. Because of the impact of the disease on patient activity, indirect cost, such as sick leave and disability leave, was assessed second. RESULTS: The average total cost for three months was €7602 higher for the ONS strategy compared to conventional strategy with a gain of 0.07 quality-adjusted life-years (QALY), the incremental cost-effectiveness ratio (ICER) was then €109,676/QALY gained. The average extrapolated total cost for one year was €1344 lower for the ONS strategy (p = 0.5444) with a gain of 0.28 QALY (p < 0.0001), the ICER was then €-4846/QALY gained. The scatter plot of the probabilistic bootstrapping had 80% of the replications in the bottom right-hand quadrant, indicating that the ONS strategy is dominant. The average indirect cost for three months was €377 lower for the ONS strategy (p = 0.1261). DISCUSSION: This ONS cost-effectiveness study highlighted the limitations of a short-time horizon in an economic study that may lead the healthcare authorities to reject an innovative strategy, which is actually cost-effective. One-year extrapolation was the proposed solution to obtain results on which healthcare authorities can base their decisions. CONCLUSION: Considering the burden of rCCH and the efficacy and safety of ONS, the demonstration that ONS is dominant should help its diffusion, validation, and reimbursement by health authorities in this severely disabled population.

How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p < 0.0001). CONCLUSION: The ESTIMET study confirms the significant benefit experienced on chronic BP by patients implanted with multicolumn SCS, independently from multicolumn lead programming. These good clinical outcomes might result from the specific architecture of the multicolumn lead, giving the opportunity to select initially the best column on a multicolumn grid and to optimize neural targeting with low-energy requirements. However, involving more columns than one does not appear necessary, once initial spatial targeting of the "sweet spot" has been achieved. Our findings suggest that this spatial concept could also be transposed to cylindrical leads, which have drastically improved their capability to shape the electrical field, and might be combined with temporal resolution using SCS new modalities.

Severe migraine and its control: A proposal for definitions and consequences for care.

Currently many patients with severe migraine do not receive appropriate treatment and are never referred to specialist headache centres. On the other hand, specialist headache centres are frequently attended by patients whose migraines could be managed adequately in the community. One reason for this may be the absence of standardised definitions of migraine severity and control and of a treatment algorithm for orientating difficult-to-treat patients to specialist headache centres. Based on a review of the relevant literature and consensus meetings, proposals have been made for these items. We propose that migraine should be considered severe if headache frequency is at least eight migraine days per month or, if headaches are less frequent, the HIT-6 score is ≥60 or ≥50% of headaches require complete interruption of activity. The proposed definition of migraine control is defined on the basis of appropriate response to acute headache therapy and to preventative therapy. A treatment algorithm is proposed to assess migraine control regularly and to adapt therapy accordingly. These proposals may contribute to developing and testing strategies for management of severe disease with appropriate and effective preventive treatment strategies. With the anticipated introduction of new possibilities for migraine prevention in the near future, the time is ripe for a holistic approach to migraine management.

21st century headache: mapping new territory.

BACKGROUND: With headache experienced by up to 75% of adults worldwide in the last year, primary headache disorders constitute a major public health problem, yet they remain under-diagnosed and under-treated. Headache prevalence and burden is changing as society evolves, with headache now occurring earlier in life. Contributing factors, mostly associated with changing life style, such as stress, bad posture, physical inactivity, sleep disturbance, poor diet and excess use of digital technology may be associated with the phenomenon that could be labelled as '21st century headache'. This is especially notable in workplace and learning environments where headache impacts mental clarity and therefore cognitive performance. The headache-related impact on productivity and absenteeism negatively influences an individual's behaviour and quality of life, and is also associated with a high economic cost. Since the majority of sufferers opt to self-treat rather than seek medical advice, substantial knowledge on headache prevalence, causation and burden is unknown globally. Mapping the entire population of headache sufferers can close this knowledge gap, leading to better headache management. The broad use of digital technology to gather real world data on headache triggers, burden and management strategies, in self-treated population will allow these sufferers to access appropriate support and medication, and therefore improve quality of life. CONCLUSION: These data can yield important insights into a substantial global healthcare issue and form the basis for improved patient awareness, professional education, clinical study design and drug development.

Neuromodulation techniques for acute and preventive migraine treatment: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Several neuromodulation methods exists for migraine treatment. The aim of the present study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on migraine treatment using neurostimulation methods. METHODS: We searched Medline and Embase up to July 1, 2020 for RCTs reporting acute or preventive treatment of migraine with either non-invasive or invasive neurostimulation methods. Two researchers independently assessed the eligibility of the retrieved studies and extracted data. Outcomes for the quantitative synthesis were 2 h pain free for acute treatment and headache days per month for preventive treatment. We performed subgroup analyses by treatment (stimulation method and site of application). Estimates were pooled using random-effects meta-analysis. RESULTS: Thirty-eight articles were included in the qualitative analysis (7 acute, 31 preventive) and 34 in the quantitative evaluation (6 acute, 28 preventive). Remote electrical neuromodulation (REN) was effective for acute treatment. Data were insufficient to draw conclusions for any other techniques (single studies). Invasive occipital nerve stimulation (ONS) was effective for migraine prevention, with a large effect size but considerable heterogeneity, whereas supra-orbital transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), and high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) were effective, with small to medium effect sizes. Vagus-nerve stimulation, left prefrontal cortex rTMS, and cathodal transcranial direct current stimulation (tDCS) over the M1 had no significant effect and heterogeneity was high. CONCLUSION: Several neuromodulation methods are of potential interest for migraine management, but the quality of the evidence is very poor. Future large and well-conducted studies are needed and could improve on the present results.

Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study.

BACKGROUND: A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful. METHODS: LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18-65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4-14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4-7 vs 8-14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9-12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing. FINDINGS: Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2·7 [95% CI 1·4-5·2]; p=0·002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups. INTERPRETATION: Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options. FUNDING: Novartis Pharma.

Dural and pial pain-sensitive structures in humans: new inputs from awake craniotomies.

Our knowledge on intracranial pain-sensitive structures in humans comes essentially from observations during neurosurgical procedures performed in awake patients. It is currently accepted that intracranial pain-sensitive structures are limited to the dura mater and its feeding vessels and that small cerebral vessels and pia mater are insensitive to pain, which is inconsistent with some neurosurgical observations during awake craniotomy procedures. We prospectively collected observations of painful events evoked by mechanical stimulation (touching, stretching, pressure, or aspiration) of intracranial structures during awake craniotomies, routinely performed for intraoperative functional mapping to tailor brain tumour resection in the eloquent area. Intraoperatively, data concerning the locations of pain-sensitive structures were drawn by the surgeon on a template and their corresponding referred pain was indicated by the patient by drawing a cross on a diagram representing the head. Ninety-three painful events were observed and collected in 53 different patients (mean age 41.2 years, 25 males) operated on awake craniotomy for left (44 cases) or right (nine cases) supra-tentorial tumour resection in eloquent areas. On average, 1.8 painful events were observed per patient (range 1-5). All the painful events were referred ipsilaterally to the stimulus. In all cases, the evoked pain was sharp, intense and brief, stopped immediately after termination of the causing action, and did not interfere with the continuation of the surgery. In 30 events, pain was induced by stimulation of the dura mater of the skull base (23 events) or of the falx (seven events) and was referred predominantly in the V1 territory and in the temporal region. In 61 cases, pain was elicited by mechanical stimulation of the pia mater or small cerebral vessels of the temporal (19 events), frontal (25 events), parietal (four events) lobes and/or the peri-sylvian region, including the insular lobe (13 events), and referred in the V1 territory. In this observational study, we confirmed that dura of the skull base and dura of the falx cerebri are sensitive to pain and that their mechanical stimulation induced pain mainly referred in the sensory territories of the V1 and V3 divisions of the trigeminal nerve. Unlike earlier studies, we observed that the pia and the small cerebral vessels were also pain-sensitive, as their mechanical stimulation induced pain referred mainly in the V1 territory. These observations suggest that small pial cerebral vessels may also be involved in the pathophysiology of primary and secondary headaches.awy005media15756834882001.

ARISE: A Phase 3 randomized trial of erenumab for episodic migraine.

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. Methods In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3. Results Patients receiving erenumab experienced -2.9 days change in monthly migraine days, compared with -1.8 days for placebo, least-squares mean (95% CI) treatment difference of -1.0 (-1.6, -0.5) ( p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) ( p = 0.010). Migraine-specific medication treatment days were reduced by -1.2 (erenumab) and -0.6 (placebo) days, a treatment difference of -0.6 (-1.0, -0.2) ( p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary - Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) ( p = 0.13) and in Migraine Physical Function Impact Diary - Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) ( p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis. Conclusions As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen). Trial registration ClinicalTrials.gov, NCT02483585.