Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

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.

Somatotopy of the sensory thalamus: inputs from directional deep brain stimulation in pain patients.

OBJECTIVE: The sensory ventroposterior (VP) thalamic nuclei display a mediolateral somatotopic organization (respectively head, arm, and leg). We studied this somatotopy using directional VP deep brain stimulation (DBS) in patients treated for chronic neuropathic pain. METHODS: Six patients with central (four) or peripheral (two) neuropathic pain were treated by VP DBS using directional leads in a prospective study (clinicaltrials.gov NCT03399942). Lead-DBS toolbox was used for leads localization, visualization, and modeling of the volume of tissue activated (VTA). Stimulation was delivered in each direction, 1 month after surgery and correlated to the location of stimulation-induced paresthesias. The somatotopy was modeled by correlating the respective locations of paresthesias and VTAs. We recorded 48 distinct paresthesia maps corresponding to 48 VTAs (including 36 related to directional stimulation). RESULTS: We observed that, in each patient, respective body representations of the trunk, upper limb, lower limb, and head were closely located around the lead. These representations differed across patients, did not follow a common organization and were not concordant with the previously described somatotopic organization of the sensory thalamus. INTERPRETATION: Thalamic reorganization has been reported in chronic pain patients compared to non-pain patients operated for movement disorders in previous studies using intraoperative recordings and micro-stimulation. Using a different methodology, namely 3D representation of the VTA by the directional postoperative stimulation through a stationary electrode, our study brings additional arguments in favor of a reorganization of the VP thalamic somatotopy in patients suffering from chronic neuropathic pain of central or peripheral origin.

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial.

BACKGROUND: Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. METHODS: ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. FINDINGS: Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. INTERPRETATION: Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. FUNDING: Allergan (now AbbVie).

Generalizability of clinical trial efficacy results to a real-world population: An example in migraine prevention.

BACKGROUND: Health care decision makers are often concerned about the external validity of randomized controlled trials (RCTs), as their results may not apply to certain patients in the real world who intend to receive treatment. OBJECTIVE: To demonstrate a methodology for assessing the generalizability of clinical trial results to a real-world population, before sufficient and appropriate real-world effectiveness data are available, using individual patient-level data from an RCT and aggregated baseline data from a real-world French registry in migraine. METHODS: The analyses were conducted in 2 steps. First, individual patient-level baseline data from the multinational CONQUER RCT were weighted to match aggregated real-world InovPain registry patient characteristic data. Matched patient characteristics were sex, age, migraine type and duration, number of monthly migraine headache days, and number of monthly headache days at baseline. Second, the weighted CONQUER patient data were used to reanalyze the primary endpoint of CONQUER (least squares mean change from baseline in the number of monthly migraine headache days during the 3-month double-blind treatment phase) using predefined methodology. Sensitivity analyses were conducted to assess the robustness of findings. RESULTS: A total of 462 patients with migraine were randomized and treated with galcanezumab or placebo in CONQUER; aggregated InovPain data were available from 130 patients with migraine. We identified no important differences in baseline patient characteristics between the 2 prespecified populations, suggesting good external validity for CONQUER. Although this limited the extent of observed differences between the original and matched CONQUER populations, weighting of CONQUER data did help harmonize the 2 datasets and allow the results obtained in CONQUER to be generalized to patients more representative of the real-world French population with migraine. Results of weighted analyses suggested that galcanezumab would be superior to placebo for reducing monthly migraine headache days in a clinical trial in patients with episodic or chronic migraine who reflected the characteristics of patients eligible to receive the drug in France. CONCLUSIONS: Findings suggest that our methods may be helpful for assessing the generalizability of clinical trial results to a real-world population before the availability of substantial real-world clinical data.

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.

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans.

Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT1B/1D receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT1F agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase®) using a comparative disproportionality analysis with triptans. VigiBase® was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden.

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.

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.

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).

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.

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.

Treatment of Chronic Refractory Pain by Combined Deep Brain Stimulation of the Anterior Cingulum and Sensory Thalamus (EMOPAIN Study): Rationale and Protocol of a Feasibility and Safety Study.

BACKGROUND: Deep Brain Stimulation (DBS) of the sensory thalamus has been proposed for 40 years to treat medically refractory neuropathic pain, but its efficacy remains partial and unpredictable. Recent pilot studies of DBS targeting the ACC, a brain region involved in the integration of the affective, emotional, and cognitive aspects of pain, may improve patients suffering from refractory chronic pain. ACC-DBS could be complementary to thalamic DBS to treat both the sensory-discriminative and the affective components of chronic pain, but the safety of combined DBS, especially on cognition and affects, has not been studied. METHODS: We propose a prospective, randomized, double-blind, and bicentric study to evaluate the feasibility and safety of bilateral ACC-DBS combined with unilateral thalamic DBS in adult patients suffering from chronic unilateral neuropathic pain, refractory to medical treatment. After a study period of six months, there is a cross-over randomized phase to compare the efficacy (evaluated by pain intensity and quality of life) and safety (evaluated by repeated neurological examination, psychiatric assessment, cognitive assessment, and assessment of affective functions) of combined ACC-thalamic DBS and thalamic DBS only, respectively. DISCUSSION: The EMOPAIN study will show if ACC-DBS is a safe and effective therapy for patients suffering from chronic unilateral neuropathic pain, refractory to medical treatment. The design of the study will, for the first time, assess the efficacy of ACC-DBS combined with thalamic DBS in a blinded way.

Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial.

BACKGROUND: The monoclonal antibody eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined. We aimed to investigate the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures. METHODS: DELIVER was a multicentre, multi-arm, phase 3b trial comprising a 24-week double-blind, placebo-controlled period and a 48-week dose-blinded extension. We recruited adults with episodic or chronic migraine with at least 4 monthly migraine days (as per International Headache Society guidelines) and documented evidence of two-to-four previous preventive treatment failures within the past 10 years, from 96 study locations across Europe (n=93) and the USA (n=3). Patients were randomly assigned (1:1:1) via a centralised randomisation system, stratified by baseline monthly headache days and country, to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1-12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. The dose-blinded extension period is ongoing. The trial is registered with ClinicalTrials.gov, NCT04418765, and EudraCT, 2019-004497-25. FINDINGS: Between June 1, 2020, and Oct 7, 2021, 891 individuals were randomly assigned and received at least one dose of study drug (safety population; eptinezumab 100 mg n=299 [34%], eptinezumab 300 mg n=294 [33%], placebo n=298 [33%]). 865 patients completed the placebo-controlled period. The change from baseline to weeks 1-12 in mean monthly migraine days was -4·8 (SE 0·37) with eptinezumab 100 mg, -5·3 (0·37) with eptinezumab 300 mg, and -2·1 (0·38) with placebo. The difference from placebo in change in mean monthly migraine days from baseline was significant with eptinezumab 100 mg (-2·7 [95% CI -3·4 to -2·0]; p<0·0001) and eptinezumab 300 mg (-3·2 [-3·9 to -2·5]; p<0·0001). Treatment-emergent adverse events occurred in 127 (42%) of 299 patients in the eptinezumab 100 mg group, in 120 (41%) of 294 in the eptinezumab 300 mg group, and in 119 (40%) of 298 in the placebo group. The most common treatment-emergent adverse event was COVID-19 (20 [7%] of 299 patients in the eptinezumab 100 mg group, 17 [6%] of 294 in the eptinezumab 300 mg group, and 16 [5%] of 298 in the placebo group). Serious adverse events were uncommon (five [2%] of 299 in the eptinezumab 100 mg group, seven [2%] of 294 in the eptinezumab 300 mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1). INTERPRETATION: In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The dose-blinded extension period will provide additional long-term safety data in patients with migraine and previous preventive treatment failures. FUNDING: H Lundbeck.

Practice guidelines for the treatment of acute migraine and chronic knee osteoarthritis with paracetamol: an expert appraisal on evolution over time between scientific societies.

BACKGROUND: Paracetamol is the commonest analgesic worldwide in primary care. Despite evidence-based recommendations for management of acute and chronic pain with paracetamol, practices seem to vary considerably in its modalities of use, with or without restrictions, between renowned scientific societies and over time. OBJECTIVE: Qualitative assessment of similarities, differences, and changes over time in guidelines for paracetamol use in acute and chronic pain. METHODS: We focused on two common pain conditions for which paracetamol is widely used: acute migraine and chronic knee osteoarthritis (OA). In 19 guidelines (10 for acute migraine, 9 for chronic knee OA) from 10 scientific societies (AAN/AHS, ACR/AF, CHS, EFNS, EHF/LTB, ESCEO, EULAR, SFEMC, SRF, OARSI) published between 1997 and 2021, methods, results and conclusions were compared, between guidelines and over time. RESULTS: In acute migraine, there was a shift from no recommendation for paracetamol or recommendation only for mild attacks to recommendation for mild to moderate attacks in updated guidelines, without restriction for use for four of the five scientific societies. In knee OA, although updated guidelines generally used the GRADE system, recommendations remained heterogeneous between scientific societies: recommendation without or with restrictions, or not recommended. Consensus is lacking regarding long-course safety and efficacy in acute pain and pain at mobilization. CONCLUSIONS: Most migraine guidelines now recommend paracetamol for mild to moderate pain. Knee OA guidelines vary on the use of paracetamol: a more holistic approach is needed for this condition, considering patient profile, disease stage, and pain management during physical activity to clarify its appropriate use.

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.

Artificial intelligence to evaluate postoperative pain based on facial expression recognition.

BACKGROUND: Pain intensity evaluation by self-report is difficult and biased in non-communicating people, which may contribute to inappropriate pain management. The use of artificial intelligence (AI) to evaluate pain intensity based on automated facial expression analysis has not been evaluated in clinical conditions. METHODS: We trained and externally validated a deep-learning system (ResNet-18 convolutional neural network) to identify and classify 2810 facial expressions of 1189 patients, captured before and after surgery, according to their self-reported pain intensity using numeric rating scale (NRS, 0-10). AI performances were evaluated by accuracy (concordance between AI prediction and patient-reported pain intensity), sensitivity and specificity to diagnose pain ≥4/10 and ≥7/10. We then confronted AI performances with those of 33 nurses to evaluate pain intensity from facial expression in the same situation. RESULTS: In the external testing set (120 face images), the deep learning system was able to predict exactly the pain intensity among the 11 possible scores (0-10) in 53% of the cases with a mean error of 2.4 points. Its sensitivities to detect pain ≥4/10 and ≥7/10 were 89.7% and 77.5%, respectively. Nurses estimated the right NRS pain intensity with a mean accuracy of 14.9% and identified pain ≥4/10 and ≥7/10 with sensitivities of 44.9% and 17.0%. CONCLUSIONS: Subject to further improvement of AI performances through further training, these results suggest that AI using facial expression analysis could be used to assist physicians to evaluate pain and detect severe pain, especially in people not able to report appropriately their pain by themselves. SIGNIFICANCE: These original findings represent a major step in the development of a fully automated, rapid, standardized and objective method based on facial expression analysis to measure pain and detect severe pain.

Ketamine in chronic pain: A Delphi survey.

BACKGROUND: There is no recommendation in Europe for the use of ketamine in patients with chronic pain. The heterogeneity of practice highlights the need to seek the advice of experts in order to establish a national consensus. This Delphi survey aimed to reach a national consensus on the use of ketamine in chronic pain in Pain clinics. METHODS: A collaborative four-round internet-based questionnaire was used. It was created after literature search on ketamine administration in chronic pain and included about 96 items. It discussed utility and advantages, adverse events and deleterious aspects, methods of administration, concomitant treatments and assessment of results. RESULTS: Twenty-eight experts completed all rounds of the survey with a total of 81.3% items reaching a consensual answer. Neuropathic pain represents the first indication to use ketamine, followed, with a good to moderate utility, by other situations (fibromyalgia, complex regional pain syndrome, central neuropathic pain, peripheral neuropathic pain, nociceptive pain, sensitization, opioid withdrawal, palliative care, depression). Experts agreed on the rare occurrence of adverse events. Concerning routes of administration, intravenous infusion with doses of 0.5-0.9 mg/kg/d for 4 days of treatment is preferred. Place of care is hospital, as in- or out-patient, with a quarterly administration of ketamine. Finally, ketamine effectiveness is assessed 1 month after infusion, and experts encourage combination with non-pharmacological treatment. CONCLUSIONS: This Delphi survey established a consensus of pain specialists on the use of ketamine in refractory chronic pain, thus providing a basis for future comparative trials. SIGNIFICANCE: This Delphi survey in chronic pain reached agreement on four main aspects: (1) Priority to treat neuropathic pain with evaluation of effectiveness at 1 month; (2) No deleterious effects in the majority of listed diseases/situations with the absence or <3% of suggested adverse events; (3) 0.5-0.9 mg/kg/d IV infusion; (4) Combination with non-pharmacological treatment.

Phantom vision after eye removal: prevalence, features and related risk factors.

AIM: Phantom eye syndrome is a poorly understood and underestimated complication of eye removal (ER). Seeing with the amputated eye, referred to as phantom vision (PV), is undoubtedly the most intriguing and confusing complication experienced by anophthalmic patients. The aim of the study was to assess PV prevalence, clinical features and risk factors after ER. METHODS: A multicentric questionnaire-based study was conducted between April 2016 and July 2017. Patients >18 years who underwent ER >3 months ago had a socket examination before inclusion. Data recorded included patients' demographics, and preoperative, surgical and postoperative features. RESULTS: One hundred patients (53 men) with a mean age of 65.1 years (29-92; SD=13.0) were included. ER indications were: uveal melanoma (n=24, 24%), trauma (n=20, 20%), retinal detachment (n=20, 20%), glaucoma (n=14, 14%) and endophthalmitis (n=12, 12%). Thirty (30%) patients experienced PV. Elementary and complex visual hallucinations were experienced by 80% and 20% of patients, respectively. PV usually appeared within the first postoperative month and tended to decrease over time. Risk factors for PV were the preoperative use of proton beam therapy (p=0.006), uveal melanoma (p=0.014), enucleation (p=0.015), anxiety with a Hospital and Anxiety Depression (HAD) score ≥8 (p=0.042), depression with a HAD score ≥8 (p=0.030), phantom eye pain (p=0.044) and phantom eye sensations (p=0.002). CONCLUSION: PV was reported by one-third of our patients. Despite being widely misunderstood, ophthalmologists and neurologists should be aware of this complication to adequately reassure patients.