Idiopathic intracranial hypertension secondary to Superior Sagittal Sinus Stenosis: a case report.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) without established etiology. Venous sinus stenosis contributes to IIH; however, it is still uncertain whether the stenosis is a primary cause of IIH or a secondary result in response to elevated ICP. Transverse sinus stenosis is frequently identified in patients with IIH and it is suggestive of raised ICP. Here, we report a case of IIH caused by intrinsic superior sagittal sinus stenosis (SSS). CASE PRESENTATION: A 43-year-old man suffered from IIH with headache, papilledema, and visual impairment. Angiography demonstrated isolated SSS stenosis with a pressure gradient of 30 mmHg. SSS stenosis was resistant to revascularization by stenting alone and intrastent balloon angioplasty was then performed to overcome such resistance. The rigidity of the vein wall suggests that the vein is not collapsed and the stenosis is intrinsic, secondary to idiopathic anatomical local changes. Post-procedure headache disappeared and visual acuity improved. CONCLUSION: An isolated SSS stenosis could lead to intracranial hypertension and this condition should be taken into account in the diagnostic workup of IIH. By now, SSS stenosis is not mentioned in any current consensus guidelines or paper on the diagnostic workflow of intracranial hypertension.

Early and sustained efficacy of fremanezumab over 24-weeks in migraine patients with multiple preventive treatment failures: the multicenter, prospective, real-life FRIEND2 study.

BACKGROUND: To verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures. METHODS: This is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21-24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored. RESULTS: Four hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21-24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason. CONCLUSIONS: Fremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.

Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study.

BACKGROUND: A novel formulation of diclofenac, complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. METHODS: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. RESULTS: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. CONCLUSIONS: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.Trial registration: EudraCT Registration No. 2017-004828-29.

Predictors of response to anti-CGRP monoclonal antibodies: a 24-week, multicenter, prospective study on 864 migraine patients.

BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study.

OBJECTIVE: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. BACKGROUND: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. METHODS: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18-65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70 mg, administered subcutaneously every 4 weeks. Treatment duration was planned to last from 6 to 12 months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9-12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). RESULTS: In total, 372 migraine patients were treated with at least one dose of erenumab 70 mg. At weeks 9-12, erenumab decreased MMDs by 4.5 ± 4.1 days (mean ± SD) in patients with HFEM and by 9.3 ± 9.1 (mean ± SD) days in those with CM compared to baseline. At weeks 9-12 VAS score was reduced by 1.9 ± 1.9 (mean ± SD), HIT score by 10.7 ± 8.8 (mean ± SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0-14.0) to 5.0 (IQR 3.0-7.0) in HFEM. In CM patients, VAS was reduced by 1.7 ± 2.0 (mean ± SD), HIT by 9.7 ± 10.4 (mean ± SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0-30.0) to 8.0 (IQR 5.0-15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24-7.40; p = 0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02-1.11; p = 0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14-3.52; p = 0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20-0.93; p = 0.003). CONCLUSIONS: Erenumab 70 mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Narrative Medicine to integrate patients', caregivers' and clinicians' migraine experiences: the DRONE multicentre project.

BACKGROUND: Although migraine is widespread and disabling, stigmatisation and poor awareness of the condition still represent barriers to effective care; furthermore, research on migraine individual and social impact must be enhanced to unveil neglected issues, such as caregiving burden. The project investigated the migraine illness experience through Narrative Medicine (NM) to understand daily life, needs and personal resources of migraneurs, their caregivers and clinicians, and to provide insights for clinical practice. METHODS: The project involved 13 Italian headache centres and targeted migraneurs, their caregivers and migraine specialists at these centres. Written narratives, composed by a sociodemographic survey and illness plot or parallel chart, were collected through the project's webpage. Illness plots and parallel charts employed open words to encourage participants' expression. Narratives were analysed through Nvivo software, interpretive coding and NM classifications. RESULTS: One hundred and seven narratives were collected from patients and 26 from caregivers, as well as 45 parallel charts from clinicians. The analysis revealed migraine perception in social, domestic and work life within the care pathway evolution and a bond between chaos narratives and day loss due to migraine; furthermore, narratives suggested the extent of the caregiving burden and a risk of underestimation of migraine burden in patients' and caregivers' life. CONCLUSION: The project represents the first investigation on migraine illness experience through NM simultaneously considering migraneurs', caregivers' and clinicians' perspectives. Comparing narratives and parallel charts allowed to obtain suggestions for clinical practice, while NM emerged as able to foster the pursuing of migraine knowledge and awareness.

Primaries non-migraine headaches treatment: a review.

In the "headache world," great attention has always been paid to migraine patients, especially for the research and development of new therapies. For the other forms of primary headaches, especially those of Chapters 2 and 3 of the classification, there are however therapies that, even if not specific, can give significant results. Tension-type headache recognizes in NSAIDs the most effective drugs to treat acute attack, while prevention is based on the use of tricyclic antidepressants and muscle relaxants. For TACs, the discussion is more complex: first of all, there are two forms of primary headache that respond absolutely to indomethacin. For these, the main problem is how to manage the possible side effects arising from prolonged treatments and possibly what to use as an alternative. For cluster headaches and short-lasting unilateral neuralgiform headache attacks, we have drugs with good efficacy as regards medical therapy, such as verapamil or lamotrigine, but in recent years, neuromodulation techniques, both surgical and non-invasive, have also been affirming themselves, which represent a more possibility for forms of headache that are often very disabling and resistant to common analgesics.

When does the brain choose pain?

Why does the brain choose pain? Why does an organ that is able to mask pain, even when intense as in fractures or in fighting wounds, decide to let pain pass and begin conscious, such as that of migraine, when there is no noxa patogena and there is no threat to the integrity of the organism, failing in the main function of pain, that of protection? In this brief review, we retrace the journey that led to the identification of the first complex mechanism of regulation of painful input, the spinal gate control system, through the identification of the predominantly thalamocortical supraspinal centers of the neuromatrix, up to the recognition of a pain matrix extremely articulate and sophisticated that integrates elementary sensations with much more complex functions, related to memory, affectivity, emotion, autonomic self-regulation, and homeostasis systems and so on. Why does the protection system lose its fundamental function in migraine in a behavioral harakiri that periodically damages only itself? This is the challenge facing those dealing with primary headaches in the next future: why migraine? The great strides made in the last decades that have led to the understanding of complex pathogenetic mechanisms risk remaining orphans if we fail to identify the primum movens at the base of one of the most common pathologies in the human race.

Current and emerging evidence-based treatment options in chronic migraine: a narrative review.

BACKGROUND: Chronic migraine is a disabling condition that is currently underdiagnosed and undertreated. In this narrative review, we discuss the future of chronic migraine management in relation to recent progress in evidence-based pharmacological treatment. FINDINGS: Patients with chronic migraine require prophylactic therapy to reduce the frequency of migraine attacks, but the only currently available evidence-based prophylactic treatment options for chronic migraine are topiramate and onabotulinumtoxinA. Improved prophylactic therapy is needed to reduce the high burden of chronic migraine in Italy. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) pathway of migraine pathogenesis have been specifically developed for the prophylactic treatment of chronic migraine. These anti-CGRP/R monoclonal antibodies have demonstrated good efficacy and excellent tolerability in phase II and III clinical trials, and offer new hope to patients who are currently not taking any prophylactic therapy or not benefitting from their current treatment. CONCLUSIONS: Treatment of chronic migraine is a dynamic and rapidly advancing area of research. New developments in this field have the potential to improve the diagnosis and provide more individualised treatments for this condition. Establishing a culture of prevention is essential for reducing the personal, social and economic burden of chronic migraine.

Validation of a self-reported instrument to assess work-related difficulties in patients with migraine: the HEADWORK questionnaire.

BACKGROUND: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them. METHODS: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well. RESULTS: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity. CONCLUSIONS: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Transcutaneous supraorbital neurostimulation for the prevention of chronic migraine: a prospective, open-label preliminary trial.

Since chronic migraine is difficult to treat and often associated with medication overuse, non-invasive neurostimulation approaches are worth investigating. Transcutaneous supraorbital neurostimulation using the Cefaly® device is promising as a non-invasive preventive treatment for episodic migraine, but no data are available for chronic migraine. Our aim was to perform a preliminary evaluation of the efficacy of the Cefaly® device for the prophylaxis of chronic migraine with or without medication overuse. Primary endpoints were 50% reduction in monthly migraine days and 50% reduction in monthly medication use over 4 months. In an open-label study, twenty-three consecutive headache center patients with chronic migraine, diagnosed according to International Headache Society criteria, were recruited prospectively. After informed consent, patients were trained to use Cefaly® and instructed to use it for 20 min daily over 4 months. All patients received active neurostimulation. Thirty-five percent of the patients enrolled in the study achieved the study endpoints. Over half the patients had a greater than 50% reduction in acute medication consumption.

Migraine with aura and white matter lesions: an MRI study.

Several studies report the presence of white matter lesions on brain magnetic resonance imaging in patients with migraine. The aim of our study was to detect the entity of white matter T2-hyperintensities in 90 high selected patients affected by migraine with aura, compared to a group of 90 healthy controls. We found no significant difference of incidence of white matter alterations comparing these two groups.

Confusional state as first symptom of HaNDL syndrome.

HaNDL (transient headache and neurological deficits with cerebrospinal fluid lymphocytosis) syndrome is an infrequent condition included at group 7 "headache attributed to non-vascular intracranial disorder" in the recent International Classification of Headache Disorders (ICHD-3), code 7.3.5. The description states "migraine-like headache episodes (typically 1-12) accompanied by neurological deficits including hemiparaesthesia, hemiparesis and/or dysphasia, but positive visual symptoms only uncommonly, lasting several hours. There is lymphocytic pleocytosis. The disorder resolves spontaneously within 3 months". In this description confusional state is not considered as a main symptom, even if in the literature this aspect is frequently reported. Here, we report the cases of two young boys presenting with confusional state as the main complaint. The possible pathogenesis of the different clinical presentation is discussed.

Early (≤ 1-h) vs. late (>1-h) administration of frovatriptan plus dexketoprofen combination vs. frovatriptan monotherapy in the acute treatment of migraine attacks with or without aura: a post hoc analysis of a double-blind, randomized, parallel group study.

The early use of triptan in combination with a nonsteroidal anti-inflammatory drug after headache onset may improve the efficacy of acute migraine treatment. In this retrospective analysis of a randomized, double-blind, parallel group study, we assessed the efficacy of early or late intake of frovatriptan 2.5 mg + dexketoprofen 25 or 37.5 mg (FroDex 25 and FroDex 37.5) vs. frovatriptan 2.5 mg alone (Frova) in the acute treatment of migraine attacks. In this double-blind, randomized parallel group study 314 subjects with acute migraine with or without aura were randomly assigned to Frova, FroDex 25, or FroDex 37.5. Pain free (PF) at 2-h (primary endpoint), PF at 4-h and pain relief (PR) at 2 and 4-h, speed of onset at 60, 90, 120 and 240-min, and sustained pain free (SPF) at 24-h were compared across study groups according to early (≤1-h; n = 220) or late (>1-h; n = 59) intake. PF rates at 2 and 4-h were significantly larger with FroDex 37.5 vs. Frova (early intake, n = 71 FroDex 37.5 and n = 75 Frova: 49 vs. 32 % and 68 vs. 52 %, p < 0.05; late intake, n = 20 Frodex 37.5, and n = 18 Frova: 55 vs. 17 %, p < 0.05 and 85 vs. 28 %, p < 0.01). Also with FroDex 25, in the early intake group (n = 74) PF episodes were significantly higher than Frova. PR at 2 and 4-h was significantly better under FroDex 37.5 than Frova (95 % vs. 50 %, p < 0.001, 100 % vs. 72 %, p < 0.05) in the late intake group (n = 21). SPF episodes at 24-h after early dosing were 25 % (Frova), 45 % (FroDex 25) and 41 % (FroDex 37.5, p < 0.05 combinations vs. monotherapy), whereas they were not significantly different with late intake. All treatments were equally well tolerated. FroDex was similarly effective regardless of intake timing from headache onset.

Comparison of frovatriptan plus dexketoprofen (25 mg or 37.5 mg) with frovatriptan alone in the treatment of migraine attacks with or without aura: a randomized study.

BACKGROUND: Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom relief. METHODS: A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg alone (Frova), frovatriptan 2.5 mg + dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg + dexketoprofen 37.5 mg (FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours, resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the judgment of the treatment. RESULTS: The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and treated for whom at least one post-dose intensity of headache was recorded. The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies ( P < 0.05). Proportions of SPF at 24 hours were 24% (22/93) for Frova, 43% (41/95) for FroDex25 ( P < 0.001) and 42% (38/91) for FroDex37.5 ( P < 0.05). SPF at 48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 ( P = NS). Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) ( P = NS), meaning a lack of improvement with the combination therapy. Statistical adjustment for multiple comparisons was not performed. No statistically significant differences were reported in the occurrence of total and drug-related adverse events. FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem to be a dose response curve for the addition of dexketoprofen. CONCLUSION: FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to this improved efficacy profile.

Efficacy of early vs. late use of frovatriptan combined with dexketoprofen vs. frovatriptan alone in the acute treatment of migraine attacks with or without aura.

Early triptan use after headache onset may help improve the efficacy of acute migraine treatment. This may be particularly the case when triptan therapy is combined with a nonsteroidal anti-inflammatory drug (NSAID). The objective of this is to assess whether the combination of frovatriptan 2.5 mg + dexketoprofen 25 or 37.5 mg (FroDex25 and FroDex37.5) is superior to frovatriptan 2.5 mg alone (Frova) in the acute treatment of migraine attacks in patients who took the drug within 30 min from the onset of pain (early use) or after (late use). A total of 314 subjects with a history of migraine with or without aura were randomized into a double-blind, multicenter, parallel group, pilot study to Frova, FroDex25 or FroDex37.5 and were required to treat at least one migraine attack. In the present post hoc analysis, traditional migraine endpoints were compared across study drugs for subgroups of the 279 patients of the full analysis set according to early (n = 172) or late (n = 107) drug use. The proportion of patients pain free at 2 h in the early drug use subgroup was 33 % with Frova, 50 % with FroDex25 and 51 % with FroDex37.5 mg (p = NS combinations vs. monotherapy), while in the late drug use subgroup was 22, 51 and 50 % (p < 0.05 FroDex25 and FroDex37.5 vs. Frova), respectively. Pain-free episodes at 4 h were 54 % for early and 34 % for late use of Frova, 71 and 57 % with FroDex25 and 74 and 68 % with FroDex37.5 (p < 0.05 for early and p < 0.01 for late use vs. Frova). The proportion of sustained pain free at 24 h was 26 % under Frova, 43 % under FroDex25 mg and 40 % under FroDex37.5 mg (p = NS FroDex25 or 37.5 vs. Frova) in the early drug intake subgroup, while it was 19 % under Frova, 43 % under FroDex25 mg and 45 % under FroDex37.5 mg (p < 0.05 FroDex25 and FroDex37.5 vs. Frova) in the late drug intake subgroup. Risk of relapse at 48 h was similar (p = NS) among study drug groups (Frova: 25 %, FroDex25: 21 %, and FroDex37.5: 37 %) for the early as well as for the late drug use subgroup (14, 42 and 32 %). FroDex was found to be more effective than Frova taken either early or late. The intrinsic pharmacokinetic properties of the two single drug components made FroDex combination particularly effective within the 2-48-h window from the onset of the acute migraine attack. The efficacy does not seem to be influenced by the time of drug use relative to the onset of headache.

Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study.

OBJECTIVE: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders). METHODS: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. RESULTS: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020). CONCLUSION: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment.