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.

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study).

BACKGROUND: Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. METHODS: This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. RESULTS: Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85-0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. CONCLUSIONS: Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study.

BACKGROUND AND PURPOSE: A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. METHODS: All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. RESULTS: A total of 156 patients (82.4% female, aged 47.3 ± 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive ≥50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). CONCLUSIONS: Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study).

BACKGROUND: The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting. METHODS: This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation. RESULTS: One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times. CONCLUSIONS: Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04803513 .

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.

Are depressive symptomatology, self-efficacy, and perceived social support related to disability and quality of life in patients with chronic migraine associated to medication overuse? Data from a cross-sectional study.

BACKGROUND: Chronic migraine with medication overuse (CM-MO) impairs quality of life (QoL) and causes disability. Psychosocial variables such as depressive symptomatology, self-efficacy, and social support have been sparingly investigated, and their impact on disability and QoL is unknown. METHODS: Patients with CM-MO under withdrawal were consecutively enrolled. Standardized measures of disability and QoL were used as outcomes; psychosocial (ie, mood state, self-efficacy, social support) and clinical (ie, headache frequency and intensity) variables were considered as associated variables. Associations between these variables, disability, and QoL were tested with Pearson's correlations. Hierarchical multiple regression was used to assess the cumulative contribution of psychosocial variables on disability and QoL variation when added to clinical variables. RESULTS: One hundred ninety-four patients were enrolled; 82.5% were females and mean age was 43.9. Disability and QoL were moderately or little correlated to clinical and psychosocial variables. Models based on clinical variables explained 7.5-14.3% of disability and QoL variation, with pain intensity being the only significant predictor; when psychosocial variables were added, the explained variation increased to 21.5-35.2%, with depressive symptomatology always having independent predictive power and perceived social support having independent predictive power in the regression model over role-prevention component of QoL. CONCLUSIONS: Adding information on psychosocial variables to headache features improved our ability to understand disability and QoL of CM-MO patients. We deem that the inclusion of psychosocial variables in standard evaluation protocols may contribute to the global assessment of CM-MO patients, and eventually to their success in reducing the personal and social impact of this condition. Future longitudinal studies are needed to confirm this hypothesis.

Chronic migraine with medication overuse: association between disability and quality of life measures, and impact of disease on patients' lives.

Patients with chronic migraine with medication overuse (CM-MO) have decreased quality of life (QoL) and increased disability: the degree to which these outcomes are connected to disease severity and the pattern of MO towards disease severity are unclear. Patients under withdrawal were administered the Migraine Disability Assessment (MIDAS), the WHO Disability Assessment Schedule (WHODAS), and the Migraine-Specific Quality of Life Questionnaire (MSQ). They overused NSAIDs, triptans, NSAIDs and triptans, and other drugs (ergotamine, caffeine, opioids/barbiturates). We calculated the correlations between MIDAS, WHODAS, and MSQ; compared WHODAS to normative scores; compared MIDAS, WHODAS, and MSQ in patients with different CM-MO severity; and run a logistic regression to predict CM-MO severity based on overused drugs. One hundred ninety-four patients were enrolled: correlations between WHODAS, MSQ, and MIDAS were moderate; wide differences on WHODAS against normative were found; and no trend was found across severity groups. Compared to triptans overusers, patients overusing NSAID and other drugs had higher odds of severe CM-MO. Coupling different disability measures with QoL assessment offered different insights on the lived experience of CM-MO. Future studies are needed to clarify the relationship between overused drugs and CM-MO severity: we added evidence that NSAIDs do not have protective effect in high-frequency CM-MO.

Validating the Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ) in Italian inpatients with chronic migraine with a history of medication overuse.

PURPOSE: The purpose of the study is to assess validity, reliability and factor structure of the Italian version of Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ) in patients suffering from chronic migraine (CM) with a history of medication overuse (MO). METHODS: Patients were enrolled at hospital admission for withdrawal from MO. Factor analysis was used to confirm the latent structure of the MSQ. Reliability was measured with Cronbach's alpha coefficient, item-total correlation and inter-item correlation. Construct validity was assessed with Pearson's coefficient and known-group analysis. RESULTS: The three-factor structure is basically confirmed. Cronbach's alpha varied between 0.85 and 0.92; item-total correlations were on average higher than 0.70; average inter-item correlation ranged between 0.63 and 0.65. Correlations were all significant; known-group analysis shows that MSQ score was lower consistently with disease severity. CONCLUSIONS: Our findings confirm the factor structure, reliability and validity of the MSQ and expand results of previous validation studies to the Italian language and to a group of patients with severe CM requiring withdrawal treatment for MO.