Multimodal digital health treatments for Chronic Migraine associated with Medication Overuse Headache: a literature appraisal and results of a single-arm open trial (the BE-HOME program).

BACKGROUND: Mindfulness-based treatments gained popularity for migraine treatment. In this manuscript we report the results of a single-arm open pilot study that evaluated the impact of a multimodal web-based intervention combining home-based medication withdrawal, patients' education, and online mindfulness-based interventions. We aimed to address whether our program had the ability to show a change in the observed parameters and the study should therefore be intended as an early phase trial. METHODS: Consecutive patients with chronic migraine associated with medication overuse headache were enrolled, followed-up for 12 months, in a program that included home-based medication withdrawal, education on the correct use of drugs and lifestyle issues, prescription of tailored pharmacological prophylaxis, and attendance to six online mindfulness-based sessions. We tested the effect of the program on improving headache frequency, medication intake, quality of life (QoL), headache impact, depression, self-efficacy, and pain catastrophizing. RESULTS: A total of 37 patients completed the study (10 dropped out). We observed a large improvement in headache frequency, medication intake, headache impact, and QoL, a moderate improvement in pain catastrophizing and a mild improvement in depression symptoms; 70% to 76% of patients achieved 50% or more reduction in headache frequency from baseline to each follow-up (p < .01). CONCLUSIONS: The results of our multimodal program showed significant improvements in headache frequency, medication intake, and patient-reported outcomes. Future studies are needed to better identify patients who might benefit most from Digital Health Interventions and to demonstrate at least an equivalence in outcome with in-person programs carried out in hospital settings.

Longitudinal neurofunctional changes in medication overuse headache patients after mindfulness practice in a randomized controlled trial (the MIND-CM study).

BACKGROUND: Mindfulness practice has gained interest in the management of Chronic Migraine associated with Medication Overuse Headache (CM-MOH). Mindfulness is characterized by present-moment self-awareness and relies on attention control and emotion regulation, improving headache-related pain management. Mindfulness modulates the Default Mode Network (DMN), Salience Network (SN), and Fronto-Parietal Network (FPN) functional connectivity. However, the neural mechanisms underlying headache-related pain management with mindfulness are still unclear. In this study, we tested neurofunctional changes after mindfulness practice added to pharmacological treatment as usual in CM-MOH patients. METHODS: The present study is a longitudinal phase-III single-blind Randomized Controlled Trial (MIND-CM study; NCT03671681). Patients had a diagnosis of CM-MOH, no history of neurological and severe psychiatric comorbidities, and were attending our specialty headache centre. Patients were divided in Treatment as Usual (TaU) and mindfulness added to TaU (TaU + MIND) groups. Patients underwent a neuroimaging and clinical assessment before the treatment and after one year. Longitudinal comparisons of DMN, SN, and FPN connectivity were performed between groups and correlated with clinical changes. Vertex-wise analysis was performed to assess cortical thickness changes. RESULTS: 177 CM-MOH patients were randomized to either TaU group or TaU + MIND group. Thirty-four patients, divided in 17 TaU and 17 TaU + MIND, completed the neuroimaging follow-up. At the follow-up, both groups showed an improvement in most clinical variables, whereas only TaU + MIND patients showed a significant headache frequency reduction (p = 0.028). After one year, TaU + MIND patients showed greater SN functional connectivity with the left posterior insula (p-FWE = 0.007) and sensorimotor cortex (p-FWE = 0.026). In TaU + MIND patients only, greater SN-insular connectivity was associated with improved depression scores (r = -0.51, p = 0.038). A longitudinal increase in cortical thickness was observed in the insular cluster in these patients (p = 0.015). Increased anterior cingulate cortex thickness was also reported in TaU + MIND group (p-FWE = 0.02). CONCLUSIONS: Increased SN-insular connectivity might modulate chronic pain perception and the management of negative emotions. Enhanced SN-sensorimotor connectivity could reflect improved body-awareness of painful sensations. Expanded cingulate cortex thickness might sustain improved cognitive processing of nociceptive information. Our findings unveil the therapeutic potential of mindfulness and the underlying neural mechanisms in CM-MOH patients. TRIAL REGISTRATION: Name of Registry; MIND-CM study; Registration Number ClinicalTrials.gov identifier: NCT0367168; Registration Date: 14/09/2018.

Efficacy of mindfulness added to treatment as usual in patients with chronic migraine and medication overuse headache: a phase-III single-blind randomized-controlled trial (the MIND-CM study).

BACKGROUND: Mindfulness gained considerable attention for migraine management, but RCTs are lacking. We aimed to assess the efficacy of a six-sessions mindfulness-based treatment added to treatment as usual (TaU) in patients with Chronic Migraine (CM) and Medication Overuse Headache (MOH) on headache frequency, medication intake, quality of life, disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. METHODS: In this Phase-III single-blind RCT carried out in a specialty Italian headache center, 177 patients with CM and MOH were randomized 1:1 to either TaU (withdrawal from overused drugs, education on proper medication use and lifestyle issues, and tailored prophylaxis) or mindfulness-based intervention added to TaU (TaU + MIND). The mindfulness-based intervention consisted of six group session of mindfulness practice and 7-10 min daily self-practice. The primary endpoint was the achievement of ≥ 50% headache frequency reduction at 12 months compared to baseline, and was analyzed on an intention-to-treat principle using Pearson's Chi-Squared test. Secondary endpoints included medication intake, quality of life (QoL), disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. The secondary endpoints were analyzed using per-protocol linear mixed models. RESULTS: Out of the 177 participants 89 were randomized to TaU and 88 to TaU + MIND. Patients in the TaU + MIND group outperformed those in TaU for the primary endpoint (78.4% vs. 48.3%; p < 0.0001), and showed superior improvement in headache frequency, QoL and disability, headache impact, loss of productive time, medication intake, and in total, indirect and direct healthcare costs. CONCLUSIONS: A mindfulness-based treatment composed of six-week session and 7-10 min daily self-practice added on to TaU is superior to TaU alone for the treatment of patients with CM and MOH. TRIAL REGISTRATION: MIND-CM was registered on clinicaltrials.gov (NCT03671681) on14/09/2018.

Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway.

AIM: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by survival of motor neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the unfolded protein response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients. METHODS: We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expression was re-established (rescue). We complemented this approach by using myoblast and fibroblast SMA patient cells and SMA mouse models of varying severities. Finally, we tested in vitro and in vivo the effect of IRE1α/XBP1 pathway restoration on SMN expression and subsequent neuroprotection. RESULTS: We report that the IRE1α/XBP1 branch of the unfolded protein response is disrupted in SMA, with a depletion of XBP1s irrespective of IRE1α activation pattern. The overexpression of XBP1s in SMA fibroblasts proved to transcriptionally enhance SMN expression. Importantly, rebalancing XBP1s expression in severe SMA-like mice, induced SMN expression and spinal MN protection. CONCLUSIONS: We have identified XBP1s depletion as a contributing factor in SMA pathogenesis, and the modulation of this transcription factor proves to be a plausible therapeutic avenue in the context of pharmacological interventions for patients.

Addressing the cost of chronic and episodic migraine and its main drivers: a short-term longitudinal analysis from a third-level Italian center.

BACKGROUND: Chronic migraine (CM) is one of the most disabling neurological diseases, often associated to medication overuse headache (MOH). These patients make high use of pharmacological and non-pharmacological treatments, and experience high work-related indirect costs. The aim of this study was to address and compare the main driver of cost associated to CM-MOH and EM, and to evaluate the effect of improvement in migraine profile on disease cost. METHODS: We selected patients with baseline CM-MOH who reverted to an episodic pattern by 3 months after structured withdrawal. Paired sample t-test was used to explore the variation in headache frequency and its costs. Regression models were run to address the impact of single cost categories on total migraine cost. RESULTS: A total of 261 patients were included. Significant reductions in headache frequency and its costs were observed, with the exception of medical prophylaxis cost. The cost of migraine from chronic to episodic pattern is reduced by 533€ per month and 80% of this reduction is accountable to reduced indirect costs, i.e., loss of productive time. CONCLUSIONS: The results of our study open to future considerations on future approaches to the treatment of CM-MOH in which new migraine-specific treatments, i.e., monoclonal antibodies, should be combined with other pharmacological and non-pharmacological ones.

Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.

OBJECTIVE: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. BACKGROUND: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. METHODS: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. RESULTS: A total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004). CONCLUSIONS: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Withdrawal failure in patients with chronic migraine and medication overuse headache.

OBJECTIVES: The management of chronic migraine (CM) with Medication Overuse Headache (MOH) consists of withdrawal therapy, education on medications' use and prescription of prophylaxis. Little attention has been given to patients who fail in achieving a successful short-term outcome after withdrawal: we aim to describe predictors of failure. METHODS: Patients with CM and MOH were enrolled at the Neurological Institute C. Besta of Milano, and included if they completed the three months follow-up. Withdrawal failure was defined as the situation in which patients either did not revert from chronic to episodic migraine (EM), were still overusing acute medications, or both did not revert to EM and kept overusing acute medications. Predictors of failure were addressed with a logistic regression, and for all variables, the longitudinal course in the two groups was described. RESULTS: In 39, out of 137 patients, withdrawal was unsuccessful: the predictors included day-hospital-based withdrawal (OR: 2.37; 95% CI: 1.06-5.29), emergency room (ER) access before withdrawal (OR: 2.81; 95% CI: 1.13-6.94) and baseline headache frequency >69 days/three months (OR: 2.97; 95% CI: 1.32-6.65). Patients who failed withdrawal did not improve on medications intake, use of prophylactic and non-pharmacological treatments, symptoms of anxiety and depression. CONCLUSIONS: Patients who were treated in day-hospital, those who recently attended ER for headache, and those with more than 69 headache/3 months, as well as to those with relevant symptoms of anxiety and depression who did not improve should be closely monitored to reduce likelihood of non-improvement after structured withdrawal.

The clinical and public health implications and risks of widening the definition of chronic migraine.

BACKGROUND: The definition of chronic migraine has long been debated. Recently, it was suggested to define subjects with at least 8/migraine days as chronic migraine; that is, incorporating so-called high frequency episodic migraine (eight or more migraine days but less than 15 headache days per month). METHODS: We addressed the possible problems that might arise based on this proposal accounting for clinical, pathophysiological, impact and public health aspects. RESULTS AND CONCLUSIONS: Defining chronic migraine on the basis of headache frequency alone does not account for clinical and pathophysiological aspects, as well as for the impact of chronic migraine in terms of disability and quality of life. Moreover, it is potentially harmful for patients in terms of allocation of resources. These issues are discussed in the present manuscript, and we support the idea of defining high frequency episodic migraine as an independent entity as a viable path to follow.

Disability, Quality of Life, and Socioeconomic Burden of Cluster Headache: A Critical Review of Current Evidence and Future Perspectives.

OBJECTIVE: To summarize the available evidence on disability, quality of life (QoL), and economic burden on societies of cluster headache (CH), and to present which tools have been used to measure these domains with indications for future research. BACKGROUND: CH is a rare and severe primary headache. The focus of research on this disorder has historically been on understanding its complex pathophysiological mechanisms, whereas personal and global healthcare impact, disability, and QoL received little attention. METHODS: We reviewed the available literature published up to 2019, identifying primary research addressing QoL, disability, impact, or impairment in daily life due to episodic CH (ECH) or chronic CH (CCH), and its societal impact. RESULTS: CH produces a significant impact on sufferers QoL, disability, and work-related aspects, with a stronger impact on CCH than ECH. The CH-related disability appears to be greater than is seen in subjects with other primary headache disorders. CONCLUSIONS: Information about patient-reported outcomes is rarely collected in patients with CH. An effort to improve the amount of information on the lived experience of patients with CH is needed and CH-specific disability and QoL measures require development.

HEADWORK Questionnaire: Why Do We Need a New Tool to Assess Work-Related Disability in Patients With Migraine?

OBJECTIVE: This article reviews current headache disability measures and clinical need, as well as presenting the rationale for a new measure addressing work-related disability in migraine patients and the steps devoted to this aim. BACKGROUND: Episodic and chronic migraine (EM and CM) constitute an enormous economic burden to societies, and the vast majority of this burden is attributable to indirect costs, ie those associated with productivity loss. A measure of work-related disability is therefore needed to quantify the impact of EM and CM on patients' ability to carry out work tasks. METHODS: We briefly present the advantages and disadvantages of the disability measures that have been most commonly used for this purpose and the rationale for developing a new measure. RESULTS: The entire process of development of HEADWORK, a questionnaire designed to assess work-related disability, is presented together with short-term sensitivity to change. CONCLUSIONS: Current headache disability measures need improvement. HEADWORK is a valid, reliable, and sensitive questionnaire to address the amount and severity of work-related difficulties and of the factors contributing to such difficulties. HEADWORK is suitable for daily clinical practice, epidemiological research and for clinical trials, and potentially to define work-related disability weights for the calculation of migraine indirect costs.

Headache in spontaneous intracranial hypotension: an overview with indications for differential diagnosis in the clinical practice.

Headache is the most common symptom of spontaneous intracranial hypotension (SIH). The present review focuses on data regarding headache features reported in the most relevant published articles and summarizes the main SIH headache features, namely, orthostatic headache, headache triggered by Valsalva maneuver, pattern of onset of headache, and location and quality of headache. Published data indicate that the clinical suspect of this disorder may be challenging, due to its protean presentation. Among the main implications for clinical practice, we suggest to suspect SIH in all patients with a new onset headache, as different forms of primary and secondary headache should be considered in the differential diagnosis of SIH, particularly cervicogenic headache, new daily persistent headache, and headaches precipitated by Valsalva maneuver. The clinical interview must include specific questions on the possible orthostatic feature of headache, although its absence should not make clinicians to reject the SIH hypothesis as headache cannot be orthostatic in each patient and in all periods of the natural history of the disease. Other disorders with orthostatic symptoms, such as in postural tachycardia syndrome (POTS) and persistent postural-perceptual dizziness (PPPD), should be considered in the differential diagnosis. Awareness that SIH can present with acute, sudden onset requires that clinicians working in the emergency settings should consider SIH in the range of diagnoses of thunderclap headache.

A prospective pilot study of the effect on catecholamines of mindfulness training vs pharmacological prophylaxis in patients with chronic migraine and medication overuse headache.

AIM: To address whether, in patients with chronic migraine and medication overuse headache, mindfulness-based treatment is associated with changes in plasma levels of catecholamines and elusive amines that are similar to those observed in patients undergoing pharmacological prophylaxis. METHODS: In this non-randomized, clinic-based effectiveness study, patients aged 18-65, with a history of chronic migraine ≥ 10 years and overuse of triptans or non-steroidal anti-inflammatory drugs ≥ 5 years, were enrolled. Upon completion of a structured withdrawal program, patients received either pharmacological prophylaxis or six weekly sessions of mindfulness-based treatment and were followed for 12 months. Daily headache diaries were used to record headache frequency and medication intake; catecholamines (noradrenaline, epinephrine and dopamine) and levels of elusive amines were assayed from poor platelet plasma. RESULTS: Complete follow-up data were available for 15 patients in the pharmacological prophylaxis-group (14 females, average age 44.1) and 14 in the mindfulness treatment-group (all females, average age 46.4), and all variables were comparable between groups at baseline. At 12 months, significant improvement ( p < .001) was found in the pharmacological prophylaxis group for headache frequency and medication intake (by 51% and 48.7%, respectively), noradrenaline, epinephrine and dopamine (by 98.7%, 120.8% and 501.9%, respectively); patients in the mindfulness treatment-group performed similarly. For elusive amines, no longitudinal changes were found. CONCLUSIONS: The similar improvement trends observed in the two groups of patients further support the utility of mindfulness-based treatment in migraine care, and reinforce the hypothesis that alteration and normalization of tyrosine metabolism are implicated in migraine chronification and in remission of chronic migraine.

Onabotulinumtoxin-A in Chronic Migraine: Should Timing and Definition of Non-Responder Status Be Revised? Suggestions From a Real-Life Italian Multicenter Experience.

OBJECTIVE: To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response. BACKGROUND: Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. DESIGN AND METHODS: We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder. RESULTS: We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with <30% and ≥30% reduction in headache frequency between T0 and T2 or T4 (respectively, "Non-Responders" and "Responders"), we found that the agreement between the classification Responders/Non-Responders at T2 and T4 was not very high (79/104 = 76.0%, with a "moderate" Cohen's Kappa of 0.51), suggesting that the status at T4 is not fully predictable by the status at T2 (λ = 0.47). Responders for headache frequency at T4 were 54.8%. Among Responders at T2, Responders at T4 were 47/62 = 75.8% (95% CI: 64.5%, 85.5%), while among Non-Responders at T2, Responders at T4 were 10/42 = 23.8% (95% CI: 11.9%, 38.1%). Similarly, even when considering the 50% reduction in painkillers consumption or in MIDAS total score between T0 and T2 as possible prognostic factors, the changes occurring at T4 are not strongly predictable by those at T2. CONCLUSIONS: A ≥30% reduction in headache frequency at T2 cut-off is not adequate in predicting a late response to treatment: more than a quarter of excluded patients would miss a clinical improvement with an ongoing treatment, while in a similar percentage of Responders the treatment would lose efficacy. Results from our real-life study suggest that we possibly have to postpone the definition of Responder/Non-Responder to OBT-A at least after 1 year of treatment (4 cycles).

Behavioral Approaches for Primary Headaches: Recent Advances.

BACKGROUND: Behavioral treatments in the management of primary headache disorders in adults and children are increasingly being recognized as effective; however, the level and durability of their effectiveness is still a matter of debate. This review aims to provide more updated information on the effects of behavioral therapies in adults and adolescents with primary headache disorders, with a special focus on new and emerging behavioral treatments. METHODS: We searched SCOPUS for peer-reviewed papers that reported randomized controlled trial or observational studies addressing behavioral treatment for headache disorders published in the period January 2010 to October 2017. RESULTS: A total of 22 publications, in which 2110 participants were recruited, were included in the review. Most of the studies referred to cognitive behavioral therapies, and a reduction of headache frequency higher than 35% was generally reported irrespective of the approach. In addition, valuable impact disability and quality of life was observed, as well as improvements in depression, anxiety, self-efficacy, and intake of medications. CONCLUSIONS: Behavioral approaches are effective and less prone to produce side or harmful effects, which makes them a valid option particularly for women who are pregnant or nursing, people with other chronic conditions requiring pharmacological treatments putting them at risk for drug-drug interactions, and children.

A Qualitative Study On Patients With Chronic Migraine With Medication Overuse Headache: Comparing Frequent And Non-Frequent Relapsers.

BACKGROUND: It is common clinical experience that, after structured withdrawal, some patients with chronic migraine and medication overuse headache (CM with MOH) are more prone than others to relapse and to be in need of further structured treatments. Our aim was to explore similarities and differences between frequent relapsers (FRs) and non-frequent relapsers (NFRs) by considering their point of view, perceptions, and perspective of their subjective experience with relapse into CM with MOH. METHODS: Patients were consecutively recruited on occasion of a structured withdrawal treatment and were interviewed individually about their headache experience and their perspectives on relapse into CM with MOH. We considered FR those patients requiring 2 or more structured withdrawals for MOH within 3 years. A narrative approach with no preconceived coding schemes was employed. To facilitate coding, categorization and organization of data the software QRS NVivo 11.0 was used: themes were defined as common to FR and NFR, or peculiar (by frequency or content) to one of the 2 groups. RESULTS: Sixteen patients (13 women; mean age of 53) were interviewed: 7 were classified as FRs. A total of 22 themes emerged from 552 single quotations (the 10 most relevant covered 82% of the entire body of quotations). Four themes were commonly reported by both FR and NFR patients, and 6 were peculiar to one group only. Common aspects included issues connected to the dilemma between disclosing, concealing and the feelings of isolation around MOH, the idea of being addicted to medication, presence of anxiety, and the attempt to use non-pharmacological therapies as an alternative to medication. Peculiar aspects included causal attribution (FRs attributed headache to uncontrollable factors); future expectations at the time point of withdrawal (FRs were generally resigned); high-performance functioning (FRs believed they are "forced" to reach high levels of performance as a consequence of others' inability); coping strategies (FRs tended to "passively accept" problems and showed avoidance-related behaviors). Moreover, FRs were less frequently aware of their problems and described more frequently depressive symptoms. CONCLUSIONS: Our results highlight that some differences between FR and NFR patients with CM and MOH exist. Frequent relapsers among patients with CM and MOH reported some important peculiarities of the lived experience of having chronic migraine; clinicians should recognize these psychosocial aspects such as social relationships, future expectations, the experience of illness, medication management, and how the withdrawal experience is regarded, as they may be associated with frequent relapse into MOH.

Multimorbidity in patients with chronic migraine and medication overuse headache.

OBJECTIVES: Patients with chronic migraine (CM) display a considerable amount of comorbidities, particularly psychiatric and cardiovascular, and the presence of multiple comorbidities, that is, the so-called multimorbidity, is a risk factor for migraine chronification or maintenance of CM. Our aim was to address the rate and impact of multimorbidity in patients with CM and medication overuse headache (MOH). MATERIALS & METHODS: In a sample of patients with CM attending a structured withdrawal for coexisting MOH, we defined multimorbidity as the presence of two or more conditions in addition to CM-MOH. We compared patients with and without multimorbidity for demographic and clinical variables, quality of life, and disability; we also tested whether patients with multimorbidity had higher likelihood to attend emergency room, relapse into CM, and require further withdrawal treatments by 12 months. RESULTS: One hundred and ninety-four patients were enrolled as follows: 61% had at least one comorbidity, the most common being mental (34%), circulatory (18%), and endocrine conditions (13%); 32% were multimorbidity cases. Patients with multimorbidity had higher headaches frequency, older age, lower education and lower employment rates, higher disability and lower QoL. They were more frequently opioids/barbiturates overusers and were more likely to attend ER (OR: 2.36), relapse into CM (OR: 2.19), and undergo another withdrawal (OR: 2.75) by 12 months after discharge, after controlling for age, gender, years of education, and headache frequency. CONCLUSIONS: Recognizing multimorbidity in patients with CM-MOH is important to enhance the management of these complex patients, who are at risk of polypharmacy and increased health care utilization.

Is Medication Overuse Drug Specific or Not? Data from a Review of Published Literature and from an Original Study on Italian MOH Patients.

PURPOSE OF REVIEW: The aim is twofold. First, to give an insight on the role exerted by different classes of drugs in favouring migraine chronification. Second, to explore the relationship between type and amount of overused medications and history of previous withdrawal treatment and of frequent relapses. RECENT FINDINGS: All drug classes were found to favour migraine chronification. No data are available for the association with relapses into CM-MOH. Our clinical study shows that patients who underwent previous withdrawal treatments were more likely to be overusers of multiple drug classes and overuse higher amounts of symptomatic medications, particularly, indomethacin, eletriptan and tramadol. Frequent relapsers were more likely to be overusers of opioids or ergotamine and caffeine derivates or of multiple classes, particularly acetylsalicylic acid and ergotamine/caffeine derivates. The joint results our review and clinical study do not seem to support the idea that MOH is drug-specific: rather, it points out that all drug classes may induce migraine chronification. Those drugs which are at higher risk of overuse are among those preferred by the "worst" patients, i.e. those who needed one or more withdrawal treatments for MOH. Our results reinforce the clinical impression that patients with CM and MOH, and particularly the most difficult to treat for their poor response to withdrawal treatments, are characterised by a particular drive towards the consumption of "whatever is likely to be perceived to provide some relief", despite these drugs that are perceived as "more powerful", are often indicated as second- or third-line medications.

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.

Impact of obesity and binge eating disorder on patients with idiopathic intracranial hypertension.

Background Idiopathic intracranial hypertension (IIH) is associated with obesity, and obesity is associated with binge eating disorder (BED). The aim of this paper is to address the presence and impact of BED in patients undergoing an IIH diagnostic protocol. Methods This was a cross-sectional study. Consecutive patients suspected of IIH underwent neurological, neuro-ophthalmologic and psychological examinations, neuroimaging studies and intracranial pressure (ICP) measurements through lumbar puncture in the recumbent position. IIH diagnosis was based on International Classification of Headache Disorders, 2nd Edition criteria; BED diagnosis was based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria. The presence of oligoclonal bands (OCBs) in the cerebrospinal fluid was also assessed. Results Forty-five patients were enrolled: 33 were diagnosed with IIH and five of them (15%) were obese with BED. Compared to non-obese patients, those who were obese, and particularly those who were obese with BED, were more likely to have an IIH diagnosis (χ2 = 14.3; p = 0.001), ICP > 200 mmH2O (χ2 = 12.7; p = 0.002) and history of abuse or neglect (χ2 = 11.2; p = 0.004). No association with OCBs was found. Conclusions We reported for the first time the presence of BED among patients with IIH and showed that BED is associated to IIH, ICP and history of abuse or neglect.