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Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. Methods All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). Results Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p = 0.7074), tryptase ( p = 0.6673), or histamine ( p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. Conclusion Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

Objective: We investigated the efficacy and tolerability of greater occipital nerve block with lidocaine plus betamethasone in adults with chronic migraine in whom two or more previous preventive treatments were unsuccessful. Methods: Ten participants were enrolled in a 24-weeks, randomized, double-blind, placebo-controlled, crossover trial conducted at a single tertiary headache center in Copenhagen (Denmark). After a 4-week run-in period, participants underwent treatment with bilateral greater occipital nerve block with lidocaine plus betamethasone (GONb) or lidocaine plus saline (placebo) with a 4-week interval wash-out phase between the 8-week crossover periods. The primary aim was to compare the number of migraine days during crossover periods after GONb or placebo. This trial is registered at ClinicalTrials.gov (NCT02686983). Results: This study was stopped before achieving the a priori sample size, due to a slow enrollment. Ten participants were recruited, completed the study and were included in the analyses. At the baseline, the mean number of monthly migraine days was 22.9 (range, 14-30). No difference between GONb and placebo on the reduction of monthly migraine days was observed (p = 0.147; 95% CI between 0.6 and 3.7 days). Adverse events were recorded in two patients after GONb, compared with three patients after placebo. Conclusions: GONb is not beneficial in patients with difficult-to-treat chronic migraine.

The treatment of migraine is often complicated by insufficient headache relief, a miscellany of side effects and the risk of developing Medication Overuse Headache (MOH). Novel acute therapies have been recently developed and are now in the early post-marketing phase. Lasmiditan is a highly selective serotonin receptor agonist that binds to the 5-HT1F receptor, while ubrogepant and rimegepant antagonize the calcitonin gene-related peptide receptor. All three medications are now prescribed in a real-world setting, and an adequate level of knowledge is the starting point for rational use. In this rapid systematic review, we have established what is known about lasmiditan, ubrogepant and rimegepant, highlighting the most relevant safety aspects available from published studies and speculating about their risk of MOH.

The involvement of calcitonin gene-related peptide in migraine and cluster headache has led to the recent development of new therapies. Galcanezumab, a novel monoclonal antibody targeting the calcitonin gene-related peptide, is approved for the migraine prevention and has recently been tested for the prevention of cluster headache. Two clinical trials have been conducted to investigate the efficacy and safety of galcanezumab in episodic cluster headache and chronic cluster headache. While efficacy endpoints were not met in the chronic subtype, galcanezumab reduced the weekly frequency of attacks in patients with episodic cluster headaches. In both studies, the antibody was well tolerated. This review summarizes and critically reviews the available data regarding the rationale behind targeting the calcitonin gene-related peptide with galcanezumab for the prevention of cluster headache.

Background In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified. Methods In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo. Results The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo ( p Conclusion Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

OBJECTIVE To narratively review the pathophysiological rationale of dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A in treatment-resistant chronic migraine prevention. BACKGROUND For the prevention of chronic migraine, several pharmacological therapies are available, including oral medications, botulinum toxin type A, and the newly approved monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. However, monotherapy does not yield benefits in some affected individuals, which raises the question of whether dual therapy with monoclonal antibodies and botulinum toxin type A hold promise in patients with treatment-resistant chronic migraine. METHOD We searched MEDLINE for articles published from database inception to December 31st, 2019. Publications were largely selected from the past 10 years but commonly referenced and highly regarded older publications were not excluded. RESULTS Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab - an antibody targeting the calcitonin gene-related peptide - mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers. CONCLUSION There is currently only indirect preclinical evidence to support a rationale for dual therapy with anti-calcitonin gene-related peptide monoclonal antibodies and botulinum toxin type A for chronic migraine prevention. Rigorous studies evaluating clinical efficacy, safety, and cost-effectiveness are needed.

Purpose of the study The pathophysiological mechanism of medication overuse headache is uncertain; no distinctive markers have been described right now. The aim of this study was to conduct proteomic analyses on serum samples from patients with medication overuse headache and healthy individuals. Specifically, mono- (SDS-PAGE) and two-dimensional gel electrophoresis (2-DE) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to evaluate changes in serum proteins. Main findings By SDS-PAGE, four over-expressed bands were revealed in patients, compared to controls. 2-DE combined with LC-MS/MS analysis allowed confirmation of some proteins preliminarily detected by SDS-PAGE: Hemopexin, alpha-1-acid glycoprotein 1, apolipoprotein A4 and haptoglobin. Moreover, other differential proteins were isolated, mostly increased in MOH patients: Alpha-1-antitrypsin, immunoglobulin heavy constant alpha 1, retinol binding protein and transthyretin. Only one protein, immunoglobulin kappa constant, was decreased in the patients’ group. Conclusions The investigation of the serum proteome can offer a better understanding about biological mechanisms underlying medication overuse headache. Specifically, medication overuse headache shares some serum biochemical markers with chronic pain conditions. Further studies might uncover the relevance of these proteins in medication overuse headache.

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP. Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month. Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days. Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo. Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P 0-12h, P =.003; AUC0-180min, P

Background: Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable. In addition, little is known on the factors leading to such heterogeneity. Research design and methods: Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression. Results: Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain (p = 0.045), influenza (p < 0.001) and URTI (p < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis (p < 0.001). Conclusions: Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.

Background Rare primary headaches are mainly included in Chapters 3, Trigeminal autonomic cephalalgias, and 4, Other primary headache disorders, Part One of the International Classification of Headache Disorders 3rd edition. Epidemiological data are scarce, mostly emerging from case series or small studies, with the exception of cluster headache. In order to overcome the knowledge gap about rare primary headaches, the RegistRare Network was launched in 2017 to promote research in the field. Methods A retrospective cohort study including patients who, from April 30, 2014 to May 1, 2017, visited seven Italian tertiary Headache Centres, was undertaken to estimate in that clinical setting prevalence and incidence of headaches included in Chapters 3 and 4, Part One of the International Classification of Headache Disorders 3rd edition. Prevalent headache is defined as a headache recorded within the study timeframe, regardless of when the diagnosis was made. Incident headache is defined as a headache diagnosed for the first time in the patient during the study period. Results Twenty thousand and eighty-three patients visited the participating centres, and 822 (4.1%) prevalent cases, of which 461 (2.3%) were incident cases, were registered. Headaches listed in Chapter 3 affected 668 patients, representing 81.3% of the total number of prevalent cases. Headaches listed in Chapter 4 affected 154 patients and represent 18.7% of the total number of prevalent cases. Cluster headaches represent the most frequently diagnosed rare headaches (70.4%). For 13 entities out of 20, no cases were registered in more than 50% (n ≥ 4) of the centres, and for 14 entities more than 50% of diagnoses were incident. Conclusions This large, multicentre study gives the first wide-ranging snapshot of the burden in clinical practice of rare headaches and confirms that cooperative networks are necessary to study rare headaches, as their prevalence is often very low. The launch of a disease registry by the RegistRare Network will favour research in this neglected population of headache patients. Trial registration NCT03416114.

Migraine, a common neurovascular brain disorder, represents a severe and widespread health problem; along with medication‐induced (medication‐overuse) headache, it is the third‐leading cause of disability worldwide. Currently, its therapeutic management remains unsatisfactory for several reasons; up to 40% of migraineurs are eligible for prophylactic treatment, but there are issues of efficacy, safety, and adherence. In recent years the evidence on the role of calcitonin gene‐related peptide (CGRP) in migraine pathophysiology has been consolidated, so new and promising treatments for migraine pain and its possible prevention have been developed. The following review reports the results of the clinical trials conducted so far with each of the new monoclonal antibodies targeting CGRP or its receptor, with particular reference to safety, tolerance, and efficacy in migraine prevention. Moreover, the pharmacological characterization and further developments of each monoclonal antibody are reported, based on current knowledge.

Background: Nummular headache (NH) is a rare headache disorder characterized by a small, circumscribed painful area of the scalp. The description of many cases in the last years has supported its re-classification as a primary headache from the International Headache Society, moving it from its previous placement in the Appendix of the International Criteria of Headache Disorders. Methods: Data were collected from a retro-prospective observational study about rare headaches promoted by the RegistRare Network, a collaborative group of seven Italian Headache Centres. According to the gender-biased profile of certain primary headaches, we have looked further NH patients from a gender perspective. Results: Nineteen NH patients (11 men, 8 women) have been enrolled in the study. Headache onset was at 39 years and preceded approximately 8 years the diagnosis. No clinically evident differences between men and women have been found, including treatment prescriptions and headache resolution. Of note, the mean time from the onset of NH to the first visit in a Headache Centre was longer in men, compared with women (13.5 vs. 0.9 years). NH attacks were efficaciously treated with nonsteroidal anti-inflammatory drugs in 60% of patients receiving treatment. Headache prophylaxis with pregabalin and amitriptyline has been reported as effective in 40% and 67% of the treated patients, respectively. Conclusions: NH is a primary headache clinically heterogeneous in terms of temporal patterns and pain characteristics. Further research is needed to investigate the existence of male and female phenotypes, by clarifying whether it may be relevant for therapeutic purposes.

BackgroundThe notion that smoking cannabis may damage the respiratory tract has been introduced in recent years but there is still a paucity of studies on this subject. The aim of this study was to investigate the relationship between cannabis smoking, pneumothorax and bullous lung disease in a population of operated patients.Methods and findingsWe performed a retrospective study on patients operated on for spontaneous pneumothorax. Patients were divided into three groups according to their smoking habit: cannabis smokers, only-tobacco smokers and nonsmokers. Cannabis lifetime exposure was expressed in dose-years (1d/y = 1 gram of cannabis/week for one year). Clinical, radiological and perioperative variables were collected. The variables were analyzed to find associations with smoking habit. The impact of the amount of cannabis consumption was also investigated by ROC curves analysis. Of 112 patients, 39 smoked cannabis, 23 smoked only tobacco and 50 were nonsmokers. Median cannabis consumption was 28 dose/years, median tobacco consumption was 6 pack/years. Cannabis smokers presented with more severe chronic respiratory symptoms and bullous lung disease and with a higher incidence of tension pneumothorax than both tobacco smokers and nonsmokers. Cannabis smokers also developed a larger pneumothorax, experienced prolonged postoperative stay and demonstrated a higher incidence of pneumothorax recurrence after the operation than nonsmokers did. The risk of occurrence of chronic respiratory symptoms and bullous lung disease in cannabis smokers was dose-related.ConclusionsCannabis smoking seems to increase the risk of suffering from respiratory complaints and can have detrimental effects on lung parenchyma, in a dose-dependent manner. Cannabis smoking also negatively affected the outcome of patients operated for spontaneous pneumothorax. A history of cannabis abuse should always be taken in patients with pneumothorax. There may be need for a specific treatment for pneumothorax in cannabis smokers.

Recommended medications for the acute treatment of migraine encompass triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. While it is true that triptans have been the first successful mechanism-driven treatment in the field, recently, new targets involved in migraine pathogenesis have emerged and new drug classes have been studied for migraine attack therapy. Areas covered: Pharmacodynamics and pharmacokinetics of the new acute treatments of migraine (i.e. ditans, gepants, and glutamate receptor antagonists), considering also marketed drugs in new formulations and administration routes. Expert opinion: Research on the administration routes of marketed drugs was performed in order to improve, in accordance with basic pharmacokinetics parameters, the speed of action of these medications. Similar to the triptans, the new acute treatments are migraine-specific medications, acting on the trigeminovascular system, albeit with different mechanisms. Although available data do not conclusively indicate the superiority of a class over the others, the pharmacodynamics explains the peculiar tolerability and safety profile of different drug classes emerging from clinical trials. Further studies are needed to investigate the possibility of combining different drug classes to optimize the clinical response and the potential role of the novel drugs in medication-overuse headache.

Background: Systemic Sclerosis (SSc) is a chronic systemic disease frequently leading to disability and low quality of life. Chronic pain (CP), due to severe disease complications and internal organs involvement, is often underestimated. Based on available data around a 60-70% of patient with SSc suffer of chronic pain but we still lacking of fine tools to better evaluate it and follow up patients Objectives: Evaluate pain in SSc patients, in terms of its intensity, sensory and affective components, the interference with physical and social activities, impact on quality of life and correlation with main SSc clinical manifestations. Methods: From January 2013 to January 2018 we retrospectively evaluated 98 patients with a diagnosis of SSc [F/M=87/11; Limited/Diffuse SSc 63/35 anti-Scl70/ACA/ANA nucleolar positivity 45/39/14; mean age 55,6 ± 12,6 DS; mean disease duration 9,9 ± 7,6 DS] according to 2013 ACR/EULAR criteria; 47 patients with a diagnosis of chronic headache (CH) as defined by the International Classification for Headache Disorders, Third Edition beta version (ICHD-3 beta) criteria [F/M 37/10; mean age 52,6 ± 14,2 DS; mean disease duration: 7 ±2 yrs DS] and 46 patients with Rheumatoid Arthritis [F/M 36/10, mean age 61±13, mean disease duration 10±2 yrs, DS]. All patients fulfilled self-complying questionnaires for the evaluation of pain and quality of life: Visual Analogic Scale (VAS), Numeric Rating Scale (NRS), Short Form-McGill Pain Questionnaire (SF-MPQ), Brief Pain Inventory Score (BPI) e Health Assessment Questionnaire (HAQ). Results: SSc patients started to suffer of CP in younger ages compared to AR/CH cohort but patients suffering of CH have higher mean scores in all questionnaires compared to AR/SSc. CH patients, have higher mean score in SFMPQ-sensory and affectory. Hundred percent (100%) of AR patients suffered of chronic pain. They, generally, had higher scores than SSc patients with a prevalence of the affectory component. The 83.9% (67/75 pts) of SSc patients experienced chronic pain [SF-MPQ PRI: 6.25±8.34DS; SF-MPQ PPI: 1.69±1.34DS; BPI-fattore1: 13.37±11.26DS; VAS: 40.7±29.6DS; NRS: 4.08±2.98DS] and in a great majority (84%) that pain interfered with their working activities and social lifes. Fortyeight percent of SSc patients had digital ulcers and 41.3% had musculoskeletal involvement. Pain used to correlate with both of them [p=0.004; p=0.041]. In patients with DUs, affectory component of pain overuled on the sensory one Conclusion: SSc patients frequently experience chronic pain and particularly those who have a history of active DUs and musculoskeletal involvement. By the way, it seems that the BPI questionnaire could be more suitable than VAS or NRS in assessing DUs’ pain. Furthermore it provides useful information on the impact of CP on social life and work impairment. Otherwise, SF_MPQ allows clinicians to better discriminate affective or sensory components of pain. References [1] The impact of systemic sclerosis on health-related quality of life assessed by SF-36: A systematic review and meta-analysis. Li L, et al.; Int J Rheum Dis. 2018 Nov;21(11):1884-1893. Disclosure of Interests: Luca Magnani: None declared, Federica Lumetti: None declared, Emanuele Cocchiara: None declared, Amelia Spinella: None declared, CArlo Baraldi: None declared, Luigialberto Pini: None declared, Lanfranco Pellesi: None declared, Gianluigi Baiocchi: None declared, Carlo Salvarani Grant/research support from: Roche, Consultant for: Eli Lilly and Company, Roche, Abbvie, Dilia Giuggioli: None declared

Cluster headache (CH) is one of the most severe forms of headache, but the number of effective treatments is still limited. Recently, we reported the case of a drug-resistant CH patient responsive to the rotigotine transdermal patch, which is used in the treatment of Parkinson’s disease. This report formed the basis for a case series where other drug-resistant CH patients were treated with rotigotine. Here are the results of this study. Twenty-two CH patients underwent the treatment. Eight were episodic cluster headache (ECH) patients and 14 were chronic cluster headache (CCH) patients. Of the eight ECH patients, four reported that their CH had been stopped by the treatment. Of the 14 CCH patients, 11 were considered responders to the treatment (5 experienced a full resolution of headache, and 6 had a headache reduction of at least 50% in terms of mean monthly number of attacks). Our case series confirms the previous observation that rotigotine could be helpful in the treatment of CH. It may even influence the monoaminergic system that has a key role in the pathogenesis of CH.

The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations. This is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed. Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0–24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0–24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported. Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations.

Drug interactions are one of the most common causes of side effects in polypharmacy. Alcoholics are a category of patients at high risk of pharmacological interactions, due to the presence of comorbidities, the concomitant intake of several medications and the pharmacokinetic and pharmacodynamic interferences of ethanol. However, the data available on this issue are limited. These reasons often frighten clinicians when prescribing appropriate pharmacological therapies for alcohol use disorder (AUD), where less than 15% of patients receive an appropriate treatment in the most severe forms. The data available in literature regarding the relevant drug–drug interactions of the medications currently approved in United States and in some European countries for the treatment of AUD (benzodiazepines, acamprosate, baclofen, disulfiram, nalmefene, naltrexone and sodium oxybate) are reviewed here. The class of benzodiazepines and disulfiram are involved in numerous pharmacological interactions, while they are not conspicuous for acamprosate. The other drugs are relatively safe for pharmacological interactions, excluding the opioid withdrawal syndrome caused by the combination of nalmefene or naltrexone with an opiate medication. The information obtained is designed to help clinicians in understanding and managing the pharmacological interactions in AUDs, especially in patients under multi-drug treatment, in order to reduce the risk of a negative interaction and to improve the treatment outcomes.

Background: Headache disorders are highly prevalent, and have a substantial and negative impact on health worldwide. They are largely treatable, but differences in structure, objectives, organization and delivery affect the quality of headache care. In order to recognize and remedy deficiencies in care, the Global Campaign against Headache, in collaboration with the European Headache Federation, recently developed a set of quality indicators for headache services. These require further assessment to demonstrate fitness for purpose. This is their first implementation to evaluate quality in headache care as a multicentre national study. Methods: Between September and December 2016, we applied the quality indicators in six Italian specialist headache centres (Bologna, Firenze, Modena, Padova, Roma Campus Bio-Medico and Roma Sapienza). We used five previously developed assessment instruments, translated into Italian according to Lifting The Burden’s translation protocol for hybrid documents. We took data from 360 consecutive patients (60 per centre) by questionnaire and from their medical records, and by different questionnaires from their health-care providers (HCPs), including physicians, nurses, psychologists and nursing assistants. Results: The findings, comparable between centres, confirmed the feasibility and practicability of using the quality indicators in Italian specialist headache centres. The questionnaires were easily understood by HCPs and patients, and were not unduly time-consuming. Diagnoses were almost all (> 97%) according to ICHD criteria, and routinely (100%) reviewed during follow-up. Diagnostic diaries were regularly used by 96% of physicians. Referral pathways from primary to specialist care existed in five of the six clinics, as did urgent referral pathways. Instruments to assess disability and quality of life were not used regularly, a deficiency that needs to be addressed. Conclusion: This Italy-wide survey confirmed in six specialist centres that the headache service quality indicators are fit for purpose. By establishing majority practice, identifying commonalities and detecting deficits as a guide to quality improvement, the quality indicators may be used to set benchmarks for quality assessment. The next step is extend use and evaluation of the indicators into non-specialist care. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Background Chronic migraine is one of the most common diseases in the world and it is often associated with medication overuse that can worsen the headache itself. Thus, it is important to adopt effective therapies to relieve pain and improve patients’ quality of life. The PREEMT studies have already demonstrated the effectiveness of OnabotulinumtoxinA in the treatment of chronic migraine. With this in mind, the aim of this real life observation has been to assess the clinical improvements as well as the impact on the quality of life of patients being regularly (every three months) administered this therapy. Methods Data from 66 chronic-migraineurs treated with OnabotulinumtoxinA after failing previous therapies were collected. Only 57 of them were analysed since 9 discontinued the therapy due to administrative reasons. For every patient enrolled, headache frequency, analgesic consumption, pain severity, headache-related disability, health-related quality of life as well as anxiety and depression symptoms were collected through the Headache Index (HI), analgesic consumption rate in one day (AC), VAS score, Headache Impact Test (HIT-6) and the Short Form (36) Health Survey questionnaire Version 2 (SF-36®), Zung Self-Rating Anxiety Scale (ZUNG-A) and Zung Self-Rating Depression Scale (ZUNG-D), respectively. All the changes vs baseline (Tx vs T0) were expressed as mean ± SD and analysed with a one-way ANOVA plus non-parametric Wilcoxon test, that was used for paired data for each subject. Results As the number of injection increased, those patients injected regularly observed a statistically significant reduction in the headache frequency, pain intensity, headache disability score and an overall marked improvement in patients’ quality of life. There was also a significant reduction in anxiety and depressive symptoms as for the ZUNG-A and ZUNG-D scales scores. At any time point, those patients who stopped the therapy worsened their overall conditions as confirmed by quality of life parameters. Conclusions This study outpoints that OnabotulinumtoxinA treatment is an effective treatment to reduce the headache-related disability and improve patients’ quality of life when patients are treated regularly every three months and consistently overtime. Therapy discontinuation leads to a general worsening of health-related quality of life. Long term treatment over one year confirms a consistently positive and sustained trend of improvement with a high safety profile.