Identification of candidate proteomic markers in the serum of medication overuse headache patients: An exploratory study.

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.

A case-control study of visually evoked postural responses in childhood with primary headaches.

BACKGROUND: Disorientation, nausea, confusion, dizziness, and displacement are frequently complained by headache-suffering children. Anyhow, the cause of these symptoms is still unclear, and a dysfunction of vestibular pathways or their alteration due to central pain pathways hyper-activation, has been proposed. The aim of this study is to use posturography to explore the balance function of headache-suffering children during pain-free periods. METHODS: Posturography was performed on 19 migraineurs, 11 tension-type headache sufferers, and 20 healthy controls. Posturographic measures were performed during headache-free periods under different conditions: with eyes opened, eyes closed, and during right and left optokinetic stimulation. The last 2 conditions were used to mimic unreliable visual signals that can confound vestibular system. RESULTS: During eyes-closed conditions, headache-suffering children displayed higher displacements than healthy controls, since statokinesiogram surface was higher in tension-type headache sufferers and migraineurs compared with controls (P value = 0.0095). Romberg's index, indicating the overall stability of the subject, was lower in healthy controls than in headache sufferers (P = 0.0139), thus suggesting a vestibular impairment in the seconds. Moreover, both during right and left optokinetic stimulation, the statokinesiogram length was higher in headache-suffering children (P < 0.0001). Thereafter, statokinesiogram surface was higher in migraineurs during right optokinetic stimulation (P = 0.0388) than in tension-type headache sufferers when stimulation was directed on the opposite side (P = 0.0249). CONCLUSIONS: These results suggest a central alteration of vestibular pathways in headache-suffering children, that makes balance function more dependent from visual inputs than healthy subjects, even in inter-ictal phases.

Exploration of candidate serum biomarkers potentially related to the chronic pain condition in Medication-overuse headache.

BACKGROUND: Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. In previous proteomic studies, several proteins have been found at high concentrations in the urine of MOH patients and in the serum of rats with neuropathic pain. The aim of this study was to compare the serum levels of lipocalin-type Prostaglandin D2 synthase (L-PGDS), Vitamin D-binding protein (VDBP), apolipoprotein E (APOE) and apolipoprotein A1 (APOA1) in MOH patients and healthy individuals, further exploring their relationship with cutaneous pain thresholds (CPTs) in the territories innervated by the trigeminal nerve. METHODS: Sixty-nine MOH patients and 42 age- and sex-matched healthy volunteers were enrolled in the study. Von Frey-like filaments were applied to the skin territories innervated by the trigeminal nerve, to determine the CPTs. L-PGDS, VDBP, APOE and APOA1 were quantified in the serum by Enzyme-linked Immunosorbent Assay (ELISA). Clinical and laboratory data were collected. Comparisons between MOH patients and healthy individuals were performed using independent t test or χ2 test. To correlate serum proteins with CPTs, Pearson correlation coefficient or Spearman's rank correlation coefficient were used. RESULTS: CPTs were lower among MOH patients. L-PGDS, VDBP and APOE had significantly different serum concentrations between groups (p < 0.01), but no correlation was found with CPTs. APOA1 serum concentrations did not differ between patients and healthy individuals. CONCLUSIONS: L-PGDS, VDBP and APOE had abnormal serum levels in MOH patients, confirming their alteration in some conditions of chronic headache and neuropathic pain. However, they had no relationship with CPTs. The in-depth study of serum proteins represents a promising approach for a better understanding of MOH, as well as the detection of candidate biomarkers for chronic headache or the risks associated with overuse medications.

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.

Easy tools to screen Italian women suffering from migraine with and without aura in early reproductive age.

OBJECTIVE: Early diagnosis of migraine with (MA)/without aura (MO) is vitally important to prevent adverse events during combined hormonal contraceptive (CHC) use and to provide personalized surveillance programs during pregnancy. The aim of this study is to provide clinicians with simple and fast tools to diagnose MO and MA in daily clinical practice. STUDY DESIGN: This study was based on a questionnaire to women of early reproductive age (18-35 years old) then randomized to undergo a neurological consultation. The ID-migraine questionnaire (PIN) and visual aura rating scale (VARS) were used. RESULTS: A total of 240 subjects were included in the study, with a total prevalence of MO diagnosed by PIN of 67.0% of subjects with headache, 49.2% of the total study population, and of MA by VARS of 12.5% subjects with headache, 9.2% of the total study population. Eighty-seven neurological examinations were randomly performed: PIN showed a sensitivity of 85.7% (95% CI 75.3%-92.9%) and a specificity of 52.9% (95% CI 27.8%-77.0%), while VARS displayed a sensitivity of 100.0% (95% CI 69.2%-100.0%) and a specificity of 45.5% (95% CI 16.8%-76.6%). CONCLUSION: High sensitivity, in particular for the presence of MA, associated with low specificity suggest that PIN and VARS questionnaires can be effective tools to identify those young patients who require specific neurological examinations in view of the prescription of a CHC or pregnancy planning.

Nabilone administration in refractory chronic diarrhea: a case series.

BACKGROUND: Daily cannabis assumption is currently associated with several physical and mental health problems, however in the past it was prescribed for a multitude of symptoms, including vomiting, abdominal pain and diarrhea. Through the years, the endocannabinoid system has been recognized in the homeostatic mechanisms of the gut, as well as in the physiological control of intestinal motility and secretion. Accordingly, cannabinoids may be a promising therapy against several gastrointestinal conditions, such as abdominal pain and motility-related disorders. CASE PRESENTATION: We retrospectively analysed the efficacy and safety of a CB1-receptor agonist administered in six patients with refractory chronic diarrhea, between April 2008 and July 2016. After three months of therapy, oral nabilone improved the health of nearly all patients, with visible improvements in reducing diarrheal symptoms and weight gain. Most of the benefits persisted through the three-month follow-up. Only one patient interrupted the treatment after one month, due to severe fatigue and mental confusion; the symptoms disappeared in the follow-up period. CONCLUSIONS: These findings encourage the study of cannabinoids acting on CB1 receptors in chronic gastrointestinal disorders, especially in refractory chronic diarrhea, offering a chance for a substantial improvement in the quality of life of selected patients, with a reasonable safety profile.

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine.

BACKGROUND: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. METHODS: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. RESULTS: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. CONCLUSIONS: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Urinary Proteomics in Biomarker Discovery of Kidney-Related Disorders: Diabetic Nephropathy and Drug-Induced Nephrotoxicity in Chronic Headache.

OBJECTIVE: Urinary proteomics is primarily applied to the study of renal and urogenital tract disorders. Here are reported two distinct successful examples of this approach for the discovery of early urinary biomarkers of kidney-related dysfunctions: diabetic nephropathy (DN), a well-known complication of diabetes frequently leading to dialysis, and drug-induced nephrotoxicity, a possible condition caused by medication-overuse headache (MOH). Early detection of kidney disorders based on selective biomarkers could permit to diagnose patients at the initial stage of the disease, where the therapy may be suspended or prevent disease advancement. METHODS: Urine samples were first concentrated and desalted. Subsequently, they were subjected to two-dimensional gel electrophoresis (2-DE) coupled to mass spectrometry (MS) for protein identification. Furthermore, some proteins were verified by Western blot and ELISA test. RESULTS: In diabetes-related study, 11 differentially expressed proteins were detected (8 up-regulated and 3 down-regulated) in type 2 diabetic (T2D) and T2DN patients compared to the healthy control subjects. In the MOH study, a total of 21 over-excreted proteins were revealed in urine of non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures abusers vs controls. Particularly, 4 proteins were positively validated by immunob-lotting and EUSA. CONCLUSION: Urinary proteomics allows non-invasive assessment of renal diseases at an early stage by the identification of characteristic protein pattern.

Genetic variation in CHRNA7 and CHRFAM7A is associated with nicotine dependence and response to varenicline treatment.

The role of nicotinic acetylcholine receptors (nAChR) in nicotine dependence (ND) is well established; CHRNA7, encoding the α7 subunit, has a still uncertain role in ND, although it is implicated in a wide range of neuropsychiatric conditions. CHRFAM7A, a hybrid gene containing a partial duplication of CHRNA7, is possibly involved in modulating α7 nAChR function. The aim of this study was to investigate the role of CHRNA7 and CHRFAM7A genetic variants in ND and to test the hypothesis that α7 nAChR variation may modulate the efficacy of varenicline treatment in smoking cessation. We assessed CHRNA7 and CHRFAM7A copy number, CHRFAM7A exon 6 ∆2 bp polymorphism, and sequence variants in the CHRNA7 proximal promoter in an Italian sample of 408 treatment-seeking smokers. We conducted case-control and quantitative association analyses using two smoking measures (cigarettes per day, CPD, and Fagerström Test for Nicotine Dependence, FTND). Next, driven by the hypothesis that varenicline may exert some of its therapeutic effects through activation of α7 nAChRs, we restricted the analysis to a subgroup of 142 smokers who received varenicline treatment. The CHRNA7 promoter variant rs28531779 showed association with both smoking quantitative measures (FNTD p = 0.026, ß = 0.89, 95% CI 0.11-1.67; CPD p = 0.006, ß = 4.82 95% CI 1.42-8.22). Moreover, in the varenicline-treated subgroup we observed association of CHRFAM7A copy number with 6 months smoking abstinence (p = 0.035, OR = 3.18, 95% CI = 1.09-9.30). Thus, our study points to a possible role of genetic variation in CHRNA7 and CHRFAM7A in tobacco addiction mechanisms and response to varenicline treatment.

Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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-drug interactions in the treatment for alcohol use disorders: A comprehensive review.

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.

Optimizing the long-term management of chronic migraine with onabotulinumtoxinA in real life.

INTRODUCTION: Management of chronic migraine is challenging. OnabotulinumtoxinA (OBT-A) is the only medication licensed for prevention of chronic migraine, and has been widely adopted in clinical practice. Limited data is available on its long-term use. Areas covered: Data from controlled trials are combined with available data on the long-term use of OBT-A in real-life studies, with information obtained in a recent survey among Italian headache centers, and the clinical experience of the authors. Six areas were identified as relevant to patients with chronic migraine: 1) definition of responders to OBT-A; 2) management of responders to OBT-A; 3) optimal timing of prophylaxis with OBT-A; 4) position of OBT-A in prevention of chronic migraine; 5) management of medication overuse, and 6) patient education. Expert commentary: This review provides an update on the latest evidence regarding the long-term use of OBT-A in chronic migraine and analyzes the critical issues in the decision-making process that emerge from the analysis of the literature and routine practice. A treatment algorithm is proposed for the adoption in the daily practice.

Long-term Treatment Benefits and Prolonged Efficacy of OnabotulinumtoxinA in Patients Affected by Chronic Migraine and Medication Overuse Headache over 3 Years of Therapy.

BACKGROUND: Chronic migraine (CM) affects about the 2% of the general population and it has been recognized as one of the most-disabling conditions worldwide by the World Health Organization. CM is often associated with the overuse of abortive medication, which determines the worsening of headache itself and the development of a secondary headache called medication overuse headache. The management of these associated conditions is difficult, but a growing amount of evidence is pointing out the effectiveness and the good safety profile of OnabotulinumtoxinA (OnabotA). Despite this, data on OnabotA effects and safety in long-term use lack. The purpose of the present article is to retrospectively assess the efficacy and safety of OnabotA in a cohort of chronic migraineurs with drug overuse from the 18th month of treatment until the third year. MATERIALS AND METHODS: 90 chronic migraineurs with medication overuse were enrolled between January 2013 and February 2017. All patients were treated with OnabotA according to PREEMPT dictates. Before every injection session the headache index, the analgesic consumption, the visual analog scale for pain score, the 36-items short form health survey questionnaire score, the 6-items headache impact test (HIT-6) score and the Zung self-rating anxiety and depression scale scores were collected. Adverse events were carefully registered. A simple linear regression was performed to explore the mean changes in the abovementioned parameters for a single injection session and mean comparison tests were performed using the one-way analysis of variance followed by Tukey-Kramer post-hoc test. RESULTS: A significantly improvement for a single injection was registered for all the above-mentioned parameters. Headache index, analgesic consumption, visual analog pain scale, and 6-items HIT-6 scores were significantly lower than baseline from the 18th month of treatment onwards. The 36-items short form health survey questionnaire scores were significantly higher than baseline at every injections session from the 18th months onwards. Zung scales did not change. No serious adverse events were assessed and no adverse events-related drop-outs were seen. CONCLUSION: OnabotA effectiveness and safety last until 3 years of therapy, raising the possibility of the use of this therapy even for many years in CM prevention.

A Critical Evaluation on MOH Current Treatments.

OPINION STATEMENT: Migraine is the most frequent neurological disorder observed in clinical practice characterized by moderate to severe pain attacks associated with neurological, gastrointestinal, and dysautonomic symptoms. Each year, 2.5% of patients with episodic migraine develop chronic migraine (CM). CM is characterized by high frequency of the attacks that may result into chronic intake of abortive medications. Nearly, the 70% of CM patients referring to tertiary head centers show acute pain medications overuse that may lead to the development of medication overuse headache (MOH). The management of MOH requires three steps: (1) education, (2) withdrawal of the overuse drug and detoxification, and (3) re-prophylaxis. In the last years, several real-life prospective studies provided further evidence in clinical setting of the onabotulinumtoxinA 155-195 U efficacy for the headache prophylaxis in CM with MOH patients. There is a general agreement on two factors: (1) withdrawal of the overuse drug is condicio sine qua non to reverse the pattern to medium-low-frequency migraine, and (2) the focus of management needs to shift from acute treatment of pain to prevention of headache. CM patients close to developing MOH, patients with high-frequency episodic migraine, and those already abusing of drugs require special attention and should refer to tertiary headache centers. For all of them, a solution could be an "early treatment." Early should be their referral to a tertiary headache center, early should be the withdrawal of the overuse drug and a proper detoxification, and perhaps early should be the start of a preventative therapy.

Therapeutical approaches to paroxysmal hemicrania, hemicrania continua and short lasting unilateral neuralgiform headache attacks: a critical appraisal.

BACKGROUND: Hemicrania continua (HC), paroxysmal hemicrania (PH) and short lasting neuralgiform headache attacks (SUNCT and SUNA) are rare syndromes with a difficult therapeutic approach. The aim of this review is to summarize all articles dealing with treatments for HC, PH, SUNCT and SUNA, comparing them in terms of effectiveness and safety. METHODS: A survey was performed using the pubmed database for documents published from the 1st January 1989 onwards. All types of articles were considered, those ones dealing with symptomatic cases and non-English written ones were excluded. RESULTS: Indomethacin is the best treatment both for HC and PH. For the acute treatment of HC, piroxicam and celecoxib have shown good results, whilst for the prolonged treatment celecoxib, topiramate and gabapentin are good options besides indomethacin. For PH the best drug besides indomethacin is piroxicam, both for acute and prolonged treatment. For SUNCT and SUNA the most effective treatments are intravenous or subcutaneous lidocaine for the acute treatment of active phases and lamotrigine for the their prevention. Other effective therapeutic options are intravenous steroids for acute treatment and topiramate for prolonged treatment. Non-pharmacological techniques have shown good results in SUNCT and SUNA but, since they have been tried on a small number of patients, the reliability of their efficacy is poor and their safety profile mostly unknown. CONCLUSIONS: Besides a great number of treatments tried, HC, PH, SUNCT and SUNA management remains difficult, according with their unknown pathogenesis and their rarity, which strongly limits the studies upon these conditions. Further studies are needed to better define the treatment of choice for these conditions.

Onabotulinumtoxin A for the management of chronic migraine in current clinical practice: results of a survey of sixty-three Italian headache centers.

BACKGROUND: Chronic migraine is a complex clinical condition often undertreated. Onabotulinumtoxin A (OBT-A) was approved in Italy in 2013 for symptom relief in patients with chronic migraine who have failed, or do not tolerate, oral prophylactic treatments. However, the impact of OBT-A in clinical practice remains to be defined. METHODS: To investigate the current management of chronic migraine with OBT-A in clinical practice, a web-based survey was conducted among clinicians working in third-level headache centers across Italy. A 26-item questionnaire was designed and developed by a group of 10 Italian headache specialists to address the following issues: treatment paradigm and OBT-A injection intervals, frequency of treatment and retreatment, definition of responders/non-responders, satisfaction with treatment potential impact of early treatment with OBT-A. Ninety-six headache centers were selected and contacted via e-mail. The online survey was anonymous and carried out using a secure website. RESULTS: Overall, 64 of the 96 centers (66.7%) completed the questionnaire. Most centers (98.4%) had been using OBT-A for >1 year. OBT-A was administered according to the PREEMPT paradigm in most centers (88.9%). While during the first year of prophylaxis with OBT-A most clinicians (93.6%) repeated OBT-A treatment every 3 months, as recommended, in the following years interval duration was variable. Response to OBT-A was defined as a ≥ 50% reduction in the headache days by 58.7% of the clinicians, and as a ≥ 30% reduction by 25.4% of them. Almost 60% of the clinicians considered OBT-A as a long-lasting therapy, while for one-third of them treatment could be discontinued in patients showing a benefit for ≥6 months. According to 80% of the clinicians, early administration of OBT-A after the onset of chronic migraine was associated with better outcomes, and 47.6% felt that OBT-A should be recommended as a first-line option. CONCLUSIONS: This survey indicates that in third-level headache centers in Italy OBT-A is used in good compliance with current recommendations. There is agreement about the definition of response as a reduction in headache days by 30% to 50%. Additional effort is required to define response to OBT-A and to establish optimal treatment duration.

Spotlight on Anti-CGRP Monoclonal Antibodies in Migraine: The Clinical Evidence to Date.

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.

Serum protein changes in a rat model of chronic pain show a correlation between animal and humans.

In previous works we showed the overexpression of some proteins in biological fluids from patients suffering chronic pain. In this proteomic study we analysed serum from a rat model of neuropathic pain obtained by the chronic constriction injury (CCI) of sciatic nerve, at two time intervals, 2 and 5 weeks after the insult, to find proteins involved in the expression or mediation of pain. Sham-operated and CCI rats were treated with saline or indomethacin. Two weeks after ligation, we identified three serum proteins overexpressed in CCI rats, two of which, alpha-1-macroglobulin and vitamin D-binding protein (VDBP), remained increased 5 weeks post-surgery; at this time interval, we found increased levels of further proteins, namely apolipoprotein A-I (APOA1), apolipoprotein E (APOE), prostaglandin-H2 D-isomerase (PTGDS) and transthyretin (TTR), that overlap the overexpressed proteins found in humans. Indomethacin treatment reversed the effects of ligation. The qPCR analysis showed that transcript levels of APOA1, APOE, PTGDS and VDBP were overexpressed in the lumbar spinal cord (origin of sciatic nerve), but not in the striatum (an unrelated brain region), of CCI rats treated with saline 5 weeks after surgery, demonstrating that the lumbar spinal cord is a possible source of these proteins.

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants.

BACKGROUND: Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms. METHODS: We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH. RESULTS: Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P = 9.1 × 10-6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P = 2.5 × 10-5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin. CONCLUSIONS: Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.