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Background: A plethora of studies have attempted to identify genetic determinants of disease susceptibility and treatment response of patients with cluster headache (CH), but results are often conflicting, and no comprehensive overview with a quantitative summary of the evidence in this field is available., Methods: A systematic search of relevant publications was performed without any language restrictions on PubMed, Web of Knowledge, Cochrane Library, and OpenGrey, up to December 2020. A standardized data extraction form was used to collect relevant data from each included study. Meta-analyses were conducted for gene polymorphisms investigated in at least two studies and the Bayesian false discovery probability (BFDP) test was applied to the pooled odds ratios (ORs) to assess the credibility of the observed associations., Results: Among the 27 articles identified by the systematic review, 17 studies evaluating 12 single nucleotide polymorphisms (SNPs) were included in the quantitative data analysis. The pooled results showed no significant association with CH risk of 10 SNPs, including five SNPs of HCRTR2 (rs2653349, rs2653342, rs3122156, rs10498801, and rs3800539), two SNPs of ADH4 (rs1800759 and rs1126671), CLOCK rs1801260, and two SNPs (rs1006417 and ADCYAP1R1 rs12668955) previously identified by a genome-wide association study (GWAS). Conversely, the pooled results revealed the association of the HCRTR2 rs9357855 A allele with a higher risk of CH (A vs. G, OR: 1.33, 95% CI: 1.04-1.72, p = 0.026), and of GNB3 rs5443 with a higher response rate of patients with CH to triptan drugs (CT+TT vs. CC, OR: 1.96, 95% CI: 1.04-3.72, p = 0.038). However, assuming a prior probability of 0.001, the respective BFDP values being higher than 0.8 (BFDP rs9357855  = 0.998; BFDP rs5443  = 0.998) revealed lack of noteworthy results., Conclusions: Well-designed GWASs and large replication studies are still needed to identify reliable genetic variants of disease susceptibility and treatment response of patients with CH., (© 2021 American Headache Society.)

Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population., Method: This descriptive cross-sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self-administered questionnaires for measuring disability, anxiety, and depression., Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T-MOH) with respect to subjects overusing simple analgesic (A-MOH). Duration of headache before chronification was longer in T-MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E-MOH, 17.8 ± 11.7 years) with respect to the A-MOH group (13.1 ± 10.9; P < .001 and P = .017, respectively) and in T-MOH with respect multiple drug classes (M-MOH, 14.9 ± 11.7; P = .030). Migraine Disability Assessment (MIDAS) score was significantly lower in E-MOH group (33.6 ± 41.6), while T-MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M-MOH (67.2 ± 62.5; P = .016 and P = .037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ 2  = 10.953, P = .027 and χ 2  = 25.725, P < .001, respectively)., Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache., (© 2019 American Headache Society.)

Objectives/background: We herein investigated the role of polymorphisms in calcitonin gene-related peptide (CGRP)-related genes looking at the association of rs3781719 (T > C) in the calcitonin gene-related polypeptide-alpha (CALCA) gene and of rs3754701 (T > A) and rs7590387 (C > G) at the receptor activity modifying 1 (RAMP1) locus with triptan response in patients with migraine without aura (MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache (MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP-related genes as determinants of clinical response to anti-migraine drugs or as risk factors for migraine chronification., Methods: Genotyping was conducted retrospectively by real-time polymerase chain reaction allelic discrimination assay in 219 patients with MwoA and 130 with MOH in whom migraine was the primary headache type. Gene variants association was evaluated by logistic regression analysis adjusted by confounding factors. The threshold of statistical significance was set according to the total number of polymorphisms analyzed in the current study and in previous publications arising from overlapping datasets., Results: No evidence of association was found between the three polymorphisms tested and triptan response in MwoA patients. Conversely, carriers of RAMP1 rs7590387GG displayed a lower risk of episodic migraine transformation into MOH (vs C allele carriers, odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.13-0.57, P = 0.0002; threshold of significance set at P < 0.0029). When genotype distribution for RAMP1 rs7590387 was compared between healthy controls (n = 209) and MOH patients, carriers of rs7590387GG were found at lower risk of developing MOH (OR: 0.43, 95%CI: 0.22-0.85, P = 0.011)., Conclusion: These results suggest that RAMP1 rs7590387 may have a role in the transformation of episodic migraine into MOH., (© 2015 American Headache Society.)

Objectives: We investigated (1) a possible relationship between the functional activity of the endocannabinoid system and the facilitation of pain processing in migraineurs with medication-overuse headache, and (2) the effect of withdrawal treatment on both., Background: The endocannabinoid system antinociception effect includes prevention of nociceptive pathways sensitization. The sensitization of the pain pathways has been demonstrated to be pivotal in the development and maintenance of chronic form of migraine, including medication-overuse headache., Methods: We used the temporal summation threshold of the nociceptive withdrawal reflex to explore the spinal cord pain processing, and the platelet activity of the enzyme fatty acid amide hydrolase to detect the functional state of the endocannabinoid system in 27 medication-overuse headache subjects before and 10 and 60 days after a standard withdrawal treatment and compared results with those of 14 controls., Results: A significantly reduced temporal summation threshold and increased related pain sensation was found in subjects before withdrawal treatment when compared with controls. A significant fatty acid amide hydrolase activity reduction coupled with a significant improvement (reduction) in facilitation of spinal cord pain processing (increase in temporal summation threshold and reduction in related pain sensation) was found in medication-overuse headache subjects at both 10 and 60 days after withdrawal treatment when compared with medication-overuse headache subjects before withdrawal treatment., Conclusions: We demonstrated a marked facilitation in spinal cord pain processing in medication-overuse headache before withdrawal treatment when compared with controls. Furthermore, the acute reduction of the fatty acid amide hydrolase activity coupled with a reduction of the facilitation in pain processing immediately (10 days) after withdrawal treatment and its persistence 60 days after withdrawal treatment could represent the consequence of a mechanism devoted to acutely reduce the degradation of endocannabinoids and aimed to increase the activity of the endocannabinoid system that results in an antinociceptive effect., (© 2012 American Headache Society.)

Background: Medication-overuse headache (MOH) refers to headache attributed to excessive use of acute medications. The role of personality needs studies to explain the shifting from drug use to drug abuse. The main aim of this study is to study personality, according to Minnesota Multiphasic Personality Inventory, comparing MOH, episodic headache, substance addicts (SA) vs healthy controls., Methods: Eighty-two MOH patients (mean age 44.5; 20 M, 62 F) and 35 episodic headache (mean age 40.2; 8 M, 27 F), were compared to 37 SA (mean age 32.5; 29 M, 8 F) and 37 healthy controls (mean age: 32.49; 20 M, 17 F). International Classification of Headache Disorders 2nd Edition criteria were employed. Chi-square test, Kruskal-Wallis test, and post hoc comparisons were used for statistics., Results: MOH patients scored higher on Hypochondriasis, Depression (only females), Hysteria (only females) (P < .000). MOH did not show higher scores than episodic headache or healthy controls in dependency scales, while SA did., Conclusion: The data obtained show that MOH and SA do not share common personality characteristics linked to dependence. Although further studies are needed to understand if such a difference is related to instrumental characteristics or to yet undiscovered psychobiological characteristics of MOH patients; however, we hypothesize that the detected difference may rely on the fact that drug dependence in the 2 groups is promoted by entirely different needs: pleasure seeking in the SA group, pain avoidance in the MOH group., (© 2011 American Headache Society.)

Objective: The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption., Background: Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month., Methods: Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month., Results: No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann-Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients., Conclusions: Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients., (© 2010 American Headache Society.)

Background: A high prevalence of nocturnal sleep-related attacks is reported in patients with cluster headache (CH). Episodic CH is considered closely related to rapid eye movement (REM) sleep., Objective: The aim of this study was to analyze the relationships between episodic CH attacks and sleep macrostructure., Methods: Data were obtained by means of 24-hour continuous ambulatory polysomnography (PSG) capturing CH attacks in 4 out of 7 episodic CH patients (all males; mean age 38.4 +/- 9.2 years) studied., Results: Eight CH attacks were captured during the PSG monitoring; 5 arose from sleep: 4 from non-rapid eye movement (NREM) sleep (stage 2 NREM), and 1 from REM sleep. One patient experienced CH attacks during both NREM and REM sleep in the same night., Conclusions: In the light of previous literature findings, the prevalence of NREM-related episodic CH attacks observed, and the finding of attacks arising during both REM and NREM sleep in the same subject, suggest that the relationship between CH and sleep stages is heterogeneous, and the existence of a specific macrostructural pattern associated with episodic CH attacks appears to be uncertain. A more comprehensive approach taking into account the microstructure of NREM and REM sleep is expected to provide more in depth information about the pathophysiology of CH, whose complexity might overcome the simplistic dichotomy of REM/NREM staging.

Hemicrania continua (HC) belongs to the group of primary headaches and it is characterized by a strictly unilateral, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied by trigeminal autonomic features. The syndrome is completely responsive to indomethacin. Here we report a case of a 49-year-old man with HC, which may be viewed as a combination of different types of headache, ie, chronic tension-type headache and trigeminal autonomic cephalalgia. The analysis of this case raises interesting issues regarding the proper place of HC among the primary headache forms.

Objective: The main aim of this study involves comparing the personality profiles of patients with medication-overuse headache (MOH) and episodic headaches, in order to elucidate the role of personality characteristics, according to one of the most widely used and validated personality assessment tool: Minnesota Multiphasic Personality Inventory (MMPI-2)., Background: Many studies have assessed the personality of headache patients by means of MMPI-2 only using clinical and content scales. In this study the supplementary scales were also used as they evaluate different aspects of personality, particularly broad personality characteristics, generalized emotional distress and behavioral dyscontrol., Methods: We recruited 219 subjects (151 women and 68 men) who were grouped in the following categories: MOH group (n = 82); episodic headache group (n = 82; 58 migraine aura; 6 migraine with aura; 6 frequent episodic tension-type headache; 12 migraine+infrequent episodic tension-type headache) and 1 group of 55 healthy controls. MMPI-2 was employed. Data were computed with one-way anova and post hoc analyses., Results: Medication-overuse headache and episodic headache patients (EH) showed a very similar pattern, differentiating each other only in the Hypochondriasis (Hs) (P = .007; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88] and Health Concerns [HEA]) (P = .005; MOH: mean 14.06 [SD 5.38]; EH: mean 11.81 [SD 5.59]) scales. Surprisingly, no differences were found between the 3 groups in the scales measuring dependence-related behavior such as Addiction Potential Scale (Aps) and Addiction Admission Scale (Aas). MOH and episodic headache patients scored significantly higher in the so-called neurotic scales Hs (P < .0001; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88];, Controls: mean 5.91 [SD 3.57]), Depression (D) (P < .0001; MOH: mean 26.44 [SD 7.01]; EH: mean 26.09 [SD 5.85];, Controls: mean 21.47 [SD 4.90]), and Hysteria (Hy) (P < .0001; MOH: mean 27.33 [SD 5.51]; EH: mean 26.81 [SD 5.68];, Controls: mean 21.95 [3.85]) and in many other scales such as Paranoia (Pa), Psychasthenia (Pt), Schizophrenia (Sc) while they scored significantly lower on Ego Strength (Es) and Dominance (Do) scales when compared with controls., Conclusions: Patients with MOH and episodic headache showed very similar patterns, differentiating only in the Hypochondriasis and Health Concerns scales. Surprisingly, there were no significant differences in the scores of the scales measuring dependence-related behavior. The clinical role of MMPI-2 in discriminating MOH patients with dependency from drugs is discussed, in order to implement a complete tests' battery for headache patients' assessment.

Objective: To quantify and characterize the similarities and the differences between chronic migraine (CM) patients with medication overuse and episodic migraine (EM) patients with only occasional analgesic use., Background: Population-level epidemiology, characteristics, mechanisms of chronic daily headache, and medication-overuse headache have been widely studied but patient characteristics have received less attention. Methods.-We compared sociodemographic data, family history, physiological and medical history, health services utilized, drugs taken/prescribed, and outcome of 2 groups of subjects: 150 patients, suffering from CM, complicated by probable medication-overuse headache (CM group), consecutively admitted during 2005 to the inpatients' ward of the Headache Centre of the University Hospital of Modena and Reggio Emilia, Italy, to undergo withdrawal from their overused medications; 100 patients suffering from EM, uncomplicated by medication overuse (EM group), consecutively referred to the outpatients' ward of the Headache Centre during November and December 2005., Results: All sociodemographic characteristics were significantly different between the 2 groups. As a whole, the CM group began to suffer from migraine earlier than the EM group. Drug and/or alcohol abuse was significantly higher among first-degree relatives of CM (19%) than of EM (6%) patients. The most frequent comorbid disorders were psychiatric (67%) and gastrointestinal diseases (43%) in the CM group, and allergies in the EM group (31%). Seventy percent of CM patients and 42% of EM patients were taking daily at least another drug, besides those for headache treatment. Most overused medications in the CM group were triptans (43%); the EM group used above all single NSAIDs (56%). At 3-month follow-up, prophylactic treatments reduced, by at least 50%, the frequency of headache in about three-fourths of patients of both the groups; however, headache remained significantly more frequent in the CM than in EM group: only a minority (15%) of CM patients reverted to a headache frequency comparable to that of the EM group., Conclusions: CM patients present more multiple comorbid disorders, polypharmacy, and social impediments than EM patients. These associated conditions complicate CM clinical management. Even after withdrawal from medication overuse, CM could not be completely reverted by current prophylactic treatments.

Purpose: To investigate clinical, MRI, and radioisotope findings and therapeutic outcome of the syndrome of spontaneous intracranial hypotension (SIH)., Background: Spontaneous intracranial hypotension is characterized by orthostatic headache, low CSF pressure, and MRI findings of diffuse pachymeningeal gadolinium enhancement without previous history of head trauma or lumbar puncture. Spontaneous CSF leakage from a spinal dural tear has been suggested as the underlying pathogenic mechanism of SIH. Most patients recover without sequelae, but subdural collections have been described in a few., Methods: Twelve consecutive patients (10 females, 2 males, mean age 39 years) with headache related to the syndrome of spontaneous intracranial hypotension were investigated., Results: Eleven patients presented orthostatic headache, one patient had continuous nonpostural headache. Additional clinical symptoms included nausea, vomiting, tinnitus, diplopia, and back pain. All the patients had low CSF opening pressure, seven had increased CSF albumin, and four had pleocytosis. Brain MRI showed diffuse pachymeningeal gadolinium enhancement. Other features included subdural fluid collections (hematoma/hygroma) in four patients, downward displacement of the brain in four patients, and enlargement of the pituitary gland in one patient. Radioisotope cisternography results indicated, in two patients, a CSF leakage site in the cervico-thoracic region, and in one patient showed limited ascent of the tracer to the cerebral convexity and early appearance of radioisotope in the bladder. All the patients had complete resolution of headache with conservative treatment., Conclusions: Patients with SIH have distinct MRI and sometimes radioisotope cisternographic abnormalities and generally respond favorably to conservative management.

Objective: To evaluate the effects of three schemes of oral hormone replacement therapy (HRT) on migraine course in postmenopausal women., Methods: Thirty-eight patients presenting for clinical evaluation of menopausal status and suffering from migraine were enrolled. The observational period lasted 7 months, during which women filled in a daily diary with the clinical features of headache attacks and analgesic use. We evaluated climacteric symptoms, anxiety and depression. After a 1-month run-in period, women were assigned to one of three regimens of HRT: estradiol hemihydrate 1 mg/day plus norethisterone 0.5 mg/day for 28 days, in a continuous combined scheme; oral conjugated estrogens 0.625 mg/day for 28 days plus medroxyprogesterone acetate 10 mg/day in the last 14 days, in a sequential continuous scheme; and estradiol valerate 2 mg/day for 21 days plus cyproterone acetate 1 mg/day from day 12 to 21 in a sequential cyclical scheme. Follow-up evaluations were performed at 3 and 6 months., Results: During the run-in period, the three subgroups of patients were similar as far as the features of migraine are concerned. Overall, a progressive increase in attack frequency (from 2.2 +/- 1.0 to 3.8 +/- 1.3, P<.001), days with headache (from 3.4 +/- 1.3 to 4.9 +/- 1.9, P<.001), and analgesic consumption (from 3.4 +/- 1.3 to 5.6 +/- 2.2, P<.001) was observed after 6 months. Duration of attacks decreased (from 18.1 +/- 7.4 to 13.6 +/- 4.2 hours, P =.005), whereas severity worsened (from 1.9 +/- 0.2 to 2.1 +/- 0.2, P<.001). The increase in number of days with headache and number of analgesics used was smaller in the group receiving the continuous combined regimen than in the other two groups., Conclusion: Although HRT typically will lead to some worsening of headache syndrome, estradiol hemihydrate plus norethisterone given in a combined continuous scheme was the regimen best tolerated by our patients.

A retrospective study was conducted on 1300 women suffering from migraine without aura referred to the Headache Centers of Parma and Pavia from 1984 to 1990. All the data concerning their reproductive life, and the modifications induced by it on the course of headache were obtained from record-charts. Migraine frequently started at menarche (10.7%); in 60% of cases the migraine attacks occurred mostly or exclusively in the perimenstrual period, in 67% of cases disappeared during pregnancy, and in 24.1% significantly (P < 0.0001) worsened with "pill" intake. This study also designated a migraine subgroup which is more influenced by changes in sexual hormones, i.e. migraine with onset at menarche. This form of migraine shows more frequently a menstrual periodicity, and usually improves during pregnancy. Furthermore, menstrual migraine patients show social and cultural characteristics with distinguish them from other women.

The effects of oral Magnesium (Mg) pyrrolidone carboxylic acid were evaluated in 20 patients affected by menstrual migraine, in a double-blind, placebo controlled study. After a two cycles run-in period, the treatment (360 mg/day of Mg or placebo) started on the 15th day of the cycle and continued till the next menses, for two months. Oral Mg was then supplemented in an open design for the next two months. At the 2nd month, the Pain Total Index was decreased by both Placebo and Mg, with patients receiving active drug showing the lowest values (P less than 0.03). The number of days with headache was reduced only in the patients on active drug. Mg treatment also improved premenstrual complaints, as demonstrated by the significant reduction of Menstrual Distress Questionnaire (MDQ) scores. The reduction of PTI and MDQ scores was observed also at the 4th month of treatment, when Mg was supplemented in all the patients. Intracellular Mg++ levels in patients with menstrual migraine were reduced compared to controls. During oral Mg treatment, the Mg++ content of Lymphocytes (LC) and Polymorphonucleated cells (PMN) significantly increased, while no changes in plasma or Red Blood Cells were found. An inverse correlation between PTI and Mg++ content in PMN was demonstrated. These data point to magnesium supplementation as a further means for menstrual migraine prophylaxis, and support the possibility that a lower migraine threshold could be related to magnesium deficiency.

In this study, the efficacy of Naproxen sodium (Nxs) in the prophylaxis of Menstrual Migraine (MM) was tested, versus Placebo (PL). Forty women suffering from MM were admitted to a double-blind treatment protocol with Nxs 550 mg twice each day by mouth or Placebo (PL), for 3 months; in the next 3 months all the women were treated with the active drug in an open study. The headache intensity and duration, as well as the number of days of headache and the analgesic consumption, were significantly reduced with Nxs compared to PL. The efficacy of Nxs, shown also in improving premenstrual pain, and its good tolerability, support the use of this drug in the prophylactic therapy of MM.