Randomised clinical trial comparing melatonin 3†mg, amitriptyline 25†mg and placebo for migraine prevention.

INTRODUCTION: Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use. METHODS: A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18-65 years, with migraine with or without aura, experiencing 2-8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups. RESULTS: Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users. CONCLUSIONS: Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

Generalized anxiety disorder, subthreshold anxiety and anxiety symptoms in primary headache.

AIMS: The aim of the present study was to evaluate the association between generalized anxiety disorder, subthreshold anxiety (SubAnx) and anxiety symptoms in the prevalence of primary headache. METHODS: This cross-sectional study evaluated 383 people from a Brazilian low-income community. One-year prevalence rates of migraine, chronic migraine and tension-type headache were calculated. Anxiety symptoms were then separated into the following groups (based on DSM-IV criteria): no anxiety criteria; one anxiety criterion; two anxiety criteria; and generalized anxiety disorder (GAD). The control group (no headaches) was compared with headache sufferers for each anxiety group using an adjusted model controlled for confounding factors. RESULTS: GAD was present in 37.0% of participants and SubAnx in 16.6%. Those with SubAnx had a 2.28-fold increased chance of having migraine; 3.83-fold increased chance of having chronic migraine, a 5.94-fold increased chance of having tension-type headache and a 3.27-fold increased chance of having overall headache. Some anxiety criteria (irritability, difficulty with sleep, concentration problems, muscle tension and fatigue) had similar prevalence to International Classification of Headache Disorders (ICHD-II) headache criteria such as unilateral pain and nausea for migraine and chronic migraine. CONCLUSION: Headache sufferers seem to have a high prevalence of anxiety symptoms and SubAnx. In addition, the presence of two or more anxiety criteria (not necessarily fulfilling all the criteria for GAD) was associated with having a headache disorder.

Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities.

OBJECTIVE: To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. BACKGROUND: Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. METHODS: Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. CONCLUSIONS: To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

A nationwide population-based study of tension-type headache in Brazil.

OBJECTIVES: To estimate the 1-year prevalence of tension-type headache (TTH) and the degree of the association of TTH with some sociodemographic characteristics of a representative sample of the adult population of Brazil. METHODS: This was an observational, cross-sectional, population-based study. We conducted telephone interviews on 3848 people, aged 18-79 years, randomly selected from the 27 states of Brazil. Trained lay interviewers administered the structured questionnaire. It included questions about the sociodemographic characteristics of the population, as well as questions about headache. The degree of the association was calculated through prevalence ratios, adjusted with Poisson regression by gender, age, years of education, marital status, household income, job status, body mass index (BMI), and physical exercise. RESULTS: The estimated 1-year gender- and-age-adjusted prevalence of TTH was 13.0% (95% CI: 11.8-14.2%); 15.4% in males and 9.5% in females. The prevalence of probable TTH was 22.6% (95% CI: 21.1-24.1%). Most (86.2%) subjects reported episodic TTH; 6.4% had chronic TTH. The prevalence was higher at 18-29 years of age (16.2%). TTH was 1.6 times more prevalent in men, and 1.54 times more in subjects with more than 11 years of education. There was no significant association of TTH with marital or job status, household income, BMI, and physical activity. CONCLUSION: This is the first nationwide epidemiological study of TTH in Brazil. The overall prevalence of TTH in Brazil is low, at 13%. TTH is significantly more prevalent in males and subjects with higher education level.

Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin.

The aim of the present work was to analyze c-fos response within the trigeminal nucleus caudalis (TNC) of pinealectomized rats and animals that received intraperitoneal melatonin, after intracisternal infusion of capsaicin, used to induce intracranial trigeminovascular stimulation. Experimental groups consisted of animals that received vehicle solution (saline-ethanol-Tween 80, 8:1:1, diluted 1:50) only (VEI, n=5); animals that received capsaicin solution (200 nM) only (CAP, n=6); animals submitted to pinealectomy (PX, n=5); sham-operated animals (SH, n=5); animals submitted to pinealectomy followed by capsaicin stimulation (200 nM) after 15 days (PX + CAP, n=7); and animals that received capsaicin solution (200 nM) and intraperitoneal melatonin (10 mg/kg) (CAP + MEL, n=5). Control rats, receiving vehicle in the cisterna magna, showed a small number of c-fos-positive cells in the TNC (layer I/II) as well as the sham-operated and pinealectomized rats, when compared to animals stimulated by capsaicin. On the other hand, pinealectomized rats, which received capsaicin, presented the highest number of c-fos-positive cells. Animals receiving capsaicin and melatonin treatment had similar expression of the vehicle group. Our data provide experimental evidence to support the role of melatonin and pineal gland in the pathophysiology of neurovascular headaches.

Reduction in hospitalizations of children.

AIM: The aim of the study was to reduce the number of hospitalizations in a population of children enrolled in the Einstein Program of the Paraisópolis Community, in São Paulo, Brazil, particularly hospitalizations caused by respiratory diseases. METHODS: All hospitalizations of this paediatric population enrolled in the Einstein Program of the Paraisópolis Community Outpatient Clinic were followed up between 2002 and 2004. The following four strategies to reduce or control respiratory diseases with an impact on hospitalizations were established: specific protocol, educational activities, vaccination against pneumococci and vaccination against influenza. RESULTS: In 2002, 1025 hospitalizations due to all causes were recorded. This number significantly decreased to 862 hospitalizations in 2004 after implementation of the program, corresponding to a reduction of 15.9% (p < 0.0001). Hospitalizations due to respiratory diseases decreased by 23.37% (p < 0.02), and those due to cases of wheezing bronchitis fell by 51.61% (p < 0.001). CONCLUSION: The strategies chosen and implemented in the Einstein Program of the Paraisópolis Community Outpatient Clinic over the first 6 months of 2003 were effective in reducing the number of children's hospital admissions due to respiratory disease.

Trigger factors in migraine patients.

BACKGROUND: Migraine is a chronic neurological disease with several trigger factors, including dietary, hormonal and environmental factors. PURPOSE: To analyse precipitating factors in a sample of migraine patients. METHOD: Two hundred consecutive migraine patients were interviewed about possible trigger factors for migraine attacks. RESULTS: Most patients showed at least one dietary trigger, fasting was the most frequent one, followed by alcohol and chocolate. Hormonal factors appeared in 53%, being the pre-menstrual period the most frequent trigger. Physical activities caused migraine in 13%, sexual activities in 2.5% and 64% reported emotional stress a trigger factor. 81% related some sleep problem as a trigger factor. Regarding environmental factors, smells were reported by 36.5%. CONCLUSION: Trigger factors are frequent in migraine patients, its avoidance may decrease headache frequency and also improve patients' quality of life.

[Psychiatric comorbidities decrease quality of life in chronic migraine patients]. / Comorbidade psiquiátrica diminui a qualidade de vida de pacientes com enxaqueca crônica.

INTRODUCTION: Chronic migraine is a common, debilitating condition affecting quality of life and social functioning with significant impact. Migraine is highly comorbid with anxiety and mood disorders, but little is known about psychiatric comorbidities impact in the migraine patient quality of life. METHOD: Fifty patients with chronic migraine diagnosed according to the International Headache Society (2004) were interviewed and met diagnostic criteria for mental disorders, according to the structured interview SCID-I/P and were evaluated by the SF-36 Health Survey questionnaire. Patients were divided in the following groups: chronic migraine with both mood and anxiety disorders, with only anxiety disorders, with generalized anxiety disorder, with only a mood disorder, and without psychopathology. The scores in the group without psychopathology were compared with the other groups. All eight domains of the SF-36 scale were compared in those groups. RESULTS: Significantly lower (p<0.05) quality of life was found on all eight SF-36 domains for CM psychiatric comorbidity patients compared to no-co morbidity patients. On the SF-36 General Health domain alone, quality of life was not significantly lower for all four CM psychiatric comorbidity groups. On the SF-36 Physical Aspects domain alone, quality of life was not significantly lower only for the Anxiety Disorders group. CONCLUSION: Chronic migraine comorbidity with mental disorder is a significant factor affecting patients' quality of life.

Phobias, other psychiatric comorbidities and chronic migraine.

BACKGROUND: Comorbidity of chronic migraine (CM) with psychiatric disorders, mostly anxiety and mood disorders, is a well-recognized phenomenon. Phobias are one of the most common anxiety disorders in the general population. Phobias are more common in migraineurs than non-migraineurs. The clinical profile of phobias in CM has never been studied. METHOD: We investigated the psychiatric profile in 56 patients with CM using the SCID I/P interview. RESULTS: Lifetime criteria for at least one mental disorder was found in 87.5% of the sample; 75% met criteria for at least one lifetime anxiety disorder and 60.7% of our sample fulfilled DSM-IV criteria for lifetime phobic avoidant disorders. Mood and anxiety scores were higher in phobic patients than in non-phobic CM controls. Number of phobias correlated with higher levels of anxiety and depression. CONCLUSION: Phobias are common in CM. Its recognition may influence its management. Early treatment may lead to better prognosis.

Mutation analysis of CACNA1A and ATP1A2 genes in Brazilian FHM families.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with aura. This disease has been associated with missense mutations in the CACNA1A and ATP1A2 genes. The aim of this study was to identify whether CACNA1A and ATP1A2 are or not related to Brazilian FHM. Here we screened four Brazilian FHM families (total of 26 individuals--13 affected and 13 asymptomatic or normal) for mutations in both genes. We found an amino acid change in a member of family FHM-D (Arg2206Gly). However since this alteration is not present in all affected individuals and is present in one asymptomatic individual it should be considered a polymorphism. Further studies with additional families will be necessary to reveal the importance of both CACNA1A and ATP1A2 genes on the pathogeneses of FHM in Brazil and to test the third gene (SCN1A) in these FHM families.

Primary headaches in obese patients.

BACKGROUND AND OBJECTIVE: Obesity is a major public health problem worldwide. Little is known about the prevalence and impact of headache disorders in obese patients. The objective of this study was to assess the prevalence of primary headaches in obese patients and controls. METHOD: Seventy-four consecutive obese patients from the obesity surgery service were studied, and compared to controls with body mass index less than 25. RESULTS: Fifty-six patients (75%) had a headache diagnosis, 49 migraine (66%), 7 tension-type headache (9%), 36 (48%) had incapacitating headaches. CONCLUSION: Primary headaches are more common and incapacitating in obese patients than controls, migraine is the most important diagnosis in this population. Headaches should be properly diagnosed and treated in obese patients.

Depression in chronic migraine: severity and clinical features.

INTRODUCTION: Chronic migraine (CM) is a common medical condition affecting 2.4% of the general population. Depression is one of the most frequent comorbid disorders in CM. METHOD: Seventy patients diagnosed with chronic migraine were studied. All patients evaluated filled out the Beck Depression Inventory (BDI). Depression severity was divided into none or minimal depression, mild, moderate, and severe. RESULTS: BDI ranged from 4 to 55, mean 21 +/- 10.7. Moderate or severe depression, were present in 58.7% of the patients. Some degree of depression appeared in 85.8% of patients. The BDI scores correlated with pain intensity (p = 0.02). Severe depression was more frequent in patients with comorbid fibromyalgia and in patients reporting fatigue. CONCLUSION: The BDI is an easy tool to access depression in CM patients. Suicide risk assessment is needed in CM patients. Patients with fibromyalgia and fatigue are at even higher risk for severe depression.

Endovascular treatment of carotid artery stenosis: retrospective study of 79 patients treated with stenting and angioplasty with and without cerebral protection devices.

We evaluate the results of stenting and angioplasty on carotid bifurcation stenotic lesions using protection systems, emphasizing the indications and technical aspects. Seventy-nine patients, mean age 64.5 years were treated from February,1998 to March, 2003. All patients were included in NASCET study criteria. Forty three patients were treated without the protection systems and thirty six were treated with carotid protection filtering system (Angioguard, EPI). Technical success and 6-months carotid Doppler ultrasound follow-up showing stent patency were achieved in all patients. One major stroke and one death due to intracranial reperfusion bleeding occurred in patients treated without cerebral protection devices. Only one patient presenting hyper perfusion syndrome improving after 7 days, was found in the group treated with the cerebral protection filter mechanism, no other neurologic symptom or death occurred in this group. Stenting and angioplasty with protection systems for thromboembolic debris is a safe endovascular method to treat stenotic lesions in the carotid bifurcation with low morbidity and mortality.

Factors associated with acute medication overuse in chronic migraine patients.

OBJECTIVE: To evaluate the prevalence of psychiatric disorders in patients diagnosed with chronic migraine with and without acute medication overuse. METHODS: Seventy-two volunteers were recruited from a Family Health Program of the Paraisópolis community in São Paulo (SP), Brazil. These patients were submitted to a detailed headache questionnaire. All participants were submitted to physical and neurological examinations. The following variables were analyzed: age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption, lifetime anxiety and mood disorders. RESULTS: Out of 72 patients, 50 (69%) had chronic migraine with medication overuse, and 22 (31%) had chronic migraine without medication overuse. Factors such as age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption were not significantly different between the two studied groups. Lifetime anxiety and mood disorders were more common in patients with acute medication overuse (p=0.003 and p=0.045, respectively). CONCLUSION: This study has shown a significant association among chronic migraine and medication overuse with lifetime mood and anxiety disorders in patients of the studied population. No association was found for other researched psychiatric disorders.

Sensitivity to aversive stimulation, posttraumatic symptoms and migraines: what do they have in common?

Studies have suggested that the high comorbidity observed between chronic migraine and anxiety disorders can be mediated through a third factor namely increased sensitivity to aversive stimulation. This trait may predispose for both chronic migraines, through medication overuse as an avoidance response, and anxiety disorders. Additional studies have shown that hyper sensitivity to aversive stimulation, migraine chronification and anxiety disorders share other characteristics such as serotonergic mediation and personality traits. Preliminary analysis of empirical data comparing the frequency the impact of traumatic events over chronic [CM] and episodic migraine [EM] patients gives further support to this hypothesis. In spite of CM and EM did not differ in terms of the occurrence of traumatic events, CM patients that had experienced at least one traumatic event during their lives had higher scores in re-experiencing and avoidance (but not in hyperarousal) symptoms than CM patients. These observations suggest that traumatic events have greater impact over CM than over EM patients.

Low urinary 6-sulphatoxymelatonin concentrations in acute migraine.

Substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms, sleep, and headache disorders. The objective of the study was to assess 6-sulphatoxymelatonin (aMT6s) levels in a large consecutive series of patients with migraine, comparing with controls. A total of 220 subjects were evaluated-146 had migraine and 74 were control subjects. Urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day (12-h period) and aMT6s was measured with quantitative ELISA technique. Among patients with migraine, 53% presented pain on the day of the urine samples collection. Their urinary aMT6s concentration was significantly lower than in the urine of patients without pain [14.0 +/- 7.3 vs. 49.4 +/- 19.0; t(143) = -15.1; 95% CI = -40.0 to -30.8; P < 0.001]. There was no significant difference in the aMT6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [49.4 +/- 19.0 vs. 42.5 +/- 27.9; t(140) = 1.7; 95% CI = -1.2 to 14.8; P = 0.094]. To our knowledge, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine.

Fatores associados ao uso excessivo de medicação sintomática em pacientes com enxaqueca crônica / Factors associated with acute medication overuse in chronic migraine patients

OBJETIVO: Avaliar a prevalência de transtornos psiquiátricos em pacientes com diagnóstico de enxaqueca crônica com e sem uso excessivo de medicação sintomática. MÉTODOS: Setenta e dois voluntários foram recrutados a partir de um Programa de Saúde da Família da comunidade de Paraisópolis, na cidade de São Paulo (SP). Esses pacientes foram submetidos a exames clínico e neurológico. As seguintes variáveis foram analisadas: idade, gênero, nível educacional, índice de massa corporal, tipo de uso excessivo de medicação, características da cefaleia, consumo de cafeína, presença de ansiedade e distúrbios de humor. RESULTADOS: Dos 72 pacientes, 50 (69%) tinham cefaleia crônica, com uso exagerado de medicação, e 22 (31%) tinham cefaleia crônica, sem uso excessivo de medicação. Os fatores idade, gênero, nível educacional, índice de massa corporal, tipo de uso excessivo de medicação, características da cefaleia e consumo de cafeína não mostraram diferença significante entre os grupos estudados. Os diagnósticos de ansiedade e de distúrbios de humor ao longo da vida foram mais comuns nos pacientes com uso excessivo de medicação (p=0,003 e p=0,045, respectivamente). CONCLUSÃO: Este estudo mostrou uma associação significativa entre cefaleia crônica e uso excessivo de medicação nos pacientes avaliados, quanto ao diagnóstico de transtornos de ansiedade e de humor ao longo da vida. Não foi encontrada nenhuma associação com outros distúrbios psiquiátricos pesquisados.

OBJECTIVE: To evaluate the prevalence of psychiatric disorders in patients diagnosed with chronic migraine with and without acute medication overuse. METHODS: Seventy-two volunteers were recruited from a Family Health Program of the Paraisópolis community in São Paulo (SP), Brazil. These patients were submitted to a detailed headache questionnaire. All participants were submitted to physical and neurological examinations. The following variables were analyzed: age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption, lifetime anxiety and mood disorders. RESULTS: Out of 72 patients, 50 (69%) had chronic migraine with medication overuse, and 22 (31%) had chronic migraine without medication overuse. Factors such as age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption were not significantly different between the two studied groups. Lifetime anxiety and mood disorders were more common in patients with acute medication overuse (p=0.003 and p=0.045, respectively). CONCLUSION: This study has shown a significant association among chronic migraine and medication overuse with lifetime mood and anxiety disorders in patients of the studied population. No association was found for other researched psychiatric disorders.

Glutamate levels in cerebrospinal fluid and triptans overuse in chronic migraine.

OBJECTIVE: Chronic migraine (CM) is a common disorder, affecting 2% to 3% of the general population. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, central sensitization, and may be linked to migraine chronification. Triptans brought a novel option for the acute migraine treatment. As the development of central sensitization impacts upon the effectiveness of triptan therapy, we hypothesized that glutamate might be related to triptan response mechanisms. METHODS: We studied 19 patients diagnosed with CM according to the International Headache Society (2004) criteria. Patients were divided in those overusing analgesics (NSAIDs); those without overuse, and those overusing triptans. RESULTS: Cerebrospinal fluid (CSF) glutamate levels were similar in patients overusing acute medications (0.335 +/- 0.225 micromol) compared to those without overuse (0.354 +/- 0.141 micromol), P= NS). In contrast, patients overusing triptans had CSF glutamate levels significantly lower than that observed in nonoverusers (0.175 +/- 0.057 vs 0.354 +/- 0.141 micromol, P= 0.015), and significantly higher than controls (0.175 +/- 0.057 vs 0.109 +/- 0.066 micromol, P= 0.039). In triptan overusers, CSF glutamate levels, although lower, were not significantly different from patients overusing other types of analgesics. CONCLUSIONS: Our study showed lower glutamate levels in CSF of CM patients overusing triptans. Glutamate may be implicated in triptan response mechanisms, triptans may work in part by reducing extracellular glutamate levels in the brain.

Cephalalgiaphobia: a possible specific phobia of illness.

Psychiatric comorbidity, mainly anxiety and depression, are common in chronic migraine (CM). Phobias are reported by half of CM patients. Phobic avoidance associated with fear of headache or migraine attack has never been adequately described. We describe 12 migraine patients with particular phobic-avoidant behaviours related to their headache attacks, which we classified as a specific illness phobia, coined as cephalalgiaphobia. All patients were women, mean age 42, and all had a migraine diagnosis (11 CM, all overused acute medications). Patients had either a phobia of a headache attack during a pain-free state or a phobia of pain worsening during mild headache episodes. Patients overused acute medication as phobic avoidance. It is a significant problem, associated with distress and impairment, interfering with medical care. Cephalalgiaphobia is a possible specific phobia of illness, possibly linked to progression of migraine to CM and to acute medication overuse headache.