Onabotulinum toxin A block of the sphenopalatine ganglion in patients with persistent idiopathic facial pain: a randomized, triple-blind, placebo-controlled, exploratory, cross-over study.

OBJECTIVE: To investigate the efficacy and safety of injecting onabotulinum toxin A (BTA) towards the sphenopalatine ganglion (SPG) using the MultiGuide® in patients with persistent idiopathic facial pain (PIFP). METHODS: This cross-over, exploratory study compared the injection of 25 units BTA versus placebo in patients who met modified ICDH-3 criteria for PIFP. Daily pain diaries were registered for a 4-week baseline, a 12-week follow-up after each injection, and an 8-week conceptual washout period in between. The primary efficacy endpoint was the change from baseline to weeks 5-8 in average pain intensity using a numeric rating scale. Adverse events were recorded. RESULTS: Of 30 patients who were randomized to treatment, 29 were evaluable. In weeks 5-8, there was no statistically significant difference in average pain intensity between BTA versus placebo (0.00; 95% CI = -0.57 to 0.57) (P = 0.996). Following both BTA and placebo injections, five participants reported at least a 30% reduction in average pain during weeks 5-8 (P = 1.000). No serious adverse events were reported. Post-hoc analyses indicated a possible carry-over effect. CONCLUSIONS: Injection of BTA toward the SPG with the MultiGuide® did not appear to provide a reduction in pain reduction at 5-8 weeks, although this finding may be influenced by a carry-over effect. The injection appears to otherwise be safe and well-tolerated in patients with PIFP.Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT03462290) and EUDRACT (number: 2017-002518-30).

Headache yesterday in Karnataka state, India: prevalence, impact and cost.

BACKGROUND: The Global Campaign against Headache has pioneered evaluation of the prevalence and impact of headache on the preceding day ("headache yesterday") as a new approach to the estimation of headache-attributed burden, avoiding recall error. We report its application in Karnataka State, southern India. METHODS: In a door-to-door survey, biologically unrelated adults (aged 18-65 years) were randomly sampled from urban and rural areas in and around Bengaluru and interviewed by trained researchers using a validated, structured questionnaire. Enquiry into headache applied ICHD-II diagnostic criteria and included questions about headache on the day preceding the interview (headache yesterday [HY]). RESULTS: There were 2329 participants (participation proportion 92.6 %; males 1141 [49.0 %], females 1188 [51.0 %]; mean age 38.0 [±12.7] years; 1103 [47.4 %] from rural areas, 1226 [52.6 %] urban). HY was reported by 138 participants (males 33 [2.9 %], females 105 [8.8 %]): the 1-day prevalence of headache was 5.9 %. Mean duration of HY was 7.0 ± 8.5 h, so that 1.7 % of the population (5.9 % * 7.0/24), on average, had headache at any moment in time yesterday. Mean intensity on a scale of 1-3 was 2.0 [±0.8]. Lost productivity due to HY was reported by 83.3 % of participants with HY: 37.7 % able to do less than half of what they had planned and 13.0 % able to do nothing. Productivity loss at population level (being the productivity loss within the entire adult population, every single day, attributable to headache) was 3.0 %. CONCLUSIONS: This method of enquiry, free from recall error, confirmed a very high level of headache-attributed burden in Karnataka: previous estimates based on 3-month recall may even have been too low. Until another study is done in the country, these are the best data for all India. They demonstrate need for action nationwide to mitigate this burden, and correct action will ultimately almost certainly be cost-saving.

The burden attributable to headache disorders in India: estimates from a community-based study in Karnataka State.

BACKGROUND: Headache disorders are common worldwide, causing pain and disability. India appears to have a very high prevalence of migraine, and of other headache disorders in line with global averages. Our objective was to estimate the burdens attributable to these disorders in order to inform health policy. METHODS: In a door-to-door survey, biologically unrelated adults (18-65 years) were randomly sampled from urban and rural areas of Bangalore and interviewed by trained researchers. The validated structured questionnaire enquired into several aspects of burden. RESULTS: Of 2,329 participants (non-participation rate 7.4 %), 1,488 (63.9 %; 621 male, 867 female) reported headache in the preceding year. Symptom burden was high. Migraine (1-year prevalence 25.2 %) occurred on average on 28 days/year but, in 38.0 % of cases (ie, 9.6 % of adults), on ≥3 days/month (≥10 % of days). All causes of headache on ≥15 days/month (prevalence 3.0 %) occurred on a mean of 245 days/year. Both these and migraine were rated severe in intensity. Participants with headache lost 4.3 % of productive time; those with migraine lost 5.8 % (equating to 1.5 % from the adult population). Lost paid worktime accounted for 40 % of this, probably detracting directly from GDP. We estimated population-level disability attributable to migraine using the disability weight from GBD2010 for the ictal state (0.433). Mean disability per person with migraine was 1.8 %, reducing the functional capacity of the entire adult population by 0.46 %. Fewer than one quarter of participants with headache had engaged with health-care services for headache in the last year. Actual expenditure on headache care was greatest among those with headache on ≥15 days/month (especially probable medication-overuse headache), but otherwise not high. Expressed willingness to pay for effective treatment for headache was higher, signalling dissatisfaction with current treatments. CONCLUSIONS: In Karnataka State, southern India, prevalent headache disorders, especially migraine, give rise to commensurately heavy burdens. Limited access to health care fails to alleviate these. Structured headache services, with their basis in primary care, are the most efficient, effective, affordable and equitable solution. They could be implemented within the health-care infrastructure of India and are likely to be cost-saving. This solution requires political will, itself dependent on awareness.

Headache disorders and public ill-health in India: prevalence estimates in Karnataka State.

BACKGROUND: Primary headache disorders are among the commonest disorders, affecting people in all countries. India appears to be no exception, although reliable epidemiological data on headache in this highly populous country are not available. Such information is needed for health-policy purposes. Our aim was to estimate the prevalence of each of the headache disorders of public-health importance, and examine their sociodemographic associations, in urban and rural populations of Karnataka, south India. METHODS: In a door-to-door survey, 2,329 biologically unrelated adults (aged 18-65 years) were randomly sampled from urban (n = 1,226) and rural (n = 1,103) areas in and around Bangalore and interviewed by trained researchers using a pilot-tested, validated, structured questionnaire. ICHD-II diagnostic criteria were applied. RESULTS: The observed 1-year prevalence of any headache was 63.9 %, with a female preponderance of 4:3. The age-standardised 1 year prevalence of migraine was 25.2%; prevalence was higher among females than males (OR: 2.1 [1.7-2.6]) and among those from rural areas than urban (OR = 1.5 [1.3-1.8]). The age-standardized 1 year prevalence of TTH was 35.1%, higher among younger people. The estimated prevalence of all headache on ≥15 days/month was 3.0%; that of pMOH was 1.2%, five-times greater among females than males and with a rural preponderance. CONCLUSIONS: There is a very high 1 year prevalence of migraine in south India (the mean global prevalence is estimated at 14.7%). Explanations probably lie in cultural, lifestyle and/or environmental factors, although the observed associations with female gender and rural dwelling are usual. Levels of TTH, pMOH and other headache on ≥15 days/month are similar to global averages, while the very strong association of pMOH with female gender requires explanation. Until another study is conducted in the north of the country, these are the best data available for health policy in a population of over 1.2 billion people.

A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study.

OBJECTIVE: The objective of this article is to see whether the effect of candesartan for migraine prevention, shown in one previous study, could be confirmed in a new study, and if so, whether the effect was comparable to that of propranolol (non-inferiority analysis), and whether adverse events were different. METHODS: In a randomised, triple-blind, double cross-over study, 72 adult patients with episodic or chronic migraine went through three 12-week treatment periods on either candesartan 16 mg, propranolol slow-release 160 mg, or placebo. The main outcome measures were days with migraine headache per four weeks (primary outcome), days with headache, hours with headache, proportion of responders (>50% reduction of migraine days from baseline), and adverse events. RESULTS: In the modified intention-to treat-analysis, candesartan and propranolol were both superior to placebo: 2.95 (95% confidence interval: 2.35-3.55%) and 2.91 (2.36-3.45%), versus 3.53 (2.98-4.08%) for migraine days per month (p = 0.02 for both comparisons, Wilcoxon's paired signed rank test, blinded statistical analysis). Candesartan was non-inferior to propranolol (and vice versa). The proportion of responders was significantly higher on candesartan (43%) and propranolol (40%) than on placebo (23%) (p = 0.025 and <0.050, respectively). There were more adverse events on candesartan (n = 133%) and propranolol (n = 143%) than on placebo (n = 90%), and the adverse event profiles of the active substances differed somewhat. CONCLUSION: It is confirmed that candesartan 16 mg is effective for migraine prevention, with an effect size similar to propranolol 160 mg, and with somewhat different adverse events. TRIAL REGISTRATION: EUDRACT (2008-002312-7), ClinicalTrials.gov (NCT00884663).

Prevalence and sociodemographic correlates of primary headache disorders: results of a population-based survey from Bangalore, India.

BACKGROUND: Headache disorders are common and burdensome throughout the world, placing high demand on health care services. Good information on their prevalence and distribution through sectors of the population are a prerequisite for planning interventions and organizing services, but unavailable for India. OBJECTIVES: To find out the prevalence of headache disorders in Karnataka State and establish important sociodemographic associations. MATERIALS AND METHODS: Using a door to door survey technique, amongst 2997 households, 2329 individuals were interviewed with a validated structured questionnaire by randomly sampling one adult member (aged 18-65 years) from eligible households in urban (n = 1226) and rural (n = 1103) areas of Bangalore, during the period April 2009 and January 2010. STATISTICAL ANALYSIS USED: Chi-square, odds ratio (OR), and logistic regression. RESULTS: The 1-year prevalence of headache was 63.9% (62.0% when adjusted for age, gender and habitation) and 1-day prevalence (headache on the day prior to the survey) was 5.9%. Prevalence was higher in the age groups of 18-45 years, among females (OR = 2.3; 95% confidence interval: 1.9-2.7) and those in rural areas. Prevalence was higher in rural (71.2 [68.4-73.8]) than in urban areas (57.3 [54.5-60.1]) even after adjusting for gender. The proportion of days lost to headache from paid work was 1.1%, while overall productivity loss (from both paid and household work) was 2.8%. CONCLUSIONS: Headache disorders are a major health problem in India with significant burden. It requires systematic efforts to organize effective services to be able to reach a large number of people in urban and rural India. Education of physicians and other health-care workers, and the public should be a pillar of such efforts.

The burden of headache disorders in India: methodology and questionnaire validation for a community-based survey in Karnataka State.

Primary headache disorders are a major public-health problem globally and, possibly more so, in low- and middle-income countries. No methodologically sound studies of prevalence and burden of headache in the adult Indian population have been published previously. The present study was a door-to-door cold-calling survey in urban and rural areas in and around Bangalore, Karnataka State. From 2,714 households contacted, 2,514 biologically unrelated individuals were eligible for the survey and 2,329 (92.9 %) participated (1,103 [48 %] rural; 1,226 [52 %] urban; 1,141 [49 %] male; 1,188 [51 %] female; mean age 38.0 years). The focus was on primary headache (migraine and tension-type headache [TTH]) and medication-overuse headache. A structured questionnaire administered by trained lay interviewers was the instrument both for diagnosis (algorithmically determined from responses) and burden estimation. The screening question enquired into headache in the last year. The validation study compared questionnaire-based diagnoses with those obtained soon after through personal interview by a neurologist in a random sub-sample of participants (n = 381; 16 %). It showed high values (> 80 %) for sensitivity, specificity and predictive values for any headache, and for specificity and negative predictive value for migraine and TTH. Kappa values for diagnostic agreement were good for any headache (0.69 [95 % CI 0.61-0.76]), moderate (0.46 [0.35-0.56]) for migraine and fair (0.39 [0.29-0.49]) for TTH. The survey methodology, including identification of and access to participants, proved feasible. The questionnaire proved effective in the survey population. The study will give reliable estimates of the prevalence and burden of headache, and of migraine and TTH specifically, in urban and rural Karnataka.

The long-term effect of insomnia on primary headaches: a prospective population-based cohort study (HUNT-2 and HUNT-3).

OBJECTIVE: Few prospective studies have evaluated the relationship between insomnia and headache. We aimed to analyze the influence of insomnia at baseline on the risk for headache 11 years later. METHODS: This longitudinal cohort study included subjects who participated in 2 consecutive surveys of the Nord-Trøndelag Health Study (HUNT-2 and HUNT-3). Among the invited individuals aged 20 years or more in HUNT-2 (n = 92,566) and HUNT-3 (n = 94,194), a total of 26,197 completed the headache section of both surveys. A proxy insomnia diagnosis based on DSM-IV at baseline and ICDH-2-based headache diagnoses at follow-up were derived from questionnaires. Headache-free individuals in HUNT-2 (n = 15,268) were selected for analysis. The relative risks (RRs) for headache in insomniacs were calculated with logistic regression. RESULTS: The presence of baseline insomnia was associated with a 40% increased risk for headache in HUNT-3 (RR = 1.4, 95% CI = 1.2-1.7). Similar results were found for tension-type headache (TTH), migraine, and non-classified headache. Subjects with insomnia-related working disability had a 60% increased headache risk (RR = 1.6, 95% CI = 1.3-2.1). The RR was larger for migraine (RR = 2.0, 95% CI = 1.3-3.1) than for TTH (RR = 1.5, 95% CI = 1.1-2.1). Insomnia at baseline was related to headache frequency at follow-up for both migraine (P trend = 0.02) and TTH (P trend < 0.001). CONCLUSION: In headache-free subjects, insomnia was associated with an increased risk of headache 11 years later. The association was particularly strong for chronic headache.

Interictal quantitative EEG in migraine: a blinded controlled study.

Abnormal electroencephalography (EEG) in migraineurs has been reported in several studies. However, few have evaluated EEG findings in migraineurs during a time period when neither the last attack nor the next attack may interact with the results. We, therefore, compared interictal EEG in migraineurs and headache-free subjects with a design controlled for interference by pre-ictal changes. Pre-ictal EEG findings in the painful cranial side during the next attack after registration were also investigated. Correlations between clinical variables and EEG are reported as well. Interictal EEGs from 33 migraineurs (6 with and 27 without aura) and 31 controls were compared. Absolute power, asymmetry and relative power were studied for delta, theta and alpha frequency bands in parieto-occipital, temporal and fronto-central areas. EEG variables were correlated to attack frequency, headache duration, attack duration, pain intensity, photo- and phonophobia. Compared with controls, migraineurs had increased relative theta power in all cortical regions and increased delta activity in the painful fronto-central region. Absolute power and asymmetry were similar among groups. In age-adjusted analyses, headache intensity correlated with increased delta activity. In this blinded controlled study, we found globally increased relative theta activity in migraineurs. A slight interictal brain dysfunction is probably present between attacks.

Cerebral cortical dimensions in headache sufferers aged 50 to 66 years: a population-based imaging study in the Nord-Trøndelag Health Study (HUNT-MRI).

Based on previous clinic-based magnetic resonance imaging studies showing regional differences in the cerebral cortex between those with and without headache, we hypothesized that headache sufferers have a decrease in volume, thickness, or surface area in the anterior cingulate cortex, prefrontal cortex, and insula. In addition, exploratory analyses on volume, thickness, and surface area across the cerebral cortical mantle were performed. A total of 1006 participants (aged 50-66 years) from the general population were selected to an imaging study of the head at 1.5 T (HUNT-MRI). Two hundred eighty-three individuals suffered from headache, 80 with migraine, and 87 with tension-type headache, whereas 309 individuals did not suffer from headache and were used as controls. T1-weighted 3D scans of the brain were analysed with voxel-based morphometry and FreeSurfer. The association between cortical volume, thickness, and surface area and questionnaire-based headache diagnoses was evaluated, taking into consideration evolution of headache and frequency of attacks. There were no significant differences in cortical volume, thickness, or surface area between headache sufferers and nonsufferers in the anterior cingulate cortex, prefrontal cortex, or insula. Similarly, the exploratory analyses across the cortical mantle demonstrated no significant differences in volume, thickness, or surface area between any of the headache groups and the nonsufferers. Maps of effect sizes showed small differences in the cortical measures between headache sufferers and nonsufferers. Hence, there are probably no or only very small differences in volume, thickness, or surface area of the cerebral cortex between those with and without headache in the general population.

Epidemiology and comorbidity of headache.

The burden associated with headache is a major public health problem, the true magnitude of which has not been fully acknowledged until now. Globally, the percentage of the adult population with an active headache disorder is 47% for headache in general, 10% for migraine, 38% for tension-type headache, and 3% for chronic headache that lasts for more than 15 days per month. The large costs of headache to society, which are mostly indirect through loss of work time, have been reported. On the individual level, headaches cause disability, suffering, and loss of quality of life that is on a par with other chronic disorders. Most of the burden of headache is carried by a minority who have substantial and complicating comorbidities. Renewed recognition of the burden of headache and increased scientific interest have led to a better understanding of the risk factors and greater insight into the pathogenic mechanisms, which might lead to improved prevention strategies and the early identification of patients who are at risk.

Angiotensin-converting enzyme gene insertion/deletion polymorphism in migraine patients.

BACKGROUND: The main objective of this study was to investigate the angiotensin converting enzyme (ACE) genotype as a possible risk factor for migraine (both with and without aura) compared to controls. We also wanted to examine whether a clinical response to an ACE inhibitor, lisinopril, or an angiotensin II receptor blocker, candesartan, in migraine prophylaxis was related to ACE genotype. METHODS: 347 migraine patients aged 18-68 (155 migraine without aura (MoA), 187 migraine with aura (MwA) and 5 missing aura subgroup data) and 403 healthy non-migrainous controls > 40 years of age were included in the study. A polymerase chain reaction (PCR) was performed on the genomic DNA samples to obtain the ACE insertion (I)/deletion(D) polymorphisms. RESULTS: No significant differences between migraine patients and controls were found with regard to ACE genotype and allele distributions. Furthermore, there was no significant difference between the controls and the MwA or MoA subgroups. CONCLUSION: In our sample there is no association between ACE genotype or allele frequency and migraine. In addition, ACE genotype in our experience did not predict the clinical response to lisinopril or candesartan used as migraine prophylactics.

The Nord-Trøndelag Health Study shows increased prevalence of primary recurrent headaches among adolescents over a four-year period.

Objective Earlier epidemiological studies have shown that headaches are frequent among adolescents, especially girls. In particular, recurrent primary headache disorders such as migraine and tension-type headaches are common complaints in this age group. Headaches are increasingly being recognized as a significant health problem in adolescents and can lead to significant disabilities by affecting their lives, their school performance and their social lives. The aim of this study was to compare the prevalence of primary headaches among adolescents aged 16-20 years in Norway in two periods. Very few replicate studies have re-evaluated the prevalence of primary headaches in this age range and it is uncertain whether the prevalence is increasing. Methods Two cross-sectional, population-based studies were conducted in Norway from 1995 to 1997 (Young-HUNT 1) and from 1999 to 2001 (Young-HUNT 2). In Young-HUNT 1, 2594 adolescents in 2nd and 3rd grade in upper secondary school (aged 16-20 years) completed a comprehensive questionnaire including one question regarding headache during the last 12 months. In addition, 1730 of the students were interviewed about their headache complaints. In Young-HUNT 2, 2373 adolescents aged 16-20 years completed the same questionnaire and 1655 were interviewed in the same way as the earlier survey. The interviews were performed by trained nurses, and respondents were asked if they had experienced recurrent headache during the last year. If so, the headache was classified as migraine (MI), tensiontype headache (TTH) or non-classifiable headache (NCH). Headache frequency during the past year was recorded according to the following categories: Less than 1 day per month (less than monthly), 1-3 days per month (monthly), 1-5 days per week (weekly), or more than 5 days per week (daily). Results The participation rate was 88% in Young-HUNT 1 and 81% in Young-HUNT 2. The overall prevalence of having had headaches during the last 12 months did not change significantly (79.4% versus 77.5%; OR: 0.89, 95%CI: 0.79-1.02, p = 0.09), whereas the prevalence of recurrent headaches increased from 30.3% in Young-HUNT 1 to 35.4% in Young-HUNT 2 (OR: 1.26, 95%CI: 1.09-1.46, p = 0.002). The prevalence of tension-type headache changed significantly from 19.0% to 21.9% (OR: 1.20, 95%CI: 1.02-1.42, p = 0.03). Also the prevalence of migraine tended to increase (7.5% versus 8.7%, OR: 1.18, 95%CI: 0.92-1.52, p = 0.18). The overall frequency of recurrent headache changed towards more monthly and less weekly headache. Conclusions This is the first large-scale population-based study among adolescents in Norway assessing changes in the prevalence of primary headaches over a four-year period of time. The overall prevalence of recurrent headaches increased significantly from Young-HUNT 1 to Young-HUNT 2. An increase was seen in all types of recurrent headaches and was significant for tension-type headache. Implications Earlier follow-up studies have examined changes in prevalence of recurrent headaches in young age, but the results are diverging. Our findings support the impression that the prevalence of recurrent headache among adolescents is increasing, and underlines the need for prospective designed studies with emphasis on prognosis and etiological factors.

The impact of the catechol-O-methyltransferase Val158Met polymorphism on survival in the general population--the HUNT study.

BACKGROUND: The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met which has been related to common diseases like cancer, psychiatric illness and myocardial infarction. Whether the Val158Met polymorphism is associated with survival has not been evaluated in the general population. The aim of this prospective study was to evaluate the impact of codon 158 COMT gene polymorphism on survival in a population-based cohort. METHODS: The sample comprised 2979 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT) in the period 1995-97. The subjects were followed up with respect to mortality throughout year 2004. RESULTS: 212 men and 183 women died during the follow up. No association between codon 158 COMT gene polymorphism and survival was found. The unadjusted relative risk of death by non-ischemic heart diseases with Met/Met or Met/Val genotypes was 3.27 (95% confidence interval, 1.19-9.00) compared to Val/Val genotype. When we adjusted for age, gender, smoking, coffee intake and body mass index the relative risk decreased to 2.89 (95% confidence interval, 1.04-8.00). CONCLUSION: During 10 year of follow-up, the Val158Met polymorphism had no impact on survival in a general population. Difference in mortality rates from non-ischemic heart diseases may be incidental and should be evaluated in other studies.

Autonomic and muscular responses and recovery to one-hour laboratory mental stress in healthy subjects.

BACKGROUND: Stress is a risk factor for musculoskeletal pain. We wanted to explore stress related physiology in healthy subjects in order to gain insight into mechanisms of pain development which may relate to the pathophysiology of musculoskeletal pain disorders. METHODS: Continuous blood pressure, heart rate, finger skin blood flow, respiration, surface electromyography together with perception of pain, fatigue and tension were recorded on 35 healthy women and 9 healthy men before, during a 60 minute period with task-related low-grade mental stress, and in the following 30 minute rest period. RESULTS: Subjects responded physiologically to the stressful task with an increase in trapezius and frontalis muscle activity, increased blood pressure, respiration frequency and heart rate together with reduced finger skin blood flow. The blood pressure response and the finger skin blood flow response did not recover to baseline values during the 30-minute rest period, whereas respiration frequency, heart rate, and surface electromyography of the trapezius and frontalis muscles recovered to baseline within 10 minutes after the stressful task. Sixty-eight percent responded subjectively with pain development and 64% reported at least 30% increase in pain. Reduced recovery of the blood pressure was weakly correlated to fatigue development during stress, but was not correlated to pain or tension. CONCLUSION: Based on a lack of recovery of the blood pressure and the acral finger skin blood flow response to mental stress we conclude that these responses are more protracted than other physiological stress responses.