Aids to management of headache disorders in primary care (2nd edition) : on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign against Headache.

The Aids to Management are a product of the Global Campaign against Headache, a worldwide programme of action conducted in official relations with the World Health Organization. Developed in partnership with the European Headache Federation, they update the first edition published 11 years ago.The common headache disorders (migraine, tension-type headache and medication-overuse headache) are major causes of ill health. They should be managed in primary care, firstly because their management is generally not difficult, and secondly because they are so common. These Aids to Management, with the European principles of management of headache disorders in primary care as the core of their content, combine educational materials with practical management aids. They are supplemented by translation protocols, to ensure that translations are unchanged in meaning from the English-language originals.The Aids to Management may be individually downloaded and, as is the case for all products of the Global Campaign against Headache, are available without restriction for non-commercial use.

The headache under-response to treatment (HURT) questionnaire, an outcome measure to guide follow-up in primary care: development, psychometric evaluation and assessment of utility.

BACKGROUND: Headache disorders are both common and burdensome but, given the many people affected, provision of health care to all is challenging. Structured headache services based in primary care are the most efficient, equitable and cost-effective solution but place responsibility for managing most patients on health-care providers with limited training in headache care. The development of practical management aids for primary care is therefore a purpose of the Global Campaign against Headache. This manuscript presents an outcome measure, the Headache Under-Response to Treatment (HURT) questionnaire, describing its purpose, development, psychometric evaluation and assessment for clinical utility. The objective was a simple-to-use instrument that would both assess outcome and provide guidance to improving outcome, having utility across the range of headache disorders, across clinical settings and across countries and cultures. METHODS: After literature review, an expert consensus group drawn from all six world regions formulated HURT through item development and item reduction using item-response theory. Using the American Migraine Prevalence and Prevention Study's general-population respondent panel, two mailed surveys assessed the psychometric properties of HURT, comparing it with other instruments as external validators. Reliability was assessed in patients in two culturally-contrasting clinical settings: headache specialist centres in Europe (n = 159) and primary-care centres in Saudi Arabia (n = 40). Clinical utility was assessed in similar settings (Europe n = 201; Saudi Arabia n = 342). RESULTS: The final instrument, an 8-item self-administered questionnaire, addressed headache frequency, disability, medication use and effect, patients' perceptions of headache "control" and their understanding of their diagnoses. Psychometric evaluation revealed a two-factor model (headache frequency, disability and medication use; and medication efficacy and headache control), with scale properties apparently stable across disorders and correlating well and in the expected directions with external validators. The literature review found few instruments linking assessment to clinical advice or suggested actions: HURT appeared to fill this gap. In European specialist care, it showed utility as an outcome measure across headache disorders. In Saudi Arabian primary care, HURT (translated into Arabic) was reliable and responsive to clinical change. CONCLUSIONS: With demonstrated validity and clinical utility across disorders, cultures and settings, HURT is available for clinical and research purposes.

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks.

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day -2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [P < 0.001 (b.i.d.) and P < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. (P < 0.001) and b.i.d. (P < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.

Perimenstrual headaches: unmet needs.

The risk of migraine is increased among women during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation. For some women with menstrual migraine, headaches that occur at this time are more severe, of longer duration, and more disabling. Although it is recognized that menstrual migraine requires specific management, there remain a number of unmet needs. In particular, comorbidity can result in women with menstrual migraine presenting to obstetrician/gynecologists or psychiatrists rather than primary care physicians or neurologists. Failure to diagnose menstrual migraine will lead to suboptimal management. Accurate diagnosis is insufficient unless it results in effective treatment strategies. Although effective and specific treatments for menstrual migraine have been developed, there is a need to define individual timing and duration of perimenstrual prophylaxis.

Relationship of sequence and structure to specificity in the alpha-amylase family of enzymes.

The hydrolases and transferases that constitute the alpha-amylase family are multidomain proteins, but each has a catalytic domain in the form of a (beta/alpha)(8)-barrel, with the active site being at the C-terminal end of the barrel beta-strands. Although the enzymes are believed to share the same catalytic acids and a common mechanism of action, they have been assigned to three separate families - 13, 70 and 77 - in the classification scheme for glycoside hydrolases and transferases that is based on amino acid sequence similarities. Each enzyme has one glutamic acid and two aspartic acid residues necessary for activity, while most enzymes of the family also contain two histidine residues critical for transition state stabilisation. These five residues occur in four short sequences conserved throughout the family, and within such sequences some key amino acid residues are related to enzyme specificity. A table is given showing motifs distinctive for each specificity as extracted from 316 sequences, which should aid in identifying the enzyme from primary structure information. Where appropriate, existing problems with identification of some enzymes of the family are pointed out. For enzymes of known three-dimensional structure, action is discussed in terms of molecular architecture. The sequence-specificity and structure-specificity relationships described may provide useful pointers for rational protein engineering.

Female sex hormones and migraine.

During the reproductive years migraine is three times more common in women than in men. Although it is often assumed that this female preponderance is associated with the additional trigger of fluctuating sex hormones of the menstrual cycle, few studies have been undertaken to confirm or refute this. There is increasing evidence confirming an association between estrogen 'withdrawal' and attacks of migraine without aura, as well as evidence for an association between high estrogen states and attacks of migraine with aura.

A circularly permuted alpha-amylase-type alpha/beta-barrel structure in glucan-synthesizing glucosyltransferases.

A motif of amino acid residues, located at the active site and specific beta-strands in alpha-amylases, is recognized in alpha-1,3- and alpha-1,6-glucan-synthesizing glucosyltransferases, leading to the conclusion that these enzymes contain an alpha/beta-barrel closely related to the (beta/alpha)8-fold of the alpha-amylase superfamily. The secondary structure elements of the transferase barrel, however, are circularly permuted to start with an alpha-helix equivalent to helix 3 in the alpha-amylases. Thus, the transferase counterpart of the long third beta-->alpha connection--constituting a domain in the alpha-amylases--is divided to precede and succeed the barrel. This architectural arrangement may be coupled to sucrose scission and glucosyl transfer. The involvement in the mechanism in glucosyltransferases of active site residues recurring in amylolytic enzymes is discussed.

The doctor and the migraine patient: improving compliance.

Migraine is an underdiagnosed and undertreated disorder. This can be attributed to the low consultation rate for migraine, for which many reasons have been proposed. These include the fact that many migraineurs self-treat and, historically, the lack of available effective treatments. Some migraineurs are referred to specialist centers for advice. These patients do not merely need effective pain relief. They also need an explanation of the cause of the migraine and reassurance that their headache pain does not have a more sinister cause. By spending time with patients and taking a full history of their migraine condition, the physician can propose a management strategy that is appropriate to each individual patient, thus providing a tailored-care approach. Thorough exploration of possible trigger factors for migraine and advice on avoidance may help to reduce attack frequency. Simple techniques can also be used to improve compliance with prescribed therapies. For example, it is important for the physician to establish that the patient understands any instructions given and to reinforce this advice at follow-up visits. Regular follow-up is important because it enables management strategies to be evaluated and helps the patients to feel involved in the management of their migraine. A correct understanding of the way a drug works and the nature of the condition, together with an explanation of any potential side effects, is likely to maximize clinical benefit.

Migraine-related disability: impact and implications for sufferers' lives and clinical issues.

Migraine is a common, debilitating disorder that imposes a large personal burden on sufferers and high economic costs on society. Sufferers have a significant level of migraine-related disability in all aspects of their daily lives, including employment, household work, and non-work activities. Despite this burden of illness, physicians often do not diagnose or treat the illness effectively. Physicians consider that specific treatment is necessary when disability information is known but, until recently, no criteria have been available for assessment of migraine severity. Two studies indicate that information on disability is an important criterion in assessing migraine severity and influences physicians in their judgments of illness severity and treatment needs. However, physicians and patients often do not seek or share migraine-associated disability, which may contribute to suboptimal management. Efforts to improve knowledge of headache-related disability in the consultation have the potential to improve migraine management. An assessment tool that could reliably quantify headache-related disability has the potential for grading migraine severity and improving care.

Anti-emetics.

Nausea and vomiting are common symptoms of migraine, which can be controlled with a variety of anti-emetics including phenothiazines and antihistamines. Metoclopramide and domperidone have an additional prokinetic effect which may be important in migraine to overcome gastric stasis and enhance absorption of oral medication.

Impact of migraine on patients and their families: the Migraine And Zolmitriptan Evaluation (MAZE) survey--Phase III.

OBJECTIVE: To investigate the impact of migraine on migraineurs and their families and evaluate migraineurs' preference for different treatment formulations. This study also assessed the prevalence and impact of migraine with menstruation. METHODS: Participants (n = 1028) from around the world (USA [39%], Canada [20%], Europe [37%] and other countries [4%]) completed an online questionnaire. Of these, 866 were migraineurs and 162 were non-migraineurs living with/related to migraineurs. Migraineurs were identified based on responses to a modified Kiel questionnaire and/or diagnosis of migraine by a doctor. Disability was quantified using the Migraine Disability Assessment Scale (MIDAS). RESULTS: Migraineurs missed more days from family/leisure activities than from work/school (mean 4.2 vs 2.4 days) in the previous 3 months. On an additional 6.2 days within the 3-month period, productivity at work/school was reduced by at least half. Inability and reduced ability (by at least half) to perform household work were reported on 6.0 and 6.5 days, respectively. Of the women surveyed, 51% identified menstruation as a trigger for attacks and 6% reported attacks solely with menstruation (i. e. attacks occurred during menstruation on at least 9 out of 10 occasions), the latter associated with a higher pain score than other attacks. Living with or being related to a migraineur decreased nonmigraineurs' ability to participate in home/family life (moderate/great impact 49%) and social/leisure activities (moderate/great impact 47%). In a tradeoff analysis, 60% of treatment choice was driven by formulation type and 40% was driven by speed of onset. As migraine disability increased, speed of onset became more important. CONCLUSIONS: This study confirms the significant burden of migraine on patients and families/cohabitants, highlighting not only reduced productivity and absences from work/school, but also time missed from family/social occasions. Many women identify menstruation to be associated with more painful attacks. Overall, in terms of treatment choice, formulation type was a more important driver than speed of onset; however, as migrainerelated disability escalates, speed of onset becomes more important. To optimise migraine management, treatment choice should be based on individual patients' needs and preferences.

Menstruation, sex hormones, and migraine.

All women with migraine are susceptible to the effects of hormonal changes. For a minority with menstrual migraine, fluctuating hormones of the normal ovarian cycle are a specific trigger, particularly during perimenopause. The author proposes that the term menstrual migraine should be restricted to migraine attacks occurring on day 1 +/- 2 days of the menstrual cycle with freedom from migraine during the rest of the cycle. This definition is compatible with the mechanism of estrogen withdrawal. Other mechanisms such as prostaglandin release also may be important for some women. The changing hormonal environment at various stages of life provides further evidence of the role of estrogen in migraine. Treatments that stabilize hormone levels in the form of estrogen supplementation for menstrual migraine, elimination of the pill-free week, and adequate, stable levels of estrogen for HRT, all are associated with an improvement in migraine. The control of the menstrual cycle, however, is extremely complex, and until further studies are undertaken using strict criteria, the mechanism of migraine triggered by hormonal events remains uncertain.

Models for the action of barley alpha-amylase isozymes on linear substrates.

The formation of maltodextrins, G1 to G12, during the hydrolysis of amylose by alpha-amylases 1 and 2 from barley malt was followed by HPLC. Similar, but not identical, distributions of products were obtained with the two alpha-amylase components. Maltose, G6, and G7 were major products, but G7 was degraded as hydrolysis proceeded. alpha-Amylase 1 produced more G1 and G3 than did alpha-amylase 2 at all stages of hydrolysis. Products formed during the hydrolysis of G9, G10, G11, and G12 by the two alpha-amylases were also determined. A different spectrum of products was observed with each substrate and small differences were observed in the action pattern of the two alpha-amylases, e.g., G3 and G7 were the major products formed during the hydrolysis of G10 by alpha-amylase 1, whereas G2 and G8 were the major products formed by alpha-amylase 2 on the same substrate. These results were used to develop a model of the active site of barley malt alpha-amylases. This site contains ten contiguous subsites with the catalytic site situated between subsites 7 and 8. The model can be used to predict hydrolysis patterns of amylose and maltodextrins by cereal alpha-amylases.

Association study of the calcitonin gene-related polypeptide-alpha (CALCA) and the receptor activity modifying 1 (RAMP1) genes with migraine.

Migraine is a common neurovascular brain disorder characterised by recurrent attacks of severe headache that may be accompanied by various neurological symptoms. Migraine is thought to result from activation of the trigeminovascular system followed by vasodilation of pain-producing intracranial blood vessels and activation of second-order sensory neurons in the trigeminal nucleus caudalis. Calcitonin gene-related peptide (CGRP) is a mediator of neurogenic inflammation and the most powerful vasodilating neuropeptide, and has been implicated in migraine pathophysiology. Consequently, genes involved in CGRP synthesis or CGRP receptor genes may play a role in migraine and/or increase susceptibility. This study investigates whether variants in the gene that encodes CGRP, calcitonin-related polypeptide alpha (CALCA) or in the gene that encodes a component of its receptor, receptor activity modifying protein 1 (RAMP1), are associated with migraine pathogenesis and susceptibility. The single nucleotide polymorphisms (SNPs) rs3781719 and rs145837941 in the CALCA gene, and rs3754701 and rs7590387 at the RAMP1 locus, were analysed in an Australian Caucasian population of migraineurs and matched controls. Although we find no significant association of any of the SNPs tested with migraine overall, we detected a nominally significant association (p=0.031) of the RAMP1 rs3754701 variant in male migraine subjects, although this is non-significant after Bonferroni correction for multiple testing.

Estrogen replacement and migraine.

Four of every 10 women will experience migraine at some time in their lives, with peak prevalence in middle life. Evidence supports estrogen 'withdrawal' as one of the important triggers of menstrual attacks of migraine without aura. Improvement of migraine without aura postmenopause is generally attributed to the absence of variations in sex hormone levels. Maintaining a stable estrogen environment is best achieved using non-oral estrogen replacement. Unlike migraine without aura, migraine with aura is recognized as a marker for increased risk of ischemic stroke. Research suggests that aura may be more likely to affect women with underlying coagulation disorders. This could, at least in part, account for both increased risk of stroke and the dose related effect of estrogen replacement on the development of aura. Hence women with migraine with aura requiring estrogen replacement should be given the lowest effective dose necessary to control menopause symptoms, by a non-oral route.

Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study.

OBJECTIVE: To assess the effect of perimenstrual estradiol supplements on menstrual attacks of migraine associated with estrogen withdrawal. METHODS: Women with regular menstrual cycles and menstrual migraine or menstrually related migraine completed an initial three-cycle assessment confirming eligibility for a six-cycle crossover study using estradiol or placebo to prevent menstrual attacks of migraine. Women collected early morning samples of urine daily for laboratory assay and used a fertility monitor to identify peak fertility associated with ovulation. Estradiol gel or placebo was first applied on the tenth day following the first day of peak fertility and continued daily until, and including, the second full day of menstruation. Women kept a daily migraine diary and continued their usual treatment for migraine. The main outcome was the number of days during gel use on which a migraine occurred. RESULTS: Data from 35 women were available for a paired analysis. Percutaneous estradiol was associated with a 22% reduction in migraine days (RR 0.78, 95% CI 0.62 to 0.99, p = 0.04); these migraines were less severe and less likely to be associated with nausea. This was, however, followed by a 40% increase in migraine in the 5 days following estradiol vs placebo (RR 1.40, 95% CI 1.03 to 1.92, p = 0.03). CONCLUSION: Although perimenstrual percutaneous estradiol showed benefit during treatment, this was offset by deferred estrogen withdrawal, triggering post-dosing migraine immediately after the gel was stopped. Further work could assess if this could be avoided by extending the duration of treatment with estradiol.