COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children

Transcription

1 COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children In this issue: Page Introduction and background 1 Management of acute migraine 2 Triptans 3 Prophylaxis of migraine 7 Other management issues 8 Successful completion of the assessment questions at the end of this issue will provide you with 2 hours towards your CPD/CME requirements. Further copies of this and any other edition in the COMPASS Therapeutic Notes series, including relevant CPD/CME assessment questions, can be found at: compass You can now complete your multiple choice assessment questions on-line and print off your CPD/CME certificate at: These guidelines aim to form evidencebased recommendations for the drug treatment of migraine attacks and of migraine prophylaxis. The non-drug management (e.g. behavioural modification) will not be included, although it is regarded as an important part of migraine management. Introduction and Background Migraine is a highly prevalent, disabling, and under-treated condition. 2 It is a primary episodic headache disorder that is characterised by attacks comprising various combinations of headache and neurological, gastrointestinal and autonomic symptoms. 3,4 Migraine can, in most cases, be successfully managed in primary care. Classification of migraine Although various schemes preceded it, the 1998 classification of the International Headache Society 5 was the first to be widely adopted. This was extensively revised in 2003 and the new system, the International Classification of Headache Disorders, 2 nd edition (ICHD- II), is the international standard. 1 It classifies migraine as: 1 Migraine without aura (formerly called common migraine ) - occurring in 75% of people. Migraine with aura (formerly called classic migraine ) occurring in 20% of people. Childhood periodic syndromes like cyclical vomiting and abdominal migraine. Retinal migraine characterised by attacks of fully reversible loss of vision in one eye associated with migraine headache. Probable migraine. Glossary of terms and abbreviations: Bilateral Relating to, or affecting the right and left sides of the body. Dysmenorrhoea Painful menstruation. EFNS European Federation of Neurological Societies. 5-HT 5-hydroxytryptamine, also known as serotonin. Hypoaesthesia Absent or reduced sensitivity to cutaneous stimulation. Medication overuse headache (MOH) Frequent or daily headaches caused by taking analgesics too often for headaches or migraine. Menorrhagia Abnormally profuse menstrual flow. Cerebral infarction that occurs during the course of a Migrainous typical attack of migraine with aura. The aura lasts longer infarction than 60 minutes, and neuroimaging shows infarction. 1 NSAIDs Non-Steroidal Anti-inflammatory Drugs. Oculogyric crisis Spasmodic attack that is marked by fixation of the eyeballs in one position usually upward. OTC Over-the-counter. Paraesthesia A sensation of pricking, tingling, or creeping on the skin. Phonophobia Intolerance of noise. Photophobia Intolerance to light; painful sensitiveness to strong light. RCT Randomised Controlled Trial. Status migrainosus A debilitating migraine that lasts for more than 72 hours. 1 Tenesmus A distressing but ineffectual urge to evacuate the rectum or urinary bladder Trismus Spasm of the muscles of mastication. Unilateral Occurring on, or affecting, one side of the body or one of its parts. Complications of migraine (chronic migraine, status migrainosus, migrainous infarction, migrainetriggered seizure). Pathophysiology of migraine During a migraine attack, nerve activation results in the dilatation of meningeal blood vessels that, in turn, causes pain, further nerve activation, and inflammation. 6 Because neural events are linked to vascular changes, migraine is considered a neurovascular headache disorder. How big is the problem? Migraine is one of the most frequent headache disorders. 7 In the UK it occurs in 15% of the adult population; in women more than in men in a ratio of 3: The first attack is often in childhood and over 80% have had their first attack by the age of In anyone over the age of 50 who experiences migraine for the first time, an alternative pathology should be considered, although rarely found. There is a family history in 70-80% of people with migraine. The prevalence of migraine in children between the ages of three and eight years is about 3% and adolescents between 10-19%. 12 Childhood onset migraine is more common in boys than in girls. 13 The mean age of onset of migraine is 7.2 years for boys and 10.9 years for girls. 14 Migraine headaches can have adverse effects on the lives of children and adolescent sufferers. These include impaired school performance, poor attendance, and diminished participation in extracurricular activities and social life. 12,15 consultations for existing migraine. 11 These numbers, however, may be misleading as many sufferers do not consult their GP. In the UK, an estimated 190,000 attacks are experienced every day, with three quarters of people affected reporting disability. As a result, it has been estimated that over 100,000 people are absent from work or school because of migraine every working day. 8 The cost to the UK economy may exceed 1.5billion per annum. Keeping a headache diary A headache diary is a useful tool for the management of any patient with migraine. A headache diary helps: Eliminate recall bias with respect to headache timing and characteristics. Identify the type or types of headache experienced. Identify possible trigger factors. Ask the patient to record the following for each headache they experience: Time of onset, duration of headache, character and site of pain. Associated symptoms. Causal factors (diet, bright lights, loud noise, travel, anxiety, depression, trauma, sleep deprivation, excessive sleep). How does the patient respond to the headache (Do they have to go to bed? Do they have to take time off work/school? Do they take medication?) It is recommended that the diary is not reviewed until there have been at least five attacks, when there may be a clear association between triggers and occurrence of attacks. In primary care, a practice of 2000 patients can expect about 5 new cases of migraine per year and 40 COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

2 Features of migraine (see Table ONE) Patients with migraine typically give an account of recurrent, episodic, moderate or severe headaches (which may be unilateral and/or pulsating) lasting 4-72 hours, associated with gastrointestinal symptoms, during which they limit activity and prefer dark and quiet. They are free from symptoms between attacks. 16 A typical migraine attack can consist of four phases: 4 1. The premonitory phase. This occurs in 20-60% of those with migraine. The premonitory phase is different from an aura and occurs hours to days before the headache. Common features are depression, tiredness, difficulty concentrating, irritability, a stiff neck and food cravings. 17,18 2. The aura The migraine aura consists of focal neurological symptoms that precede, accompany, or (rarely) follow an attack. Aura usually develops over 5-20 minutes, lasts for less than 60 minutes, can be visual, sensory, or motor, and can involve language or brainstem disturbances. 5 Headache usually follows within 60 minutes of the end of the aura. 3. The headache The typical headache is unilateral, of gradual onset, throbbing, aggravated by movement and having pain of moderate to severe intensity. Anorexia is common. Nausea occurs in almost 90% of patients, whilst vomiting occurs in about a third. 19 Sensory hypersensitivity results in patients seeking a dark, quite room. 19 Blurry vision, nasal stuffiness, anorexia, hunger, tenesmus, diarrhoea, abdominal cramps, polyuria, facial pallor, sensations of heat or cold, or sweating might occur. Depression, fatigue, anxiety, nervousness, irritability and impairment of concentration are common. 4. The resolution After the headache, the patient often feels tired, washed out, irritable or listless, and can have impaired concentration, scalp tenderness, or mood changes. Childhood migraine features In children, headache is often bilateral, attacks are shorter (1-48 hours) and photophobia may be inferred from their behaviour. 20,21 Apart from these differences, the ICHD-II criteria for migraine are the same for children as for adults. In both adults and children, the diagnosis of migraine is based on the typical patient s history and a normal neurological examination. 7 At least five attacks must have occurred before the diagnosis can be established. Features indicative of a more sinister pathology The following are features that may indicate a more sinister pathology: 16 Thunderclap headache (intense headache with abrupt or explosive onset). Headache with atypical aura (duration longer than one hour or including motor weakness). Aura occurring for the first time in a patient during the use of combined oral contraceptives. New onset headache in a patient older than 50 years. New onset headache in a patient younger than 10 years. Progressive headache, worsening over weeks or longer. Headache associated with postural change. New onset headache in a patient with a history of cancer. New onset headache in a patient with a history of HIV infection. Medication overuse headache Medication overuse headache (MOH) is a frequent or daily headache caused by taking analgesics too often for headaches or migraine. It is estimated that 1 in 50 adults suffer from MOH. 22 MOH is often at its worst on awakening in the morning and increases after physical exertion. Associated nausea and vomiting are rarely pronounced. 16 MOH most commonly results from chronic overuse of analgesics such as NSAIDs, paracetamol, codeine and dihydrocodeine. 22 There is also increasing evidence of MOH related to triptan overuse. 23 The exact mechanism of medication overuse headache is unknown but it is generally believed to involve a disturbance of central pain systems. Frequency of dosing is important: low daily dosing carries a greater risk than larger intermittent dosing. The only effective treatment is to stop the drugs, either immediately or by gradually reducing the amount over several weeks. Up to 60% of sufferers who are withdrawn from drugs improve, although it can take up to 3 months before full improvement is seen and the relapse rate is high. 22 Aims/goals of migraine management Patients need to understand that cure is not a realistic aim. The shared objective should be control of symptoms so that the effect of the illness on a person s life is minimal. To this end, patients should work through the treatment options in a rational order, and continue to do so until it is certain they have found what suits them best. 16 As soon as a clinical diagnosis of migraine is made and disability and comorbidities have been assessed, the next task is to develop an individualised Table ONE: Features of migraine Migraine without aura Migraine with aura Migraine in children Headaches last 4-72 hours and have at least two of the following Features are fairly An aura has at least one features: similar to adults, of the following: Unilateral including being Visual disturbances completely well between Pulsating/throbbing Paraesthesia or attacks. However, the Moderate to severe pain numbness. headache is often Pain aggravated by movement. Headache begins bilateral or in the middle In addition there is at least one of: around the time the aura of the head. Attacks may Nausea finishes and has similar be shorter (1-72 hours) Vomiting features to migraine and gastrointestinal Photophobia without aura. disturbance more Phonophobia. prominent. treatment plan. 24 This plan usually has a number of goals that vary in priority with the patient s headache characteristics and treatment preferences. The plan usually includes educating patients about their illness and its management (e.g. mechanisms, recognising triggers, and lifestyle changes), acute treatment and preventative treatment. Management of acute migraine The objective of acute migraine therapy is to restore the patient s ability to function by rapidly and consistently alleviating pain and associated symptoms. 25 Acute treatment can be subdivided into non-specific agents (such as aspirin, paracetamol, and NSAIDs) and migraine-specific treatments (triptans and ergotamine). The two approaches to treatment of acute migraine A stepped approach, as recommended by the British Association for the Study of Headache (BASH) and Clinical Knowledge Summaries (CKS), 3,16 refers to the initial use of safe, effective, and most cost-effective medications as firstline agents in acute migraine attacks of any severity. 26 All patients should start on the first step of this ladder and it is suggested that failure during three separate migraine episodes should be the criterion for progressing to the next step. Another management strategy that has been studied is stratified care. This approach selects treatment based on the patient s level of disability and symptoms. Mild symptoms might be treated with simple analgesics, while more severe disease might be treated with a triptan. Which approach is more effective is still an open question. 27 A Stepped Approach to Migraine Management STEP ONE (a): Oral analgesic or NSAID, with or without anti-emetic. Analgesics The evidence for the use of analgesics in migraine is limited but this is probably due to the fact that there have been few high-quality trials rather than that they are ineffective. The following are good choices in adults: 3 - aspirin milligrams 28,29 - ibuprofen milligrams 30,31 COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

3 In either case, they are best taken in buffered soluble or orodispersible formulations 32,33 and early in the attack when absorption may be least inhibited by gastric stasis. Up to four doses may be taken in 24 hours. In children: Simple analgesics or NSAIDs often are quite effective in children and adolescents with mild to moderate migraine. 7,13 Ibuprofen ( milligrams per kilogram body weight) or paracetamol (15 milligrams per kilogram) have been shown to be effective in treatment of childhood migraine. 34,35 A full discussion on the contraindications, adverse effects, monitoring issues, and interactions of NSAIDs is beyond the scope of this guidance. However, in brief, consider the following prescribing issues for NSAIDs: Consider patient co-morbidity (including cardiovascular risk assessment). NSAIDs commonly cause GI adverse effects. Do not give without gastroprotection if there is a history of peptic ulceration. NSAIDs can worsen asthma, hypertension, renal impairment, and heart failure. Anti-emetics The role of anti-emetics in acute migraine is two-fold: 1. Anti-emetics treat commonly occurring GI symptoms such as nausea and vomiting. 2. During an acute migraine attack, gastric stasis may result in delayed or wholly suppressed absorption of drugs. Anti-emetics like metoclopramide and domperidone are able to speed up gastric emptying and should be administered as soon as possible at the beginning of the attack Metoclopramide and domperidone should NOT be given to children. For nausea and vomiting in adults: Metoclopramide 10 milligrams up to three times a day, or Prochlorperazine 3-6 milligrams buccal tablet, 39 dissolved between gum and cheek up to twice in 24 hours, or Domperidone 10 milligrams, up to four times a day. Domperidone has fewer adverse effects than metoclopramide, but the evidence for it is less substantial than for metoclopramide. Domperidone is available as a suppository (Motilium suppositories) if vomiting is a problem. Metoclopramide is effective but can cause extrapyramidal adverse effects (spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, spasm of extra-ocular muscles including oculogyric crises, unnatural positioning of the head and shoulders) especially in younger people. STEP ONE (b): NSAID combined with a prokinetic anti-emetic. As in STEP ONE (a), aspirin or ibuprofen can be used but the following are also suitable: Tolfenamic acid rapid release 200 milligrams, 40 repeated once if necessary after 1-2 hours, or Naproxen milligrams 41,42 with a further milligrams up to twice in 24 hours, or Diclofenac-potassium (Voltarol Rapid) milligrams repeated up to a total of 200 milligrams in 24 hours. In all cases use a non-delayed release formulation combined with domperidone or metoclopramide to promote gastric emptying. Prescribing notes for STEP ONE: Start acute treatment early in the attack. Where possible use soluble or orodispersible formulations. Do NOT use modified-release formulations. Consider using combination preparations; MigraMax (aspirin 900 milligrams and metoclopramide 10 milligrams) 46,47 and Paramax (paracetamol 500 milligrams and metoclopramide 5 milligrams) are available as dispersible granules. These are the only dispersible forms of metoclopramide available. Most patients will have tried at least one (and often several) analgesics before consulting a GP. 48 However, they may not have used them at a sufficient dose and at the correct time. Recommended analgesic doses for acute migraine are typically greater than standard doses to achieve rapid therapeutic levels against a background of gastric stasis. An initial approach may be to ensure that the dose taken is adequate and that analgesics are carried by the patient at all times, and taken as soon as the onset of an attack is recognised. 49 Owing to an association with Reye s syndrome, it is advised that aspirincontaining preparations should NOT be given to children under 16 years of age. Codeine and codeine-containing preparations are particularly UNSUITABLE in migraine. (Note: Migraleve tablets contain codeine). Are there any drugs that are LESS suitable in the management of acute migraine? Paracetamol in adults, evidence shows that paracetamol alone is ineffective. 50 Also, opioid analgesics should be avoided for the following reasons: 16 They have no proven pain relieving effect in migraine. They can cause nausea and vomiting which can exacerbate existing problems. They reduce gastric motility, which can decrease the uptake of other drugs. They have an addictive potential and are implicated in medication overuse headache. 48,49,51 STEP TWO: Rectal analgesia with or without a rectal anti-emetic Diclofenac suppositories 100 milligrams (up to 200 milligrams in 24 hours) for pain plus domperidone suppositories milligrams (up to 120 milligrams in 24 hours) when needed. STEP TWO can be by-passed if rectal administration is unacceptable to the patient. If symptoms do not respond to STEP ONE/TWO treatments or treatment is poorly tolerated, move to STEP THREE. If symptoms respond to STEP ONE/TWO treatment but are severe, or occur more than twice per month, consider prophylaxis (see later). 3 STEP THREE: Specific antimigraine drugs (usually triptans). If migraine attacks are unresponsive to adequate doses of analgesic and antiemetic, consider replacing them with a triptan. 3 See later for guidance on choosing a triptan. When triptans are taken orally, concomitant administration of a prokinetic anti-emetic, metoclopramide or domperidone, is suggested on theoretical grounds: there is some evidence to support the former. 36 If STEP THREE fails: Review the diagnosis. Review compliance and manner of use of the medication. STEP FOUR may be worth trying. If symptoms respond to treatment but are severe or occur more than twice per month, consider prophylaxis. STEP FOUR: Combinations There is some evidence that the combination of sumatriptan 50 milligrams and naproxen 500 milligrams is superior to either drug alone. 52 Other combinations of steps ONE and THREE may be worth trying, followed by steps TWO and THREE. 16 How can a stratified approach be worked in? STEP ONE would be an appropriate place to start for someone with mild to moderate migraine in a stratified approach. In a stratified approach to management, patients identified as having moderate to severe migraine should move straight to STEP THREE. Triptans The development of the selective 5- HT 1B/1D receptor agonists, also known as the triptans, in the latter part of the 20 th century revolutionised the treatment of migraine. Seven triptan medications are now available and this is a tribute to the efficacy of sumatriptan as the first of this class. 53 Triptans are of proven efficacy and are well established as antimigraine drugs These drugs have now become an integral part of migraine management and are generally used when symptoms are not controlled by analgesics and anti-emetics. Studies have shown an improvement in headache in 30-40% of patients within 60 minutes of administration of a triptan. This increases to 50-70% after two hours. COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

4 How do triptans work in migraine? Triptans selectively stimulate 5- hydroxytriptamine (5HT 1, also known as serotonin) receptors. Specifically, triptans act on the 5-HT 1B and the 5-HT 1D receptors these are not necessarily responsible for starting a headache but are important in stopping one. 53 What are the contraindications to the use of triptans? Triptans should not be given to people with: 57 Uncontrolled hypertension. Coronary heart disease or cerebrovascular disease. Coronary vasospasm. At what stage of an acute migraine should a triptan be taken? It is important that a triptan is taken ONCE THE HEADACHE HAS STARTED but the pain is still mild. 58 Unlike analgesics or NSAIDs, triptans should not be taken too early. Triptans are ineffective if taken during the aura phase of a migraine. 59,60 Common problems encountered using triptans: 1. The initial dose of triptan is ineffective If the first dose of triptan is ineffective, a further dose is unlikely to be effective and should not be taken. The exception to this is zolmitriptan, where an additional dose can be tried after two hours even if the first was unsuccessful. 3 Non-response has been attributed to a variety of factors including: 61 Low and inconsistent absorption. Use of the triptan too early or too late in the attack. Inadequate dose. Individual biological variability. Evidence from trials confirms the common clinical observation that patients with a poor response to one triptan can benefit from another in subsequent attacks. 62 Ideally, each triptan should be tried in three attacks before it is rejected for lack of efficacy. 16 Not only a different triptan but also dosage and a different route of administration should be considered The patient experiences relief of their headache but has unacceptable side-effects. Try using a lower dose of triptan e.g. rizatriptan 5 milligrams or eletriptan 20 milligrams (unlicensed). Alternatively, use a triptan known to have fewer adverse effects. Naratriptan, frovatriptan, and almotriptan are reputed to be the triptans with highest tolerability. 54,63 3. The chosen triptan initially relieves pain but the headache returns within 24 hours. This is known as headache recurrence or headache relapse and is a significant problem with all triptans. Headache recurrence is defined as a recurring or worsening of headache after pain-free or mild pain has been achieved with a drug within 24 hours. 64,65 Up to 40% of people taking an oral triptan experience headache recurrence. 66,67 What can be done about headache recurrence? There is good evidence that a second dose of triptan is effective for headache recurrence. 16 In most people it is the sensible option, with a minimum of two hours between doses and within the total daily dose limitation for the particular triptan. But in some people, relapse appears to be a manifestation of rebound and repeated dosing can give rise to repeated rebound over several days. 23 There is no clear consensus on the best management of these people, but naproxen 500 milligrams 52 or tolfenamic acid 200 milligrams 68 may be preferable for the first or second relapse. Ergotamine may be an alternative but efficacy has not been formally established; it should not be used within 24 hours of giving a triptan. For patients who consistently relapse, there is some evidence that naratriptan, 63 eletriptan 69 and frovatriptan 53 are associated with relatively low relapse rates More than two triptans are ineffective. Consistent lack of response to triptans is rare, as 79-89% of patients respond in at least one of three treated attacks. 54 Thus, Review the diagnosis. Review compliance and determine whether drugs are being used correctly. If the diagnosis is correct and drugs are being used correctly but are not effective, try combining a triptan with standard analgesia with or without an anti-emetic, and if migraines are very frequent consider using prophylactic drug treatment. 5. The person is nauseated or cannot swallow tablets. Try: Sumatriptan injection Sumatriptan nasal spray, or Zolmitriptan nasal spray, or Rizatriptan dissolvable wafer, or Zolmitriptan orodispersible tablets. 6. The person is vomiting. Use sumatriptan injection. Alternatively, zolmitriptan nasal spray can be considered. (Note: sumatriptan nasal spray may NOT be effective if the patient is vomiting because its bioavailability depends largely on ingestion 16 ). 7. The chosen triptan does not work for every migraine attack. This is to be expected. Efficacy in only two of three attacks is regarded as good. 7 Are there important differences between the triptans? The triptans are a very homogeneous group of drugs. Meta-analyses comparing triptans have shown that all oral triptans are generally effective and Prescribing notes: Triptans Do not prescribe triptans with other migraine drugs such as ergotamine. 74 Recommend that a triptan is taken when the headache starts rather than at the time of the aura. 74 Orodispersible tablets and wafers may be useful if swallowing is a problem. 3 Nasal sprays give rapid relief. 3 Subcutaneous injection (sumatriptan) gives the most rapid relief. 3 Triptans are contraindicated in patients with ischaemic heart disease, uncontrolled hypertension, or risk factors for coronary heart disease and cerebrovascular disease. 74 Reduce the dose of rizatriptan to 5 milligrams if the person is taking propranolol, as plasma levels of rizatriptan are almost doubled by propranolol. 75 well tolerated. 49,54,71 In addition, there is no evidence that any particular triptan is safer to use than another. 3 However, there are small but clinically significant differences which might suggest the use of one agent over another in individual patients: Comparative efficacy - There is a high degree of variability in individual response to specific triptans. If a particular triptan is not effective in an individual, another can be tried. Onset of action sumatriptan subcutaneous has the fastest onset of action (about 10minutes) and naratriptan the slowest (up to 4 hours). 72,73 Consistency - Rizatriptan 10mg, eletriptan 80mg and almotriptan 12.5mg have the highest likelihood of consistent success. 54 Adverse effects - if a particular triptan is poorly tolerated it can be switched; in particular almotriptan, naratriptan, or frovatriptan may cause fewer adverse effects. Availability of different formulations See Table TWO. Cost See Table TWO. As well as these differences, patient characteristics and preferences vary, and individual responses to a triptan cannot be predicted. Thus, it is possible to say that differences between triptans are small, but they may be important for some patients. Hence, treatment should be individualised for each person. What is a reasonable first-line triptan choice? It is reasonable to start with a standard dose of any oral triptan (sumatriptan 50 milligrams, zolmitriptan 2.5 milligrams, rizatriptan 10 milligrams, almotriptan 12.5 milligrams, eletriptan 40 milligrams, or naratriptan 2.5 milligrams). However, the majority of the clinical trial data is related to the use of sumatriptan, with 50 milligrams being the recommended dosage. Also, as sumatriptan is available generically, it is a good first-line choice. 76 COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

5 Table TWO: Comparison of the triptans 3,16,57 Triptan Sumatriptan Zolmitriptan Rizatriptan Available formulations Sumatriptan 50mg tablets (generic) Sumatriptan 100mg tablets (generic) Cost of single treatment dose 1.44* 2.16* Imigran 50mg tablets Imigran 100mg tablets Imigran 6mg/0.5ml injection Imigran 10mg nasal spray Imigran 20mg nasal spray Imigran RADIS 50mg tablets. Imigran RADIS 100mg tablets. Imigran Recovery 50mg (available from pharmacies without prescription) Zomig 2.5mg tablets Zomig Rapimelt 2.5mg (orodispersible tablets). Zomig Rapimelt 5mg (orodispersible tablets) Zomig 5mg nasal spray Maxalt 5mg tablets Maxalt 10mg tablets Maxalt Melt Wafers 10mg Comments The longest established and most extensively studied triptan. The only triptan available as a subcutaneous injection. The 50mg tablet (available generically) is appropriate for first use of a triptan. 16 When response is inadequate, the 100mg tablet, Imigran RADIS 100mg tablet or 20mg nasal spray may be used according to preference. 77,78 Imigran RADIS tablets can be swallowed whole or dispersed in water. Total dose per 24 hours should not exceed 300mg orally, 40mg intranasally, or 12mg subcutaneously. The nasal spray is NOT useful if vomiting precludes oral therapy since its bioavailability depends largely on ingestion. 16 Oral sumatriptan has an onset of efficacy of about minutes. 54 For adolescents (12-17 years), sumatriptan 10mg nasal spray is a specifically licensed formulation. Similar efficacy and adverse effect profile to sumatriptan. Total dose per 24 hours should not exceed 10mg. Zolmitriptan 5mg nasal spray produces a more rapid response than oral zolmitriptan, 79 and may be useful if vomiting is already occurring since up to 30% is absorbed through the nasal mucosa. 16 Rizatriptan 10mg tablet and 10mg Melt Wafers are alternatives to sumatriptan 100mg. 80,81 The total dose per 24 hours should not exceed 20mg. Metabolism is affected by propranolol and patients on this drug should take 5mg tablet with a maximum dose per 24 hours of 10mg. 16 Naratriptan Naramig 2.5mg tablets slow onset of effect limit its use in patients seeking rapid response. 82 It is recommended when side effects to other triptans are troublesome. Naratriptan 2.5mg tablet is well tolerated but its relatively low efficacy and The total dose per 24 hours should not exceed 5mg. Almotriptan Almogran 12.5mg tablets sumatriptan 100mg and it is well tolerated. 83,84 Almotriptan 12.5mg has shown similar efficacy and relapse rates to The total dose per 24 hours should not exceed 25mg. Eletriptan Relpax 20mg tablets Relpax 40mg tablets Eletriptan 80 mg is the most effective oral triptan but also has the most side-effects. 54 Eletriptan is unlike other triptans in exhibiting a clear dose-response relationship for efficacy in the range 20-80mg. 85,86 The standard dose is 40mg orally. Those who find this dose well-tolerated but not efficacious may benefit from 80mg (two tablets). A 20mg tablet is marketed for those with mild or moderate renal impairment, but may be used if side-effects occur at higher doses. The total dose per 24 hours should not exceed 80mg. Frovatriptan has a substantially longer half-life (26hours) than all other triptans. 87 This may translate into lower relapse rates. Frovatriptan Migard 2.5mg tablets Frovatriptan 2.5mg is less effective than sumatriptan 100mg 87 but has fewer adverse effects. 88 The total dose per 24 hours should not exceed 5mg. Post-marketing experience is needed to establish the position of frovatriptan amongst other triptans. 16 * Price based on Northern Ireland Drug Tariff October Price based on BNF 56. COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

6 What are the adverse effects associated with the triptans? The adverse effects associated with the triptans can be divided into two main groups: 1. Common, mild, but annoying effects. 2. Rare but potentially serious adverse effects. 1. Mild adverse effects The so called triptan sensations include warm/hot sensations, tightness, tingling, flushing, and feelings of heaviness or pressure in areas such as the face, limbs, and occasionally the chest. Such sensations can mimic angina and cause considerable alarm. However, when patients are forewarned about these sensations, they cause less distress should they occur. 49,89,90 It is advised that the triptan is discontinued if there are particularly intense sensations or chest pain. 3 Other adverse effects are generally mild and self-limiting for all triptans. They include nausea, dizziness, dry mouth, weakness/fatigue, drowsiness, and palpitations Potentially serious effects The main concern with all triptans is their potential for coronary vasoconstriction. There are theoretical concerns that this may increase the likelihood of myocardial infarction, but extensive experience with these drugs, especially sumatriptan, have shown this is very rare. 49 A longterm, post-marketing review concluded that triptans were very safe as long as they were not used in people with cardiovascular disease or major risk factors for cardiovascular disease. 104 Which type of triptan formulation is most popular? Although oral absorption of drugs is delayed during migraine attacks, most patients prefer oral formulations; they account for more than 90% of all triptan prescriptions. 62 Can triptans be used in children? With the exception of Imigran 10 milligram nasal spray which can be used from the age of 12 years, none of the triptans are licensed for use in patients under the age of 18 years However, several studies on the use of triptans in children and adolescents have shown that : Nasal sumatriptan is effective and safe in 5-12 year olds. 105,106 Rizatriptan is effective and safe for acute treatment of migraine in adolescents. 107 Zolmitriptan is well tolerated and safe in adolescents, although it was found to be similar to placebo for efficacy. 108 In a single study of eletriptan in adolescents, there was no statistical difference between eletriptan and placebo. 109 A small study of almotriptan in year olds found it to be safe and effective. 109 Which drugs are known to interact with triptans? The following clinically significant interactions are recognised: ,110 MAOIs the oral triptans are metabolised by the monoamine oxidase pathway, and should not therefore be administered with MAOIs. Propranolol when rizatriptan is given to patients taking propranolol, the rizatriptan dose should be reduced from 10 to 5 milligrams. Macrolide antibacterials and antifungal agents eletriptan should not be used concomitantly with clarithromycin, erythromycin, itraconazole, or ketoconazole as these results in increased plasma concentrations of eletriptan. SSRIs the weight of evidence suggests that the concurrent use of triptans and SSRIs is normally uneventful, but adverse reactions do occur occasionally. Caution and close monitoring is advised when two such agents are used together. 111,112 Ergotamine ergotamine should not be taken concomitantly with a triptan. Availability of sumatriptan over-the-counter Sumatriptan 50 milligram tablets (Imigran Recovery) can now be obtained without prescription at community pharmacies, for designated patients aged years. The obvious concern with triptans is the likelihood of use by those with coronary risk factors and the possibility that this may lead to significant numbers of coronary events. For this reason, pharmacists are required to give advice at point-of-sale. In addition, advice to patients at the time of purchase is essential to ensure that sumatriptan is administered appropriately. Otherwise, it is likely that OTC sumatriptan will be used for headaches that are not migrainous, or too early or too late for best effect. See Panel ONE for guidance on supply of sumatriptan without prescription. Summary Triptans Triptans are of proven efficacy and are well established as antimigraine drugs. Triptans should be taken once the headache has started. If a first dose is ineffective, a second dose is unlikely to be effective. It is worthwhile trying a different triptan if the initial choice has been shown to be ineffective. Naratriptan, frovatriptan and almotriptan have fewer adverse effects than other triptans. Headache recurrence/relapse can be managed with a second dose of triptan. Differences between triptans are small, but they may be important for some patients. Treatment should be individualised for each person. Adverse effects of the triptans are generally mild but all triptans have the potential for causing coronary vasoconstriction. Panel ONE: Royal Pharmaceutical Society of Great Britain Guidance on sumatriptan OTC: 113 OTC sumatriptan is indicated for the acute treatment of migraine attacks with or without aura in adults aged years. (Patients over the age of 50 who are experiencing their first ever migraine attack need to seek medical advice). It should only be used where there is a clear diagnosis of migraine. Patients should have an established pattern of migraine attacks. It should not be used prophylactically. OTC sumatriptan is useful secondline therapy when analgesics are unsuccessful. Advice from pharmacists to anyone purchasing sumatriptan should include: Take a single tablet as soon as possible after the onset of a migraine headache. If the first dose of sumatriptan is ineffective, a further dose is unlikely to be effective and should not be taken. However, if symptoms return after initial relief, a second dose can be taken after two hours. Sumatriptan can cause drowsiness caution with driving or operating machinery. Do not take St John s Wort preparations along with sumatriptan. The following individuals should not be supplied with sumatriptan: Anyone with a history of cardiovascular disease or those at high risk of cardiovascular disease. Those under the age of 18 or over 65. Patients over the age of 50 who are experiencing their first ever migraine attack. Pregnant or breast-feeding women. For comprehensive guidance on the supply of sumatriptan without prescription, readers are directed to the RPSGB Web site ( Ergotamine Ergotamine is no longer generally recommended for migraine management. 57 The value of ergotamine is limited by its adverse effects (particularly nausea, vomiting, abdominal pain, and muscular cramps) and poor oral bioavailability. In addition: Treatment should not be repeated at intervals of less than four days and should not be used more than twice per month. Regular intake of ergotamine may lead to ergotism (marked by spasms, cramps, paraesthesiae, nausea and gangrene). Regular use may also result in an increase in migraine frequency and finally in a daily headache (ergotamine-induced headache). It has NOT been shown to be superior to newer migraine-specific agents. 114 COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

7 Does ergotamine still have a role in migraine management? Ergotamine 1-2 milligrams has significantly lower relapse rates which may be due to its prolonged duration of action. 115 Ergotamine may therefore still have a place if relapse is a particular problem, 16 but toxicity and misuse potential are greater risks with ergotamine than with triptans. How much ergotamine is being used in Northern Ireland? In Northern Ireland between July 2007 and June 2008, preparations containing ergotamine accounted for only 533 prescription items. 62 Prophylaxis of migraine To minimise the impact of the illness on their lives, people with frequent, severe or disabling migraine headaches may benefit from taking a drug to prevent attacks. On average, two thirds of patients will have a 50% reduction in headache frequency with most preventative drugs. 116 Thus, even when prophylaxis of migraine is successful the patient will, in most cases, still suffer some attacks, 117 so, when indicated, prophylactic therapy is used in addition to acute therapy, not in place of it. 16 When is it appropriate to consider introducing prophylaxis? The decision to initiate preventative treatment should NOT be based solely on the number of attacks, but is best made by examining a combination of frequency, duration and severity of attacks, and patient preference, 49 especially as compliance with migraine prophylaxis is often poor. 64 Although there is no commonly accepted indication for starting a prophylactic treatment, the European Federation of Neurological Societies (EFNS) recommends that prophylaxis should be considered when: 7 The quality of life, work, or school attendance is severely impaired. Frequency of attacks per month is two or higher. Migraine attacks do not respond to acute drug treatment. Frequent, very long, or uncomfortable auras occur. Prophylaxis is used to reduce the number of migraine attacks in circumstances when acute therapy, used appropriately, gives inadequate symptom control. Patients themselves are usually the best judge of symptom control. In children, an index of this is frequency of absence from school because of migraine. How should prophylaxis be introduced and for how long should it be continued? It may take 1-3 months for the full effect of the preventative drug to be seen. Each preventative drug should be started at a low dose and then increased to an acceptable maximum. If the drug is effective it should be used for 4-6 months. 3,118 How is a prophylactic drug judged to be effective? Migraine prophylaxis is regarded as successful if the frequency of migraine attacks per month is decreased by at least 50% within three months. For therapy evaluation, a migraine diary is mandatory. 7 What factors influence the choice of drug for migraine prophylaxis? The choice of preventative medication is empiric; it is influenced by efficacy, adverse effects and the patient s coexistent and comorbid conditions. 119 Once-daily dosing has also been shown to improve compliance. 120 What agents are recommended for migraine prophylaxis? Table THREE gives guidance on the choice of agents which can be used for migraine prophylaxis. What if migraine prophylaxis fails? Review the diagnosis. Review compliance with treatment (often poor, especially with multiple daily doses). Review other medication, especially for medication overuse. Consider using a combination of agents. If prophylaxis still fails to have measurable benefit, discontinue it. 16 When and how should migraine prophylaxis drugs be stopped? If prophylactic drugs are successful in reducing the frequency of migraines, drugs should be continued for at least 4-6 months. 121 At the end of this period drugs should be tapered down over a period of 2-3 weeks to establish if they are still required 3,118 and to minimise the possibility of rebound migraine headache. 121 Migraine prophylaxis in children There is little formal evidence of efficacy of prophylactic drugs in children. For the few children who need prophylaxis, paediatric headache specialists employ the full range of treatments used in adults, often with benefit. Beta-blockers are often viewed as one of the first-line agents. Propranolol has been found to be effective for the prevention of migraine in children and adolescents. 14,122 However, the results obtained are inconsistent Timolol, atenolol, metoprolol and nadolol may be alternative choices. 13 Antidepressants may also be useful. Amitriptyline, 126,127 and other tricyclics are widely employed and selection is generally a matter of personal preference and experience. There are no comparative data. Topiramate is effective in paediatric migraine prophylaxis 128,129 but is not licensed under the age of Agents used in prophylaxis but with limited/uncertain efficacy. Pizotifen is an antihistamine and serotonin antagonist structurally related to the tricyclic antidepressants. 57 Pizotifen has been widely used for many years but with little clinical trial evidence What should be discussed with a patient starting migraine prophylaxis? The chosen agent will need to be taken every day. Migraine attacks are unlikely to stop completely. However, the number and severity of attacks are often much reduced. It may take 1-3 months for maximum benefit, so do persevere. It is usual to take these drugs for 4-6 months. After this we can consider stopping them to see if they are still needed. You can still take painkillers or a triptan for migraine attacks if they occur. It is worth trying a different medicine if the first one does not work. of efficacy. 131 Despite poor evidence of effect, in 2007/8 nearly 20,000 prescription items for pizotifen were dispensed in Northern Ireland. 62 Feverfew (Tanacetum parthenium) is a medicinal herb reputed to prevent migraine attacks. However, there is little evidence to support this assertion. 132,133 Marketed preparations lack standardisation. Its toxicity is not well understood and its long-term effects are unknown. These factors make it particularly unsuitable for children. 16 Butterbur (Petasites hybridus) is a perennial shrub found throughout Europe and parts of Asia and North America. 24 Its efficacy has been studied in two trials 134,135 which found that butterbur milligrams twice-daily may be an alternative preventative treatment for migraine. Although butterbur is well tolerated it should be used with caution because products are unregulated and therefore quality control and product standardisation may be lacking. Summary - Migraine Prophylaxis Evidence for the agents used is mixed and they often have intolerable side-effects. Beta-blockers are the most widely used class of prophylactic migraine drug. Other than some beta-blockers, most agents used in migraine prophylaxis are not licensed for this indication. It may take 1-3 months for the full effect of the preventative drug to be seen. On average most patients will have a 50% reduction in headache frequency with most preventative drugs. If the drug is effective it should be used for 4-6 months then slowly tapered off over 2-3 weeks. COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April

8 First-line Betablockers Amitriptyline Second-line Valproate Atenolol milligrams twice daily (unlicensed). Bisoprolol 5-10 milligrams daily (unlicensed). Propranolol 40 milligrams two or three times daily initially, increasing to a maintenance dose of milligrams daily. 57 Metoprolol milligrams daily in divided doses. 57 Timolol milligrams daily in 1-2 divided doses Start at a low dose (10-25 milligrams at night) and increase to a maintenance dose of milligrams at night. 57 Sodium valproate milligrams twice daily. (unlicensed) Table THREE: Drugs used in migraine prophylaxis. 7,16,26,119 Contraindications include asthma, depression, heart failure or peripheral vascular disease. Side-effects include lethargy, tiredness, bradycardia, heart failure, peripheral vasoconstriction, bronchospasm, postural symptoms. They are useful where a co-existing disease (e.g. hypertension or anxiety) is present. Evidence consistently showed the efficacy of propranolol, and timolol, for the prevention of migraine. There is limited evidence of a moderate effect for bisoprolol, atenolol, 145,146 and metoprolol Bisoprolol and timolol can be given once daily. Commonly used for prophylaxis of migraine, despite NOT being licensed for this indication. May be useful when migraine co-exists with tension-type headache, insomnia, or depression. Use with caution in heart disease and epilepsy. Dry mouth, sedation, dizziness and nausea are common side-effects in the first couple of weeks and usually settle with continued use. The only antidepressant with consistent support for efficacy in migraine prevention Consistent evidence supports efficacy in migraine prevention. 153 Common side-effects include drowsiness, nausea, diarrhoea, weight gain, tremor, hair loss, foetal abnormalities, haematological or hepatic abnormalities. 154 As sodium valproate can cause birth defects, women of child-bearing age should be given the drug with caution and should use adequate birth control. 57 Initiation should be restricted to specialist care and treatment should be managed under specialist supervision. Topiramate Third-line Gabapentin Methysergide Topiramate 25 milligrams once daily to 50 milligrams twice daily (licensed). 300 milligrams daily to 800 milligrams three times a day. 159 Initially 1 milligram at bedtime, increased gradually over about two weeks to 1-2 milligrams three times a day. 57,160 Safe and effective in migraine prophylaxis In trials for migraine prophylaxis the following side-effects were reported: fatigue, paraesthesia, dizziness, hypoaesthesia, language problems, nausea, diarrhoea, dyspepsia, dry mouth, weight decrease, anorexia, somnolence, difficulty with memory, difficulty with concentration, insomnia, anxiety, mood problems, depression, taste perversion, abnormal vision. 130 Initiation should be restricted to specialist care and treatment should be managed under specialist supervision. Trial results are not conclusive. 159 Common side-effects include dizziness, sedation, dry mouth, nausea, vomiting, constipation, weight gain. Methysergide has 5HT agonist activity which may be responsible for the severe rebound headache experienced by many patients attempting to withdraw from this drug after several months of usage. Common side-effects include drowsiness, leg cramps, hair loss, nausea, vomiting, abdominal pain, retroperitoneal fibrosis (one month drug holiday required every 6 months). Other management issues Menstrual migraine What is menstrual migraine? Menstrual migraine is defined as attacks of migraine without aura that occur regularly on day one of menstruation + two days and at no other time. 161 For most women with menstrual attacks, migraine also occurs at other times of the month ( menstrually related or menstrually-associated migraine). 1,162 Fewer than 10% of women report migraine exclusively with menstruation and at no other time of the month ( true or pure menstrual migraine). 1, Correct diagnosis of true menstrual migraine is essential for successful management. The diagnosis is clinical and confirmed by diary card evidence over three months. 16 How should menstrual migraine be managed? There are several options which can be tried in whatever order seems appropriate.. 16 Use a triptan for acute attacks when they happen. 166 Start the NSAID at the onset of menstruation and continue until the last day of bleeding. Mefenamic acid or naproxen are suitable choices. 138,167 This option is particularly valuable in migraine occurring with menorrhagia and/or dysmenorrhoea. Transdermal oestrogen 100 micrograms can be used from three days before the onset of menses for seven days in total. 168 When this is effective but not well tolerated, 50 micrograms may be tried. Estradiol gel 1.5 milligrams can be applied daily from day minus three for seven days. Taking the combined oral contraceptive pill (provided it is not contraindicated) continuously for nine weeks rather than three (tri-cycling), COMPASS Therapeutic Notes on the Treatment and Prevention of Migraine in Adults and Children April