Migraine Headaches : Acute treatment in Thailand

M igraine headache is a very common, chronic neurovascular disorder with a prevalence of 11.7% in the United States of America, and 29.1% in Thailand. Females tend to experience migraine more often than males. The common age group is between 30 and 39 years of age.1, 2 Migraine is characterized by episodes of unilateral, pulsating or throbbing pain which is moderate to severe in its intensity and is often debilitating. It is also associated with nausea, vomiting and hypersensitivity to either light, sound, or smell. Headaches are usually aggravated by routine physical activity and are often alleviated by sleep within appropriate surroundings, such as in a dark, silent and cool place. If untreated or unsuccessfully treated, symptoms can persist from 4 to 72 hours.3 Approximately 90% of the migraineurs have moderate or severe pain. Approximately 75% of cases said their routine functions deteriorated whilst 53% reported serious impairment or required bed rest during attacks.2, 4 At least one half migraineurs complained of decreased productivity and one third missed at least one day of work or school in the previous year.5-7

(iii) headache phase (usually unilateral, pulsating), and (iv) postdrome phase (e.g., tiredness, head pain). 3,20,21 Tprodrome or premonitory phase may occur for hours or up to one day prior to the onset of headache in 70% of migraineurs. 22[25] Aura symptoms occur in one fifth of migraineurs.Typical aura is characterized by fully reversible focal neurological disturbances such as visual symptoms, sensory symptoms or dysphasia / aphasia that gradually develop over ≥ 5 minutes and last for ≤ 60 minutes. 3isual aura is the commonest aura found in 99% of cases, followed by a sensory aura (54%), and aphasic aura (32%). 26,27 eadaches could start simultaneously or after aura onset.However, most migraineurs (80%) usually developed the headache within 60 minutes after the end of aura. 28 20% of patients, headaches can consistently occur at the same side.However, in 40% of cases headaches may develop bilaterally.Head pain could be aggravated by routine physical activities such as walking or climbing stairs.[31] Postdrome phase is reported in 68% of migraineurs.Symptoms include tiredness (71.8%), head pain (33.1%), cognitive difficulties (11.7%), hangover (10.7%), gastrointestinal symptoms (8.4%), mood change (6.8%), and weakness (6.2%).Postdrome is frequently found in females (69.1%) and is associated with a full-blown migraine attack. 32e International Classification of Headache Disorders (ICHD-2) criteria were introduced in 2004 for standard diagnosis and research.Migraine was classified into six major categories.Two major sub-types were recognized; (1) Migraine without aura is a clinical syndrome characterized by headache with specific features and associated symptoms, and (2) Migraine with aura is primarily characterized by the focal neurological symptoms that usually precede or sometimes accompany the headache.ICHD-2 criteria for diagnosis of the two major types of migraine are shown in Table 1.

Strategies in migraine treatment
There are two approaches in migraine treatment: step care and stratified care. 33Step care starts treating the attack with general pain-killer medications e.g., acetaminophen, NSAIDs, or combination of simple analgesics.If headaches are not responsive within two hours, migraine-specific medication such as triptan or ergot should be commenced.
In the other approach, known as stratified care, the person with migraine is firstly evaluated for severity of disability by using the Migraine Disability Assessment (MIDAS). 34,35 his is a 5-item questionnaires which assesses lost time caused by headache over 3 months.A MIDAS score of more than '10' indicates moderate to severe disability that requires migraine-specific treatment.Another validated disability tool is the Headache Impact Test (HIT-6).A HIT-6 score more than 60 indicates severe impact from migraine. 36The Disability in Strategies of Care (DISC) study showed stratified care is superior to step care, resulting in better patient outcomes, and also reduced time loss. 37,38 ratified care is recommended in current guidelines for migraine treatment. 33,39

Analgesics
NSAIDs inhibit cyclooxygenase (COX) and reduce prostaglandin within the central nervous system (CNS) and outside the blood-brain-barrier.Selective cyclooxygenase -2 (COX-2) inhibitors, refecoxib and valdecoxib, have been studied and demonstrated their efficacy in acute migraine treatment but they were withdrawn from the market because of increase in cardiovascular risk.Celecoxib, an available selective COX-2 inhibitor, could be used for acute migraine attack with doses between 100 and 400 mg.Since it causes less gastrointestinal side effects, it should be considered in people with gastrointestinal intolerance. 40,41 lgesics such asacetylsalicylic acid (ASA) up to 1000 mg, [42][43][44] naproxen 500 -1000 mg, 45 ibuprofen 200-800 mg, 46 diclofenac potassium 50 -100 mg, 47 and paracetamol 1000 mg 48 are the first medications for mild to moderate migraine.0][51] The United States Headache Consortium recommended that NSAIDs and AAC can be effective for non-disabling migraine (Level A). 39,52 Migraine Headaches : Acute treatment in Thailand Classification of Recommendations. 39,52 el A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population.(Level A rating requires at least two consistent Class I studies)

Medications for acute migraine treatment
Ketorolac, a parenteral NSAIDs, has not yet been researched in placebo-controlled study to assess it in acute migraine treatment.The efficacy of ketorolac in acute migraine treatment was similar to meperidine and led to headache resolution similar as antiemetic medications. 53,54 etorolac can be administrated intravenously at a dosage of 15 to 30 mg or intramuscularly at 30 to 60 mg per dose.6][57] The U.S. Headache Consortium stated that enteral and parenteral opioid may be added for acute migraine should the sedative effect not put patients at risk: moreover the risk for abusive use of opioids has been addressed (Level B). 52 Opioid should be limited and reserved for some particular circumstances such as pregnancy, lactation, contraindication to triptans or NSIDs (Level U). 52 Parenteral opioid should be used as a back up for acute migraine when sedation side effects will not increase patient risk and when the risk of abuse has been addressed (Level B). 52

Antiemetics and Neuroleptics
Nausea and vomiting are common associated symptoms of migraine and can be as disabling as the headache.Antiemetic in acute migraine is recommended to treat these symptoms.It increases gastric emptying times resulting in optimizing absorption and effectiveness of oral medications.However, large prospective, placebocontrolled randomized trials are still lacking.
Intravenous metoclopramide showed superiority over placebo and ibuprofen in acute migraine treatment. 58,59 peated doses of metoclopramide plus intramuscular dimenhydrinate were found to have an effectiveness similar to subcutaneous sumatriptan. 60However, using oral metoclopramide alone, as monotherapy, is not effective for acute migraine treatment (Level A) but it can still be considered as an adjunctive therapy to NSAIDs or triptans (Level B). 52 Intravenous 10 to 20 mg metoclopramide is recommended for adults and adolescents (Level A). 39,52 Intravenous chlorpromazine demonstrated a higher efficacy than meperidine and lidocaine. 61Dose of 0.1 mg/kg chlorpromazine intravenously achieved a pain free response within 30 minutes compared with placebo. 62hlorpromazine should be used for patients requiring parenteral therapy (Level A). 52 Both metoclopramide and chlorpromazine share common side effects which include drowsiness, sedation, and hypotension.Extrapyramidal side effects such as acute dystonic reaction and akathisia are uncommon. 63

Triptans
Triptans are selective 5-hydroxytryptamine (5-HT) 1B/1D-agonists and ameliorate headache without sedative effect.Agonist of serotonin-1D receptors inhibit CGRP and inflammatory neuropeptide release in the meninges that cause extravasation of dural plasma protein, and block pain transmission from peripheral trigeminal pathway to the centrally trigeminal nucleus caudalis in brain stem.They also work via the 5HT1B receptor to constrict vessels dilated by CGRP.On the present market, there are seven types of triptans: sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan.In Thailand, however, only two triptans are available, sumatriptan and eletriptan.Non-oral routes are also not available in Thailand.5][66][67] Triptans can be effective at any time during a migraine attack.However, there is evidence that the earlier triptans are taken, the better their efficacy.Triptans should be taken when the headache is mild, ideally within less than 30 minutes from onset. 74,75 riptans are also effective in about 60% of NSAIDs non-responder.All triptans should be used for acute treatment of mild, moderate, and severe migraine unless contraindicated (Level A). 39,52 Sumatriptan was the first triptan to be introduced in 1991.Sumatriptan 100 mg (oral form) is significantly more effective than placebo for complete headache relief at 2 and 4 hours.Doses of 50 mg and 100 mg sumatriptan are more effective than dose of 25 mg.Dose of 50 mg is associated with a lower incident of adverse events than the dose of 100 mg. 62,68 umatriptan is extensively metabolized in liver by monamine oxidase-A (MAO-A) and therefore it should not be used in patients who take MAO-A inhibitors.
Eletriptan is rapidly absorbed and has a higher bioavailability (50% vs. 14%) with longer half-life (5.5 hours vs. 2 hours) than sumatriptan. 69Eletriptan 20, 40, and 80 mg have been studied in double blind, placebocontrolled trials which revealed that eletriptan provided higher favorable outcome compared with placebo.[72][73] Vongvaivanich K Active metabolism of eletriptan, N-desmethyl eletriptan, is catalyzed by cytochrome P-450 system (CYP3A4).Thus eletriptan should not be used with potent CYP3A4 inhibitors such as ketoconazole and clarithromycin.
Triptans are contraindicated in those with coronary artery disease, high risk for occult cardiac disease, cerebrovascular disease, peripheral vascular disease, uncontrolled hypertension, and pregnant woman.The most common adverse effects are fatigue, dizziness, asthenia and nausea.[66] Contraindication of Triptans

Conclusion
Migraine is a common, chronic and mostly debilitating neurovascular disorder, which impairs quality of life.Its pathophysiology is still not fully discovered but cerebral hyperexcitability either from genetic mutation or environmental factors can trigger central and peripheral pain pathway.Stratified care is recommended for migraine treatment.Persons with headaches should establish the correct diagnosis and evaluate their level of disability together with impact of migraine, prior to treatment.NSAIDS and ACC are the drugs of choice for those with mild to moderate migraine headaches.Ketorolac is a solely parenteral NSAID recommended for acute migraine treatment.Opioid should be avoided due to sedative side effect and risk of abuse.Intravenous metoclopramide and chlorpromazine can be used in patients with nausea/vomiting and who require parenteral therapy.Triptans are specific treatment for acute migraine headache and should be used in disabling migraineurs in the absence of vascular contraindications.
Answer 2: b.Acute onset of aura should cause suspicion of causes other than migraine, such as transient ischemic attack (TIA) or seizure aura.Migraine aura is characterized by gradual onset of symptoms in more than 5 minutes.Visual, sensory, aphasic and motor aura are recognized as transient neurological dysfunction in migraine.Aura can occur in isolation without headache.Cortical spreading depression that clinically represented aura can be suppressed by antiepileptic medications.
Answer 3: b.HIT-6 is an easy and reliable tool with which to assess severity and impact of migraineurs in the last month.MIDAS is another tool for assessing severity and impact in migraineurs in the 3 month follow up period.
Answer 4: c.Triptans (Eletriptan, sumatriptan) are recommended in debilitating migraine, according to stratified strategy (level of evidence A).NSAIDs and combination of ergotamine, and caffeine (Cafergot®) can be used in non-disabling migraine attack.
Answer 5: b.Ketorolac is the only parenteral NSAIDs that is approved for acute migraine treatment.Metoclopramide can be used in acute migraine attack because it is binding in a non-selective fashion on dopamine receptors.However, it can cause dystonic reaction, and akathisia.Opioids, such as meperidine, tramadol should be avoided in migraine and other headache treatment because they can induce central sensitization and also have addictive effect.

Table 1 :
3CHD-2 criteria for migraine headache.3 A. At least 5 attacks fulfilling criteria B-D B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs) D. During headache at least one of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia E.Not attributed to another disorder Migraine with aura (Typical aura with migraine headache) Diagnostic criteria: A. At least 2 attacks fulfilling criteria B-D B. Aura consisting of at least one of the following, but no motor weakness:1.fully reversible visual symptoms including positive features (e.g., flickering lights, spots or lines) and/or negative features (i.e., loss of vision) 2. fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e.,

Acute treatment in Thailand
Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population.(LevelB rating requires at least one Class I study or two consistent Class II studies) Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population.(LevelC rating requires at least one Class II study or two consistent Class III studies)Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.