FAR 453/3

Applied Therapeutic I

Case Study
Title: Migraine Lecturer: Pn. Maisharah
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 CHAI SHIAW FUNG CHONG VEN YEE GOH MING YI KHOR MING PEI LAW YEN SIN LIM KHOON HUP MOHD. IQBAL BIN NASARUDDIN MUHAMMAD MUSTAQIM B JUHARUL ZAMAN PHOON SEOW YEE STEVEN MUN ANAK UNJAI TAN WEI SHENG TEOH ER ZHEN ZAMRIAH BT ZULKIFLI Name Matric Number 99553 99560 99569 99577 99584 99592 90775 99614 UF080002 99653 99661 99667 99675

Group 3

CASE STUDY: Chief complaint I dont think this new medication is working for my headache, and now I have been gaining weight! History of Present Illness A 35 years old woman came to clinic for follw-up of migraine headache. She stated that she used to get about two migraines episodes per month; however the condition has increased to about four to five episodes per month after her marriage divorce. She stated that the migraines usually occur in the morning, and there was is no association between the headache and her menses. Her typical headache evolves quickly (within 1 hour) and involves severe throbbing pain that is unilateral and temporal in nature and preceded by an aura, which consist of nausea and pastel lights flashing throughout her visual field. It always involved photofobia and she might experience vomiting in extreme headache. She reports that the severe migraine always cause her to missed 2 days of work each month. She was also not being able to complete household work for the 2 days she had severe migraine attacks. She also complaints of having mild migraine attack lasting 3 days per month during which her performance at work and home were reduced by half and she will missed jogging during that days. She needed a relaxation in dark and quite room, or else the severity of the migraine will be increased. She rates her migraine of 8-9 on an increasing pain scale of 10. At her previous visit to the clinic 2 months ago, she was prescribed Cafergot 2 tablet orally be taken at the onset of headache. However, Cafergot has not been effective for half of the migraines she has had in the last 2 months. She states she has taken her medications exactly as advised. She prefers to use medications that can be taken orally. She was also

Started on valproic acid at her last clinic visit for prophylaxis and has noticed a 5 kg weight gain since then. She inquires about switching from valproic acid to another medication. Past Medical History Migrain with aura since age 29; previous medical work-up demonstrated no PVD< CVA, brain tumor, infection, cerebral aneurysm, or epileptic component. Drug therapies involves including: Past Medication History Abortive Therapy 1. Simple analgesics, NSAIDS (good efficacy until 2 months ago) 2. Narcotics (good efficacy, but puts her out of commission for days) 3. Cafergot (limited efficacy) Prophylactic 1. Valproic acid 500 mg orally (weight gain) 2. Propanolol 20 mg BD (increased episodes of dizziness and lightheadedness; patient self-discontinued medications) Family History Parents were positive for migraine and hypertension. Mother had Type 2 Diabetes Mellitus. Social History She is a law firm secretary. Recently divorced. Had 3 boys aged 1, 3 and 5 years old. Denied smoking and alcohol use. Occasional caffeine intake. ROS Complaints of increased frequency of headache starting about 6 months ago and limited efficacy with Cafergot; no nausea, vomiting, diarrhea, or flashing lights at present. Current medications: 1. Cafergot 2 tablet orally at the onset of migraine 2. Metochlorpramide 10 mg orally at onset of migraine 3. Valproic acid 50 mg orally at bedtime. Allergic NKDA Physical Examination Gen WDWN women in moderate distress VS BP 131/85, HR 78, RR 18 reg, T 37.1C; Wt 70kg; Ht 162 cm Skin Normal skin turgor, no diaphoresis

HEENT PERRLA; EOMI; no funduscopic exam performed Chest Good breath sound bilaterally; clear to A&P CV RRR, S1 and S2 normal; no murmur Abd Soft, NT/ND, no hepatosplenomegaly, (+) bowel sound Ext UE/LE strength 5/5 with normal tone, radial and femoral pulses 3+ bilaterally; no edema; no evidence of thrombophlebitis; full ROM Neuro A&O X 3; no dysarthria or aphasia; memory intact; no nystagmus; no fasciculations, tremor, or ataxia; CN- intact; Babinski negative.

Laboratory results Na 138 mEq/L, K 4.0 mEq/L, Cl 99 mEq/L, BUN 10 mg/dL, SCr 0.6 mg/dL, CO2 30 mEq/L, WBC 8.7 103/mm3,Hgb 13 g/dL, Plt 301 103/mm3, AST 24 IU/L, ALT 26 IU/L, Alkaline phosphatase 37 IU/L, Urine pregnancy test (-)

1. Identify and define the patients problem (Definition of common migraine or classical migraine). This patient is having migraine. Headache is pain in the head whereas migraine is a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia, preceded by constriction of cranial arteries, often with resultant prodromal sensory, especially ocular, symptoms (aura), and commencing with the vasodilation that follows. Migraine is a very painful type of headache. Migraine headache is commonly bilateral in young children; an adult pattern of unilateral pain usually emerges in late adolescence or early adult life. Migraine can be divided into two major sub-types. Migraine without aura (common migraine) is a clinical syndrome characterised by headache with specific features and associated symptoms. Migraine with aura (classical migraine) is primarily characterised by the focal neurological symptoms that usually precede or sometimes accompany the headache. Most patients with migraine have exclusively attacks without aura. Many patients who have frequent attacks with aura also have attacks without aura.

A common migraine occurs without the occurrence of aura but patient may experience premonitory symptoms in the hours or days before the onset of headache. Premonitory and resolution symptoms include hyperactivity, hypoactivity, depression, craving for particular foods, repetitive yawning and other less typical symptoms reported by some patients. Other symptoms may include psychological symptoms which include anxiety, depression, euphoria, irritability, drowsiness, hyperactivity, and restlessness. Autonomic symptoms and constitutional symptoms may also occur but the neurologic symptom is the most common. Headache with the features of migraine without aura usually follows the aura symptoms. International Headache Society has list out some diagnosis criteria for common migraine or migraine without aura. A. At least 5 attacks that fulfill criteria in B, C, and D B. Headache attacks that last 4 to 72 hrs (untreated or unsuccessfully treated) C. Headache has at least 2 of the following characteristics: 1. Unilateral site 2. Pulsating quality 3. Moderate to severe intensity 4. Aggravation by walking stairs or similar routine physical activity D. During headache, at least 1 of the following symptoms: 1. Nausea or vomiting (or both) 2. Photophobia and phonophobia 3. No evidence of related organic disease According to National Institute of Neurological Disorder and Stroke, classical migraine is preceded by an aura, visual disturbances that appear as flashing lights, zig-zag lines or a temporary loss of vision. The aura is the complex of neurological symptoms that occurs just before or at the onset of migraine headache. The aura typically evolves over 5 to 20 minutes and last less than 60 minutes. Headache usually occurs within 60 minutes of the end of aura. Diagnosis criteria that have been listed by International Headache Society for migraine with aura are: A. At least 2 attacks that fulfil criteria in B and C B. At least 3 of the following 4 characteristics: 1. One or more completely reversible aura symptoms that indicate focal cerebral cortical or brain-stem dysfunction (or both) 2. At least one aura symptom develops gradually over >4 min or two or more symptoms occur in succession 3. No aura symptom lasts >60 min 4. Headache follows aura in <1 hr C. No evidence of related organic disease In this case, she is experiencing common migraine rather than classical migraine. It is because: A) She acknowledged being more sensitive to the light (photophobia). B) She described the headache as a severe, throbbing (pulsating) and right-sided headache (unilateral). C) She has 4-5 migraine attacks per month that lasting 12-48 hours per episodes after her marriage divorces. D) Headache with the features of migraine without aura usually follows the aura symptoms.

2. What signs/symptoms identified by the patient are consistent with this problem? The symptoms she experienced: A) She complains of having the worst headache ever and experienced neurological symptoms including photophobia. B) Besides that, she experienced severe, throbbing, right-sided headache which indicates migraine. C) She also has family history of migraine for her mother and brother. The signs she experienced: A) The headache then becomes more severe within the last 36 hours with a score of 8-9 out of 10 of the pain scale. B) Patient has a past medical history of intermittent headache over the last 6 months with 6 to 8 time a month and each attack lasting for 12 to 48 hours. C) Apart from that, patient has blood pressure of 131/85 mmHg is a sign of migraine. 3. Discuss factors which may precipitate migraine headache in this patient. In this case, factors that may precipitate migraine in this patient are caffeinated beverages. She consumes caffeine moderately. Besides that, she works as a law firm secretary and has three young children. She may face much of stress from her work and taking care of her children. This is also a risk for her to get migraine. Her marriage failure also contributes to her migraine as well. The sudden psychological changes had made her into severe migraine attack. The positive family history of migraine is compatible with the genetic basis suggested in migraine. The use of migraine drug such as cafergot will cause rebound headache as one of the side effects. And many factors are listed below that will contribute to migraine. Foods

Aged cheese Alcohol (particularly red wine and champagne) Monosodium glutamate (contained in seasonings and processed foods) Chocolate Nuts, oranges, and tomatoes Caffeinated beverages Nitrates and nitrites (hot dogs, sausages, luncheon meats) Avocado Smoked or pickled fish or meats Onions Aspartame (dietary sweetener) Yeast or protein extracts (brewers yeast, marmite)

Medications Vasodilators (nitroglycerin, isosorbide dinitrate) Hormones (oral contraceptives, estrogens, clomiphene, danazol) Anti-hypertensives (nifedipine, captopril, prazosin, reserpine, minoxidil) Histamine-2 blockers (cimetidine, ranitidine) Antibiotics (trimethoprim-sulfa, griseofulvin)

Selective Serotonin Reuptake Inhibitors

Lifestyle Fasting or skipping meals Sleep (too little or too much, changes in patterns, e.g., jet lag, shift changes) Letdown following stress (weekends, vacations, after exams) Caffeine withdrawal Others

Weather changes High altitude (air travel, mountain climbing)

4. Could any of the patients problems have been caused or exacerbate by her drug therapy? The occurrence of drug-induced headache had been reported during prolonged and uninterrupted treatment of cafergot. After you stop taking metoclopramide, you may have unpleasant withdrawal symptoms such as headache, dizziness, or nervousness. Some other side effects mentioned even less often are elevated blood ammonia levels, suggested by sleepiness, headache, confusion, or nausea caused by valproic acid. It is essential when using NSAIDs for head pain that they not be taken too frequently or they can actually cause headaches referred to as "Rebound Headache. Concurrent use of several NSAIDs potentiates the risk of gastrointestinal bleeding. Caffeine intake could precipitate migraine.

5. Calculate the patients MIDAS score and describe the severity of her migraine headaches. (refer MIDAS questionnaire. )
Items 1. 2. On how many days in the last 3 months did you miss work or school because of your headaches? 6 How many days in the last 3 months was your productivity at work or school reduced by half or more because of your headaches? (Do not include days you counted in question 1 where you missed work or school) 3-4 On how many days in the last 3 months did you not do household work because of your headaches? 6 How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches? (Do not include days you counted in question 3 where you did not do household work) 6 On how many days in the last three months did you miss family, social or leisure activities because of your headaches? 6

3. 4.

5.

Total score: add answers to the questions above > 21 Interpretation

Grade Definition I II III IV Minimal or infrequent disability Mild or infrequent disability Moderate disability Severe disability

Score 0-5 6-10 11-20 21+

This patient is having severe migraine as she had done the MIDAS score that is on grade IV. She is having frequent migraine attack and severe migraine attack because she got at least 2 times attack per month and she rates her migraine of 8-9on an increasing pain scale of 10. 6. Create a list of patients drug therapy problems at this clinic visit. Cafergot has not been effective for half of the migraines she has had in the last two months and can cause drug-induced headache during prolonged and uninterrupted treatment. Weight gain had been occurred as one of the side effects of valproic acid.

AQ1. What are the goals of therapy in this patient? The goals for successful treatment of acute migraine attacks:1 Treat migraine attacks rapidly and consistently without recurrence. Minimize the use of back-up and rescue medications. Restore the patients ability to function. Optimize self-care for overall management. Be cost-effective in overall management. Have minimal or no adverse events.

The goals of long-term migraine treatment would be to:1 Reduce the attack frequency, severity, and disability. Avoid rebound headaches or acute headache medication overuse. Improve the quality of life. Reduce headache-related distress and psychological symptoms.

Q2. What pharmacotherapeutic alternatives are available for the abortive treatment of this patients migraine attacks?

Medication Ergotamine tartrate Oral tablet (1mg) with caffeine 100mg Sublingual tablet (2mg) Rectal suppository (2mg) with caffeine 100mg Dihydroergotamine Injection 1mg/mL

Dosage 2mg at onset; then 1-2mg every 30 minutes as needed. Insect to 1 suppository at onset; repeat after 1 hour as needed 0.25-1mg at onset intramuscular or subcutaneous; repeat every hour as needed

Nasal spray

One spray (0.5mg) in each nostril at onset; repeat sequence 15 minutes later (total dose is 2mg or 4 sprays)

Serotonin agonists (triptans) Sumatriptan - Injection Oral tablets Nasal spray

6mg subcutaneous at onset; can repeat after 1 hour if needed. 50mg, 100mg at onset; can repeat after 2 hours if needed. 5, 10, or 20mg at onset; can repeat after 2 hours if needed. 2.5mg or 5mg at onset as regular or orally disintegrating tablet; can repeat after 2 hours if needed. 5mg(one spray) at onset; can repeat after 2 hours if needed. 1 or 2.5mg at onset; can repeat after 4 hours if needed. 10mg IV at onset; or 15-20 minutes oral prior to other oral therapy agent. 10mg IV or IM at onset.

Zomitriptan - Oral tablets

Nasal spray

Naratriptan

Miscellaneous Metoclopramide Prochloperazine

Q3. What pharmacotherapeutic alternatives are available for the prophylaxis treatment of this patients migraine attacks? Medication Dosage Tricyclic antidepressants 10 to 300mg per day Amitriptyline (Elavil) 10 to 200mg per day Doxepin (Sinequan) 10 to 200mg per day Imipramine (Tofranil) 10 to 150mg per day Nortriptyline(Aventyl, Pamelor) Calcium channel blockers 90 to 360mg per day Diltiazem (Cardizem) 120 to 720mg per day Verapamil (Calan, Isoptin) Selective serotonin reuptake inhibitors Fluoxetine (Prozac) Serotonin antagonists

10 to 80mg per day

Cyproheptadine (Periactin)

Methysergide (Sansert)

4 to 16mg per day; Daily maximum: Children aged 2 to 6: 12mg per day Children aged 7 14: 16mg per day 2 to 8mg per day; maximum: 14mg per day 30 to 90mg per day

Monoamine oxidase inhibitors Phenelzine (Nardil)

Q4. Design an optimal pharmacotherapeutic plan for abortive treatment and prophylaxis of the patients migraine headache, by considering past success and failure in treating it. Abortive treatment: - Metoclopramide 10mg is administered orally 15 to 30 minutes prior to oral acute migraine therapy since she might experience vomiting in extremely headache. - Sumatriptan 50mg orally is given. Dose may be reated after at least 2 hours if migraine recurs. Maximum dose is 300mg perday. Prophylaxis treatment: - Amitriptyline, initially 10mg at night is given orally. Dose is increased if necessary to maintenance of 50-75mg at night.

Q5. What are the monitoring parameters should be assessed regularly to evaluate the recommended therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects? i. Neuroimaging techniques. Advanced neuroimaging has made significant contribution to our understanding of the pathophysiology of migraine. It has identified mechanisms involved in the transformation of migraine from an episodic disorder to one with near continuous symptomatology.2 Lab test for calcitonin gene-related peptide (CGRP) in migraineurs. Elevation of CGRP is involved in the genesis of migraine and other primary headache disorders. 3 Luminance and color perimetry as well as black and white attern reversal visualevoked potentials were performed in migraineurs either with or without aura tested interictally. Disturbances of visual perception are a common feature in migraine.4 Clinical signs and diagnostic tests of sympathetic nervous system. Migraine is a disorder of chronic sympathetic dysfunction where an imbalance of sympathetic cotransmitter release.5

ii. iii.

iv.

Q6. What information should be provided to the patient regarding her new abortive and prophylactic therapies? i. ii. iii. iv. v. vi. vii. Metoclopramide promoting gastric emptying and normal peristalsis which enhanced absorption of oral medications.1 Sumatriptan should be taken as the aura of a migraine abates and the actualpain has begun.6 Ergot alkaloids such as ergotamine will increase risk of vasospasm when taking concomitant with sumatriptan. 7 Rebound headache with frequent or daily use of sumatriptan is rare. Sumatriptan is effective in relief of pain, nausea, vomiting and photophobia.1 Tricyclic agents other than amitriptyline for treatment of migraine is not well established.6 Patients should be instructed to keep a headache calendar before and after initiating preventive therapy, recording headache frequency, duration and severity. This calendar will aid the physician in assessing the efficacy of a preventive regimen.6 Patients should be aware that prophylactic treatments will not work immediately; results may not be seen for at least 2 months. They should understand that prophylactic treatment does not mean that they will never have another migraine, but that their migraines will decrease in severity and duration.

viii. ix.

1. Review the literature regarding the clinical use of the following drugs that are used in the treatment/prophylaxis of migraines. a) Beta-blockers Beta-blockers are the first-line agent for migraine prophylaxis, with propanolol highly preferred due to its safety, efficacy, favorable adverse effect profile and the large number of studies that support its effectiveness. Although the mechanism of antimigraine action by betablockers is unknown, it was generally assumed that they raise the migraine threshold by modulating adrenergic or serotonergic neurotransmission in cortical or subcortical pathways. Selection of a -blocker is based on -selectivity, convenience of the formulation, and tolerability. Although only propanolol and atenolol are approved by FDA for migraine prophylaxis, propanolol, nadolol, timolol, atenolol, and metoprolol have proven efficacy in controlled clinical trials. Atenolol is an alternative when patient cannot tolerate propanolols central nervous system adverse effects. On the other hand, beta-blockers with intrinsic sympathomimetic activity including pindolol, acebutolol, alprenolol and oxprenolol are ineffective for migraine prophylaxis. Beta-blockers should be used with caution in patients with congestive heart failure, peripheral vascular disease, atrioventricular conduction disturbances, asthma, depression, and diabetes. Medications Atenolol Metoprolol Nadolol Propanolol Timolol Doses 25100 mg/day 50300 mg/day in divided doses 80240 mg/day 80240 mg/day in divided doses 2060 mg/day in divided doses

b) Antiepileptics sodium valproate Sodium valproate is an important alternative for migraine headache prophylaxis and particularly useful in migraineurs with comorbid seizures, anxiety disorder, or bipolar disorder. It has multiple mechanisms of action, including enhancement of -aminobutyric acid (GABA) mediated inhibition, modulation of the excitatory neurotransmitter glutamate, and inhibition of sodium and calcium ion channel activity. The dose for sodium valproate is 500-1500mg/day in divided doses. Hepatotoxicity is the most serious side effect of valproate therapy, thus baseline liver function tests should be obtained, but routine followup studies are not necessary in asymptomatic adults on monotherapy. Valproate is contraindicated in pregnant women (owing to potential teratogenicity) and patients with a history of pancreatitis or chronic liver disease.

c) Pizotifen Pizotifen is a serotonin and histamine antagonist indicated for migraine prophylaxis. Nevertheless, its mechanism of action has not fully elucidated. The initial dose of pizotifen for migraine prophylaxis is 0.5mg at bedtime, then increase gradually to 0.5mg 3 times/day. The usually dosage range is 1-6mg/day. Pizotifen should be used cautiously in pregnancy women, patient intolerant to anticholinergic agents, patient with narrow angle glaucoma, myasthenia gravis, bladder outlet obstruction, renal or hepatic insufficiency, diabetes, cardiovascular disease or obese. It is contraindicated with concurrent use of MAO inhibitor and in patient with gastric outlet obstruction.

d) Cyproheptadine Cyproheptadine is a first generation histamine H1 antagonist, as well as a serotonin antagonist and calcium channel blocker. Although cyproheptadine is not FDA approved for migraine prophylaxis, it is particularly useful for migraine in children. In a double blind controlled study of propanolol and cyproheptadine in migraine prophylaxis, cyproheptadine alone had improved the frequency, duration and severity significantly (0.05) but dropouts (23.6%) and the (persons with) side effects were more than in the combination group (cyproheptadine and propranolol). The dose of cyproheptadine is 4mg - 8mg 3-4times/day. Cyproheptadine is contraindicated in patients with narrow angle glaucoma, bladder neck obstruction, symptomatic prostatic hyperplasia, acute asthmatic attack, stenosing peptic ulcer, GI tract obstruction and concurrent use of MAO inhibitors.

e) Clonidine Clonidine is an alpha2-adrenergic agonist used for migraine prophylaxis although there is no benefits found in some studies and its use in migraine prophylaxis is not approved by FDA. The dose used is 0.1-0.2mg 2-3times/day. Clonidine should be used cautiously in patient with severe coronary insufficiency, conduction disturbances, recent myocardiac infarction or chronic

renal insufficiency. It is also not recommended for use in patients with severe cardiovascular disease or hemodynamic instability.

f) Tricyclic antidepressants Tricyclic antidepressants have show effectiveness in migraine prophylaxis, particularly amitriptyline, which is the most widely studied antidepressant for migraine prophylaxis and demonstrated efficacy in placebo-controlled and comparative studies. Other tricyclic antidepressants (TCAs) that have been used successfully for migraine prophylaxis include doxepin, nortriptyline, protriptyline, and imipramine. Along with propanolol and valproate, amitriptyline is considered a first-line therapy for migraine prophylaxis. The mechanism of amitriptyline anti-migraine effect is independent of its antidepressant activity. In fact, it is related to its ability to block the reuptake of serotonin at central sites. Nevertheless, some tricyclic antidepressants that block 5-HT reuptake such as clomipramine are ineffective for migraine prophylaxis. Due to associated sedation, evening doses of tricyclic antidepressant are preferred. Besides that, anticholinergic side effects of these agents limit their use in patients with benign prostatic hyperplasia and glaucoma. However, the more favorable side-effect profile of nortriptyline and protriptyline could prove advantageous in patients who are particularly intolerant of the anticholinergic and sedative side effects of amitriptyline. Medications Doses 25150 mg at bedtime Amitriptyline 10200 mg at bedtime Doxepin 10200 mg at bedtime Imipramine 10150 mg at bedtime Nortriptyline 530 mg at bedtime Protriptyline

g) Calcium channel blockers (CCB) CCB are second- or third-line options for migraine prophylaxis when other drugs with established clinical benefit are failed or contraindicated. The mechanism of CCB in migraine therapy is still unclear. Whether the efficacy of CCBs is due to their vasoactive properties, modulation of neurotransmitter release or a serotogenic effect is unknown. Of the CCBs, verapamil is the choice for preventive treatment because it is effective and has been extensively studied in randomized controlled trials. The recommended dose for verapamil is 240-360mg/day in divided doses. Headache frequency, intensity and duration are reduced in 50% of patient treated with verapamil. Nevertheless, verapamil has a limiting property whereby it should be continued for at least 2 months to properly evaluate response therapy since its observable benefits may not be noted for up to 8 weeks after initiation of therapy. Other CCBs that have been used to treat migraine include nifedipine, diltiazem and nimodipine. However, on the basis of current evidence, neither nifedipine nor diltiazem is recommended for migraine prophylaxis until other, better-established therapies have failed. Nimodipine also has little utility as a prophylactic agent due to the inconsistent results from placebo-controlled trials and the high cost of nimodipine.

2. Explain the meaning of rebound headache and medication misuse headache. According to The International Classification of Headache Disorders, 2nd Edition (ICHDII), rebound headache is also known as medication-overuse headache, drug-induced headache or medication misuse headache. Rebound headache occurs as a result of frequent or excessive use of acute migraine medications leading to a pattern of increasing headache frequency and drug consumption. Rebound headache evolves as a self-sustaining headache-medication cycle. As the migraine medication effect wears off, the headache returns and patients tend to consume more medication to relieve migraine, which at the same time increases the risk of medication overuse and thus rebound headache. Rebound headache is a subset of chronic daily headache, occurring on 15 or more days per month but with the added criterion of medication overuse, that is regular overuse for more than 3 months of at least one acute migraine medications including: Ergotamine, triptans, opioids, or combination analgesic medications on 10 or more days per month on a regular basis for more than 3 months, or Simple analgesics or any combination of ergotamine, triptans, analgesics, or opioids on 15 or more days per month on a regular basis for more than 3 months without overuse of any single class alone. NSAIDs, antihistamines, decongestants, OTC (over the counter) agents like Excedrin and Tylenol and prescription medications. Another criterion of rebound headache is that the patients headaches must worsen in terms of frequency and intensity as the use of acute medications becomes more frequent. Rebound headache is associated with nonrestorative sleep, neck pain, and vasomotor instability. Comorbid depression and anxiety are common and may complicate treatment. Patients can also suffer from the physiologic and psychological consequences of the overused medications. To prevent the development of medication-misuse headache, it is recommended that the use of acute migraine therapies is limited to 2 or 3 days per week. Discontinuation of the offending agent leads to a gradual decrease in headache frequency and severity and a return of the original headache characteristics within 2 months. References: 1. GLEN AUKERMAN, M.D., DOUG KNUTSON, M.D., and WILLIAM F. MISER, M.D., M.A.; Management of the Acute Migraine Headache; Am Fam Physician. 2002 Dec 1;66(11):2123-2131 2. Todd J Schwedt MD, David W Dodick MD; Advanced neuroimaging of migraine; THE LANCET Neurology; Volume 8, Issue 6, June 2009, Pages 560-568 3. Stewart J. Tepper, MD; Mark J. Stillman, MD; Clinical and Preclinical Rationale for CGRP-Receptor Antagonists in the Treatment of Migraine; Medscape News; 2008; 48(8): 1259-1268 4. Milena De Marinis, MD; Steno Rinalduzzi, MD; Neri Accornero, MD; Impairment in Color Perception in Migraine With and Without Aura; Medscape News; 2007;47(6):895904. 5. Stephen J. Peroutka; Migraine: A Chronic Sympathetic Nervous System Disorder; Medscape News; 2004;44(1) 6. Inland empire health plan; Clinical Practice Guideline for the diagnosis and management of migraine. 7. British National Formulary 59 March 2010.

8. Lloyd Y. Young, Koda-Kimble, Applied Therapeutic: The Clinical Use of Drugs,9th edition, San Francisco. 9. Joseph T. Dipiro et al. Pharmacotherapy. A Pathophysiologic Approach, 7th edition. Elsevier, London. 10. Drug Profiles: Anti-inflammatory Drugs, Nonsteroidal AKA: NSAIDs. Available at: http://www.migraines.org/treatment/pronsaid.htm. 11. Metochlopramide: Available at: http://www.emedicinehealth.com/drugmetoclopramide/article_em.htm. 12. Common side effects of valproic acid.Available at: http://www.epilepsy.com/medications/p_valproicacid_commonside . 13. Cafergot by norvatis. Available at: MIMS Annual Malaysia 2009/2010. 14. EPILIM by sanofi-aventis. Available at: MIMS Annual Malaysia 2009/2010. 15. International headache society: Available from: http://ihsclassification.org/en/02_klassifikation/02_teil1/01.02.00_migraine.html.