Migraine Lecture 2002 Jin-Hyeun Huh Pharmacy Practice Leader TWH, UHN

What are the patient’s current and / or likely (potential) undesirable signs and symptoms? working hours per day drinking 6-8 cups of coffee daily skipping meals and eating poorly. Minimal to no relief with aspirin, ibuprofen and even OTC acetaminophen with codeine over the last few months –gave up taking these medications two days ago the attacks come on suddenly without warning “a terrible throbbing on one side of her head”. The headaches are often accompanied by severe nausea and commonly vomiting. some relief by taking frequent breaks and going to lie down with the lights off. E.T. has been having at least two headaches per week with one occurrence lasting over twelve hours resolving with sleep. She had her last headache three days ago

Urgency Quality of Life issue Prognosis –Stroke: Higher risk with migraine with Aura Higher risk with hemiplegic migraine –Epilepsy prolonged or chronic headache –Psychological disorders ( depression, etc.)

Migraine Disability Assessment Scale (MIDAS)

Are the patient’s signs and symptoms caused by a drug? If so, how is it related to drug therapy? Triggers Vasodilators rebound analgesic HA

Medication Induced Headache Drugs implicated –ASA, NSAIDS, Opiods, acetaminophen,triptans Clinical Presentation/Hallmarks –daily HA, sometimes throbbing –Frequent use of analgesics Treatment: –Remove offending agents –Provide effective acute treatment –Consider prophylaxis

Are the patient’s signs and symptoms suggestive of a disease process? Differential diagnosis

Are the patient’s signs and symptoms suggestive of a disease process? –hypoglycemia –Hypertension emergency –Ischemic stroke –Subarachnoid hemorrhage –meningitis –head trauma

Risk Factors: Migraine Age: –Peak ages  adolescence or in the 20’s –By age 50  Most migrainers report complete remission –New onset  unlikely after 40 Sex: –Females  % overall are female –Prior to puberty : incidence is equal Family Hx: –70% of patients have relatives with Headache history

Triggers Stress Emotion Glare Hypoglycemia Altered Sleep Pattern Menses Exercise Alcohol Excess caffeine /withdrawal Foods containing –MSG –tyramine –nitrates –phenylethylamine –aspartame Drugs –Estrogen (eg. OC) –Nitroglycerin –Excess analgesic use or withdrawal

History of HA : what questions would you ask?

History : Profile of HA time from onset to peak usual time of onset (week, month, season, hour of day) frequency & duration change over lifetime description : pulsating, pressing, sharp location : unilateral or bilateral or changing severity precipitating factors Aggravating factors factors that relieve the headache effectiveness of pharmacological or non-pharmacological treatments Aura

Definition of Migraine Migraine: –recurring headache disorder manifesting in attacks lasting 4-72 hrs. Typical characteristics: unilateral (sometimes bilateral) location, pulsating quality, mod or severe intensity, aggravation by routine physical intensity, and association with nausea, photo- and phono- phobia.

Classification 2 major types –Classic : migraine with aura –Common: migraine without aura Other less common –Hemiplegic –Status Migrainosus –Menstrual

Diagnosis Migraine without Aura Number of attacks Associated symptoms

Diagnosis Migraine without Aura 5 attacks ; each lasting hrs each attack to be accompanied by one of the following: nausea or vomiting phonophobia photophobia 2 of the 4 pain characteristics unilateral location pulsating quality moderate to severe intensity aggravation by physical activity

Diagnosis: Migraine with aura Number of attacks Associated symptoms

Diagnosis: Migraine with aura At least 2 attacks Include any 3 of the following –one or more fully reversible aura symptoms –aura developing over more than 4 minutes –aura lasting less than 60 minutes –headache following aura with a free interval of less than 60 minutes

Pathophysiology: 3 Systems Sympathetic –NE Parasympathetic –NO, VIP Trigeminal –CRGP

Pathophysiology: Triggers

Response to Vasoconstriction

Treatment Strategies & Goals Acute Treatment (Abortive) Prophylaxis

Treatment Strategies & Goals Acute Treatment –decrease duration of attack Prophylaxis –decrease severity, duration and frequency Based on severity & frequency of migraine attacks

Non-pharmacological methods Effective > 50% –Diet, education re: triggers,relaxation Moderately effective 30-50% –Stop smoking, exercise, riboflavin Ineffective <30% –Avoiding tyramine, aspartame,chocolate –Magnesium, feverfew

Drug related problems MH is suffering from migraine and requires effective acute therapy. MH may be experiencing headache due to analgesic overuse and requires effective acute therapy.

Treatment Strategies: Acute Treatment Analgesics :Acetaminophen, NSAIDS Analgesics with barbiturates Analgesics with OPIODS ergotamine derivatives “triptans or 5-HT1 agonists neuroleptics antiemetics Misc. (divalprolex, lidocaine, magnesium, NOSI, propofol)

Treatment : Factors influencing efficacy Severity of migraine Time to onset Efficacy Duration of effect/headache recurrence Side effects

Acetaminophen Severity of migraine: mild Time to onset: 1-2 hrs Effiacy : 1st line agent Duration of effect/ headache recurrence 2-3 hrs with increasing frequency of use, effectiveness may decrease Side effects: –well tolerated –liver problems > 4g daily

NSAIDS Severity of migraine : mild Time to onset: depends on agents 1-2 hrs Efficacy : partial Duration of effect/ headache recurrence : depends on agents with increasing frequency of use, effectiveness may decrease Side Effects GI bleeding renal dysfunction

Ergotamine derivatives Severity of migraine : severe Time to onset:IN, SC, PO, IV, IM 15 min -2 hrs Efficacy : % Duration of effect/ headache recurrence : 4 hrs 2-3 hrs Side effects N & V -incr BP -incr. MI, stroke

1st generation 5-HT1 agonist Sumatriptan Severity of migraine :Severe Time to onset:10 min -60 min IN/SC PO Efficacy : % Duration of effect/ headache recurrence : 2 hrs 40-50% Side effects N & V - chest tightness dizziness

Sumatriptan (Imitrex) Dosage forms: PO, IN, SC pharmacokinetic: –T ½ :2 hr –Onset :10 min –1hr –Metabolism :MAO Pharmacodynamic –Efficacy at 2 hrs Pain free % mg Sustained effect 17-20% mg

Assessment of 2 nd generation triptans Dosage forms: bioavailability Pharmacokinetic: T ½ Onset Metabolism Pharmacodynamic Efficacy at 2 hrs

Rizatriptan (Maxalt) Dosage forms: pharmacokinetic: T ½ : Onset : Metabolism : Pharmacodynamic Efficacy at 2 hrs Pain free Sustained effect

Rizatriptan (Maxalt) Dosage forms: Po tablets, wafers pharmacokinetic: T ½ :2 hrs Onset (peak) :1 hr Metabolism :MAO Pharmacodynamic Efficacy at 2 hrs Pain free 30-40% 5-10 mg Sustained effect 19-25% 5-10 mg

Zolmitriptan (Zomig, -Rapimelt) Dosage forms: pharmacokinetic: –T ½ : –Onset : –Metabolism : Pharmacodynamic –Efficacy at 2 hrs Pain free Sustained effect

Zolmitriptan (Zomig, -Rapimelt) Dosage forms: Po tablets, pharmacokinetic: T ½ :3 hrs Onset (peak) :4 hr Metabolism :MAO/CYP450 Pharmacodynamic Efficacy at 2 hrs Pain free 30-32% mg Sustained effect 20-22% mg

Naratriptan (Amerge) Dosage forms:, pharmacokinetic: T ½ : Onset (peak) : Metabolism : Pharmacodynamic Efficacy at 2 hrs Pain free Sustained effect

Naratriptan (Amerge) Dosage forms: Po tablets, pharmacokinetic: T ½ :5-6.3 hrs Onset (peak) :2-3 hr Metabolism :renal 70% CYP450 Pharmacodynamic Efficacy at 2 hrs Pain free 20% 2.5 mg Sustained effect 15% 2.5 mg

Triptans comparison N Engl J Med,Vol.346,N.4 ·January 24,2002

Triptans comparison N Engl J Med,Vol.346,N.4 ·January 24,2002

Triptans comparison N Engl J Med,Vol.346,N.4 ·January 24,2002

Triptans comparison N Engl J Med,Vol.346,N.4 ·January 24,2002

Triptans Side Effects

Common Reasons for Prophylactic Treatment failure Analgesic or ergot overuse Inadequate trial duration –8 weeks at effective doses Inadequate trial of non-pharmacological regimens DI interactions Inaccurate diagnosis

Criteria for Migraine Prophylaxis 2-3 attacks/month duration of attack is greater than 48 hrs extreme severity inadequate relief / side effects with acute medication migraine attacks occur after a prolonged aura

Treatment Strategies: Prophylaxis Beta-blockers Antidepressants Calcium channel blockers Anti-convulsants Serotonin antagonists Natural products Newer treatments ( BOTOX)

Prophylaxis Beta blockers –dose/frequency: –efficacy: –side effects: Calcium channel blockers –dose/frequency: –efficacy: –side effects:

Prophylaxis Antidepressants (TCA) –dose/frequency –efficacy –side effects valproate –dose/frequency –efficacy –side effects

Prophylaxis Natural products –feverfew –magnesium –vitamin B Newer treatments –Botox

Outcomes Clinical Outcomes –Improve quality of life –Decrease frequency of migraine attacks –Decrease severity of attacks Pharmacotherapeutic Outcomes

Pharmacotherapeutic Endpoint

Therapeutic Plan Acute treatment /Prophylaxis ? Acute therapy –Which triptan ? Why ? –Route of triptan ? –Dose of triptan ? –Time frame to assess efficacy Cafergot

Therapeutic Plan Prophylaxis –Which agent? Why ? –BB : propanolol, metoprolol,atenolol –TCA: amitriptyline Metoprolol prn

Monitoring Plan Side effects of medication Oral contraceptives