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Migraine Management in the Office

• “23 yo patient into her second day of a migraine. Has taken sumatriptan Headache Treatment: Evidence‐based 100 mg yesterday morning, afternoon and at 4 AM this morning. She is miserable, in bed, with extreme nausea and vomited yesterday. She has Protocols for the Office and Emergency only been able to take sips of water. She calls your office nurse about what Department to do next”. • Anticipate the needs of your patients to avoid costly Sylvia Lucas MD, PhD and unpleasant urgent office or emergency Clinical Professor of Neurology & Rehabilitation Medicine department visits University of Washington Medical Center • Provide a written or easily referenced plan for urgent Seattle, Washington October 13, 2012 care to your patients • Re‐assess and modify treatment plans as needed

Management Issues at First Visit Escalation of Migraine Pain Optimal Delivery • Initial therapy – Match treatment needs to attack profile, associated symptoms and level of disability (stratify the care) – Explain recurrence Fast • Back‐up therapy Intensity – If initial treatment fails • Rescue therapy Slow • Education – Treat early and optimally, lifestyle changes, avoid triggers Time

Rescue therapy Urgent Care Delivery: The Outpatient Clinic Some Things to Consider • Patient has already used oral and usual • Transportation medication – Drugs may cause sedation or cognitive slowing • Injectable treatment used most often in office • Timing – PiPatient obibservation – Severe pain and later in the headache • Staffing – Gastroparesis, nausea or vomiting – Avoid being rushed: establish cut‐off times for calls • Both patient and physician desire rapid relief • Severity of Symptoms – Need resources for sicker patients – Rehydration or electrolyte imbalance may preclude – Need the room outpatient delivery

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Outpatient Treatment Protocols Outpatient Treatment Protocols A combination approach‐if infusion is not an option • Ask about medication allergy or drug hypersensitivity • Treatment with injectable anti‐nausea medication • Recent medication history (everything) – Dopamine antagonist if sedation is not an issue (e.g. prochlorperazine IM) • Be aware of maximum daily dosing to avoid toxicity – Ondansetron if sedation is to be avoided (e.g . 8 mg ODT) – Maximum daily dose of sumatriptan is 200 mg orally; 12 mg SQ; 20 mg nasal spray • Treatment with a migraine specific therapy – Maximum daily dose of DHE‐45® is 3 mg – Subcutaneous sumatriptan (usually 4‐6 mg SQ) – Use rational polypharmacy – DHE‐45® (usual dose 1 mg SQ or IM) • Respect half‐lives of medication and drug interactions • Treatment with injectable NSAID especially if allodynia is present (e.g. ketorolac 60 mg IM) Jakubowski M, Levy D, Goor-Areh I. et al. Headache 2005;45:850-861.

Neuroleptics (D2 receptor antagonists) Dopamine Antagonists

• Phenothiazines Medication Delivery and Dose Maximum Daily Dose

– Prochlorperazine, chlorpromazine, promethazine Chlorpromazine 12.5 mg‐25 mg IM/IV 300 mg • Butyrophenones Droperidol 0.625 mg‐2.5 mg IV 10mg – DDidlroperidol, hhlaloperid idlol • Metoclopromide Prochlorperazine 5‐10 mg IM/IV 40 mg

• Anti‐adrenergic, anti‐cholinergic, anti‐seritonergic, Promethazine 12.5‐25 mg IM/IV (AE w/IM) 100 mg anti‐histaminic effects Metoclopromide 5‐10 mg IM/IV 60 mg – Sedation, drowsiness, EPS – Prevent EPS (dystonia and akasthesia) by premedicating with an anticholinergic

Headache Medications: Risk of Arrhythmia

Risk of Torsades Possible Risk Unlikely to cause Risk if has de Pointes Torsades de Torsades de congenital Pointes Pointes long QT syndrome Chlorpromazine Fosphenytoin Amitriptyline Extensive list, all Domperidone* Lithiuum Citalopram in column 1 Droperidol Octreotide Clomipramine and 2 and Haloperidol Ondansetron Desipramine many from Methadone Quetiapine Doxepin column 3, and Pimozide Risperidone Fluoxetine many others Tizanidine Imipramine See: Venlafaxine Mexiletine www.torsades.org Ziprasidone Nortriptyline Paroxetine Protriptyline Sertraline Trimipramine

Table adapted from Goodman & Gilman “Pharmacological Basis of therapeutics” Information from: www.torsades.org

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Therapy for acute refractory migraine Office, urgent care or emergency department (ED) • Approximately 50% of migraine patients are undiagnosed Emergency Department Treatment • More than 50% of migraine patients use OTC or simple analgesics; many use no treatment • Headache is the 4th most common reason to go to the ED (1.4‐3.3 million visits per annum) • More than 2/3rds are for a primary headache diagnosis

Urgent Care: The Emergency Department Frequency of Medication Class Use Percentage of Patient Use • Not the usual headache: unusually severe or 80 70 prolonged 60 • Unusual symptoms such as new or prolonged 50 % 40 aura 30 • Ineffective usual treatment and backup 20 10 treatment 0 Dopamine Opioids NSAIDs Migraine Specific • Prolonged vomiting and dehydration Antagonists • No physician or no insurance Gupta,MX, Silberstein SD, Young WB, et al. Headache 2007;47:1125-1133.

Evidence‐based Treatment for Refractory Comparative Sumatriptan Efficacy Migraine Medication Comparator % Pain % Pain Study Design • Few controlled, randomized studies of Relief Free Sumatriptan 6 mg Placebo 70 vs 35 31 vs 13 Akpunonu et al R/DB/P (1995) common drugs utilized in the ED SQ (p<.01) Sumatriptan 6 mg none 60 Miner et al Observational – (2007) Placebo arms rare SQ Sumatriptan 6 mg DHE 1 mg SQ 85 vs Winner et al R/DB – Use of combinations of medication complicate (1996) No difference at 3 hrs SQ comparison of single agents with each other (86 vs 90%) Sumatriptan 6 mg Chlorpromazine 12.5 mg 85 vs 73 42 vs 41 Kelly et al (1997) R All got SQ IV P=.002 metoclopromide 10 mg IV Sumatriptan 6 mg Metoclopromide 20 mg 70 vs 83 35 vs 59 Freidman et al R/DB (2005) With IV SQ IV diphenhydramine 25 mg Sumatriptan 6 mg Proclorperazine 10 mg 70 vs 96 Kostic et al R/DB (2010) With SQ IV diphenhydramine 12.5 mg SQ Adapted from Table 1. Kelley NE and Tepper DE. Headache 2012;52:114-128.

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Comparative DHE Efficacy Ketorolac (Toradol®) Medication Comparator % Pain Relief % Pain Study Design Free DHE 1 mg IV placebo 82 vs 20 Klapper and Stanton R/DB/P with • Usual dose 30 mg IV or 30‐60 mg IM (P<.002) (1991) metoclopromide 5‐10 mg IV DHE 1 mg IV Ketorolac 60 mg 78 vs 33 Klapper and Stanton R/DB with – Maximum use 3 consecutive days IV/5 days IM IM At 1 hour (P=.031) (1991) metoclopromide 5 mg IV DHE .5 mg IV Meperidine 75 86 vs 77 Scherl and Wilson R with • GI protection mg IM At 1 hour (1995) mettloclopromid e 10 mg IV/promethazine 25 mg IM

DHE 1 mg IV Valproate 500 45 vs 50 Edwards et al (2001) R with • High risk for renal injury or GI bleed mg IV At 4 hours metoclopromide 10 mg IV

DHE 1 mg IV Meperidine 75 38 vs 0 Belgrade et al (1989) R with • No concurrent steroids mg IM >90% pain reduction metoclopromide 10 mg IV/hydroxyzine 50 mg IM (P<.01) – Hold oral NSAIDs DHE 1 mg IV Meperidine 75 93 vs 21 Klapper and Stanton R/DB with mg IM (1993) metoclopromide 10 mg IV/hydroxyzine 75 mg IM DHE 1 mg IV Chlorpromazine 37 vs 80 (p<.05) 23 vs 33 Bell et al (1990) R/SB 12.5 mg IV Could be repeated once

Adapted from Table 2. Kelley NE and Tepper DE. Headache 2012;52:114-128.

Comparative Ketorolac (Toradol®) Efficacy Magnesium Sulfate Medication Comparator % Pain % Pain Free Study Study Design Relief Ketorolac 30 mg IV Proclorperazine 52 vs 68 Seim et al (1998) R/DB • 1‐2 grams IV every 12 hours 10 mg IV At 1 hr (P=.04) Ketorolac 30 mg IV Sumatriptan 6 64 vs 0 Jakubowski et al R/DB • Monitor reflexes with repeated dosing mg SQ At 2 hrs (P<.05) (2005) Delayed treatment after 4 hours Ketorolac 30 mg IM Meperidine 75 6 vs 30 Larkin and Prescott R/DB • If no side effects, may reach 1.5 times the mg IM At 1 hr (P<.05) (1992)

Ketorolac 60 mg IM Meperidine 50 44 vs 60 Harden et al (1996) R/DB/P upper range of magnesium plasma level mg IM Placebo 55 With promethazine 25 mg IM • Contraindicated with renal insufficiency Ketorolac 60 mg IM Meperidine 100 24 vs 20 Duarte et al (1992) R/DB mg IM (P=.76) With hydroxyzine 50 mg IM • Side effects: brief flushing, diarrhea, mild Ketorolac 60 mg IM DHE 1 mg IV 33 vs 78 Klapper and Stanton R/DB At 1 hr (1991b) With metoclopromide 5 mg IV (P=.031) hypotension Ketorolac 60 mg IM Meperidine 75 50 vs 64 22 vs 21 Davis et al (1995) R/DB mg IM At 30 min At 30 min With promethazine 25 mg IM

Adapted from Table 2. Kelley NE and Tepper DE. Headache 2012;52:467-482

Magnesium Efficacy Valproic acid (Depacon®) Efficacy Medication Comparator % Pain Relief % Pain Free Study Study Design Medication Comparator % Pain Relief Study Study Design Mg 1 gm IV Placebo (normal 100 vs 7 87 vs 7 Demirkaya et al R/SB/P saline) (P<.0001) (2001) 70% MA Valproate 500 DHE 1 mg IV with 50 vs 45 Edwards et al. R At 30 min mg IV Metoclopromide At 4 hours (2001) Mg 2 gm IV Placebo 15 vs 22 Corbo et al (2001) R/DB/P All with 10 mg IV metoclopromide 20 mg IV Valproate 500 Prochlorperazine 13 vs 86 Tanen et al R/DB Mg 2 gm IV Placebo 19 vs 24 Frank et al (2004) R/DB/P mg IV 10 mg IV (P<.01) (2003)

Mg 1 gm IV Placebo 33 vs 17 MWA 23 vs 10 MWA Bigal et al (2002) R/DB/P Valproate 300 none 73 Mathew et al Observational 50 vs 13 MA (P<.05) 37 vs 7 MA mg IV In 30 min (2000) At 1 hour

Mg 1 gm IV Placebo 47 vs 35 Cete et al (2004) R/DB/P

Mg 2 gm IV Proclorperazine 10 56 vs 90 (P=.04) at 30 12 vs 40 Ginder et al (2000) R/DB/P mg IV min

Mg 1 gm IV None 80 Mauskop et al Observational At 15 min (1996)

Adapted from Table 2. Kelley NE and Tepper DE. Headache 2012;52:114-128. Adapted from Table 4. Kelley NE and Tepper DE. Headache 2012;52:292-306.

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Steroids Dexamethasone Efficacy

• Usual dose of methylprednisolone (Solu‐Medrol®)is Medication Comparator % Pain Relief % Pain Free Study Study Design Dex 6 mg IV Placebo (NS) 78 vs 20 Klapper and Stanton R/DB/P (1991) With metoclopromide 5‐ 100‐250 mg as a one time dose or up to 3 days At 30 min (P<.002) 10 mg IV Dex 6 mg IV Placebo 25 vs 19 55 vs 47 Friedman (2007) R/DB/P • Usual dose of dexamethasone (Decadron®) is 6‐24 With metoclopromide 5‐ sustained 10 mg IV mg Dex 24 mg IV Placebo 82 vs 55 Innes (1999) R/DB/P sustained • Monitor glucose Dex 24 mg IV Placebo 65 vs 55 Donaldson (2008) R/DB/P • Increases WBC sustained Dex 15 mg IV Placebo 78 vs 68 Rowe (2008) R/DB/P • GI protection sustained Dex 10 mg IV Placebo 78 vs 68 Fiesseler (2011) R/DB/P • May cause psychosis or mania sustained Dex 10 mg IV Placebo 70 vs 66 Baden and Hunter R/DB/P (2006) As adjuvant to prevent 87 vs 42 sustained recurrence 48‐72 hr

Adapted from Table 3. Kelley NE and Tepper DE. Headache 2012;52:467-482

Percent Patients with Pain Relief Percent Patients with Pain Freedom

90 82 60 80 78 77 53 53 70 67 65 50 70 40 35 41 36 60 58 60 40 45 30 50 43 30 37 21 22 % 40 32 % 20 30 14 20 10 10 0 0

Weighted averages of percentages of pain free for all medications for which there were at least 2 Weighted averages of percentages of pain relief for all medications for which there were at least 2 randomized randomized trials with drug used as a single agents. Adapted from Fig. 2 in: Kelley NE and Tepper DE. trials with drug used as a single agents. Adapted from Fig. 1 in: Kelley NE and Tepper DE. Rescue Therapy for Acute Migraine, Part 3: Rescue Therapy for Acute Migraine, Part 3: Opioids, NSAIDs, Steroids, and Post-Discharge Medications. Headache Opioids, NSAIDs, Steroids, and Post-Discharge Medications. Headache 2012;52:467-482 2012;52:467-482

Conclusions Summary • Based on weighted averages of percentage pain relief for medications studied in at least 2 randomized single agent trials: • Prochlorperazine and metoclopromide are the – Recommend combination of: most frequently studied medications used in • Droperidol or proclorperazine IV (77‐82% pain relief) • Sumatriptan 6 mg SQ or DHE IV (67‐78% pain relief) the ED with efficacy superior to placebo • Ketorolac 30 mg IV or dexamethasone 6 mg IV (69‐78% pain relief) • Triptans and DHE are equivalent to the • Based on weighted averages of percentage pain free for medications studied in at least two randomized trials with drugs used as single agents: dopamine antagonists for migraine pain relief – Recommend combination of: • Opioids are superior to placebo in efficacy • Proclorperazine IV or chlorpromazine IV (53% pain free) • Meperidine IM, sumatriptan SQ or magnesium IV (30‐36% pain free) • Steroid use can decrease headache recurrence • IV is the preferred route of administration and recurrence may be decreased after discharge. by the addition of dexamethasone • May add diphenhydramine 12.5‐25 mg with DA to minimize movement disorders

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Drugs and Pregnancy

• Peak prevalence of migraine occurs during women’s childbearing years Drug Safety During Pregnancy • Majority of migraineurs improve during pregnancy; 7% note onset during pregnancy • Increase in age at which women become pregnant means more chronic medical conditions • 60% of pregnancies are unplanned • Pre‐pregnancy planning session: review prescription, OTC, supplements, caffeine, nicotine, alcohol use – may need to change to safer drugs at their lowest effective dose

US FDA Categories of Medication Risk in Concept of Drug Safety during Pregnancy Pregnancy • “Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the A Controlled human studies show no risk fetus” B No evidence of risk in humans, but no – “if benefit outweighs risk” controlled studies – Drug use ddiuring pregnancy could be considered “off label” C Risk to humans has not been ruled out – Drugs not tested on pregnant women D Positive evidence of risk to humans from – Significant benefit to woman with severe migraine human or animal studies – Risk difficult to ascertain, but document a “risk‐ benefit” conversation X Contraindicated in pregnancy

Some Limitations of FDA Rating Scale FDA Categories to Avoid • Information is difficult to interpret for use in • Category D counseling women on drug safety for the majority of – Divalproex sodium, carbamazepine, tetracycline are known drugs which are rated B or C teratogens – – Either animal studies have not demonstrated fetal risk but But also clonazepam, atenolol, and topirimate (new) – NSAIDs become D in the 3rd trimester no controlled studies in pregnant women (B) • Category X – Either studies in animals have shown adverse effects on – Avoid ergotamine, methysergide and other ergot‐related drugs fetus and there are no controlled studies in pregnant • Decrease uterine blood flow (fetal hypoxia and growth women or studies in women and/or animals are not retardation) available (C) • Increase uterine muscle tone/contractions – Dihydroergotamine not linked to increased risk of congenital • Half of FDA‐approved drugs do not have a rating malformation, but possible fetal bradycardia in late pregnancy category – Blue cohosh (yellow ginseng)‐uterine stimulant; CHF in infants • Classification often not changed when new data are – Misoprostol‐uterine bleeding and abortion – Ribivarin and Interferon alfa‐2B (Rebetron)‐potent teratogen available (e.g. COC, bendectin, spermicides) – Cholesterol‐lowering agents

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Acute Treatment of Migraine in Pregnancy Acute therapy: Mild to moderate, slow onset of pain Avoid Known Teratogens Medication Caution FDA Risk • The Teratology Society has proposed that the Acetaminophen Hepatotoxicity with B chronic use >200 FDA abandon the current classification in favor mg/kg/d of evidence‐based narrative statements Codeine Sedation, respiratory C • DDfidefined as ddiysgenesis of fftletal organs as didepression, evidenced either structurally or functionally constipation, (e.g. restricted growth, fetal death, neonatal withdrawal carcinogenesis, malformation, brain function) Hydrocodone B Meperidine C NSAIDs (not Nausea, edema, GI B/C; D in 3rd 3rd) bleed, premature closure of D.A.

Acute Treatment of Migraine in Pregnancy Acute therapy: Moderate to severe, rapid pain escalation/urgent care Medication Caution FDA Risk Triptans Triptan sensation C Inpatient Treatment Protocol Ondansetron Rare transient B headache, (modified Raskin protocol) constipation, dizziness Metoclopromide Sedation, Diarrhea, B EPS Opioids (lozenges, Sedation, respiratory B/C suppositories, depression, injectable) constipation,neonatal withdrawal

STRATEGIES FOR REFRACTORY PATIENTS CONSIDER HOSPITALIZATION

• Tertiary referral Symptoms are severe and refractory to outpatient treatment or multiple ED visits Accompanied by drug overuse or toxicity not • Intensive outpatient treatment treatable as outpatient Intensity of neuropsychiatric and behavioral • Hospitalization comorbidity renders outpatient treatment ineffective Confounding medical illness

Treatment urgency of clinically desperate patient

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Orders for Dihydroergotamine Mesylate (DHE‐45) PRINCIPLES OF HOSPITAL TREATMENT Administration for Migraine Headaches Interrupt daily headache pattern with parenteral protocols • Code Status: ______• Allergies: ______Discontinue offending analgesics if rebound is present • Diet: Regular • IV Therapy: Heparin Lock Implement preventive pharmacotherapy • Activity: As tolerated • AiAntiemet ic: Identify effective abortive therapy – a. Metoclopromide 10 mg IV q 8 h – b. Prochlorperazine 5 mg IV q 8 h Treat behavioral and neuropsychiatric comorbidities – c. Droperidol 0.625 mg IV q 8 h – d. Promethazine 25 mg IV q 8 h Education, discharge and outpatient planning – e. Hydroxyzine 25 or 50 mg IM q 8 h – f. Odansetron 8 mg IV q 8 h

Saper JR et al. Handbook of Headache Management. 1993. Raskin ND. Neurology. 1986. Silberstein SD et al. Headache. 1990.

DHE‐45® Administration Rescue Medications • Drug Administration Protocol Antiemetic to be given q 8 h 30 minutes after antiemetic give 0.5 mg IV DHE over 2‐3 min • Chlorpromazine 12.5 mg IV q 8 h

Evaluate in one hour: • Droperidol 0.625 mg to 2.25 mg q 8 h A. If patient is nauseated, no DHE for 8 h, then give 0.3 or 0.4 mg IV q 8 h. DHE is always to follow antiemetic by 30 min • Ketorolac 30‐40 mg IV q 8 h B. If headache is gone and no nausea, give 0.5 mg IV DHE q 8 h. DHE is always to follow antiemetic by 30 min • Valproate sodium (Depacon) 500 mg IV C. If headache persists but no nausea, repeat 0.5 mg IV DHE at one hour without antiemetic q 8 h

Evaluate again in one hour: . If nausea persists, give 0.75 mg IV DHE q 8 h 30 min after antiemetic . If no nausea, give 1 mg IV DHE q 8 h 30 min after antiemetic

If no nausea, antiemetic may be discontinued after 6th dose.

Detoxification from simple analgesics with or Detoxification from opioid, barbiturate/analgesic or without caffeine benzodiazepine medication • Stop cold turkey • Taper medication by 10 % of dose weekly with • Advise patients of 7‐10 days of withdrawal headache preventive and acute therapy for breakthrough (“worse before better”) • If opioid overuse, may use clonidine tablets or • Acute treatment for breakthrough headache ( patches naproxen sodium 550 mg, ketorolac 30‐40 mg, or • May change to long acting opiate and taper or triptans) buprenorphine IV tapering over 3 days • May need preventive medication‐can reassess after • If barbiturate overuse, change to long acting withdrawal or institute during withdrawal based on phenobarbital 30 mg tid for 2 days then 30 mg QD headache history and co‐morbid conditions for 2 days • IV DHE protocol

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PROGNOSIS Medication‐Overuse Headache: Long‐Term Outcomes Numerous studies show varying degrees of efficacy • The success rate of withdrawal therapy (often accompanied by pharmacologic and/or behavioral Detox and maintenance of medication and intervention) in patients overusing analgesics, psychiat ri c t reat ment necessary ergotamine, or both was between 48% and 91% 50%-75% gain prolonged benefit; relapse can • In 10 of 23 papers reviewed, the reported rate occur was 77% or higher

Lake AL et al. Headache. 1993.

Silberstein SD, Silberstein JR. Headache. 1992. Silberstein SD and Saper JR. In: Wolff’s Headache and Other Head Pain. SD Silberstein SD, Lipton RB, and Dalessio DJ, eds. Oxford University Press, New York, NY. 2001; 273-274.

Thank you

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