WAPA Winter Conference 2013Headache Review

Sylvia Lucas MD, PhDClinical Professor of Neurology and Neurosurgery

Adjunct Rehabilitation MedicineUniversity of Washington Medical Center

January 29, 2013

IHS Classification 2nd Editon – ICHD II

Primary HA1. Migraine2. Tension-type3. Cluster and its relatives

(TACs)4. Other primary

headaches (exertional, coital, hypnic, etc.)

Secondary HA5. Posttraumatic6. Vascular disease7. Abnormal ICP, Neoplasm, etc8. Substances9. CNS infection10. Metabolic11. Cervicogenic, Eyes, Sinuses12. Psychiatric HA13. Neuralgias14. Other

AGE- AND GENDER-SPECIFIC PREVALENCE OF MIGRAINEAGE- AND GENDER-SPECIFIC PREVALENCE OF MIGRAINE

Lipton RB, Stewart WF. Neurology. 1993.

Mig

rain

e Pr

eval

ence

(%)

Secondary Headache Warnings

• “Worst or first”• New headache pattern• Change in headache pattern • Progressive headache syndrome• Onset with valsalva or intercourse• Papilledema or abnormal neurological exam• New headache over the age of 50• History of cancer or HIV

32 year old womanHeadache since age 12

Severe painStabbing, jabbingKnife through her eye

Nausea and vomiting

Scalp hurtsLight hurtsSound hurtsMovement hurts

Stays in bedLasts 24-36 hours

Can’t workMisses 2 days of workper month

What kind of headache is this?

Differentiating Migraine andTension-Type Headaches

Migraine• Usually lasts 4-72 hours• Moderate to severe• Often unilateral (60%), aura

in a minority of patients• Exacerbated by routine

activity• Nausea, vomiting,

photophobia, and phonophobia are common

Tension type• Low impact• Usually bilateral, mild to

moderate headache• Photo- or phonophobia

sometimes present• No nausea or vomiting

Dowson AJ et al. Curr Med Res Opin. 2002;18:414-439.

ONE-YEAR PREVALENCE OF COMMON HEADACHE DISORDERS

18

6

41 40

52.8

0

10

20

30

40

50

Migraine Episodic Tension-TypeHeadache

Frequent Headache

%

(>15 attacks per month)

Female

Male

Lipton RB, Stewart WF. Neurology. 1993.Schwartz BS et al. JAMA. 1998.Scher AI et al. Headache. 1998.

What causes headache?

• Genetics– A headache brain is inherited– A headache brain is

hypersensitive and hyperexcitable

– If one parent has migraine: 50% chance that a child will have migraine

• Environment– Internal and external triggers

Migraine is a Transmission Problem Same headache-different genes

• FHM-I CACNA1A: P/Q voltage-gated Ca2+ channel on chr 19 (Ophoff et al. Cell 1996; 87:543-552)

• FHM-II ATP1A2: Na+/K+ ATPase on chr 1q23 (De Fusco et al. Nat Genetics 2003;33:192-196)

• FHM-III SCN1A: sodium channel gene on chr 2q24 (Dichgans et al., Lancet 2005;366:371-377)

– Effect of mutation (SCN5A) 2-4x accelerated recovery from fast inactivation

Phases of a Migraine Headache

Adapted from Cady RK. Clin Cornerstone. 1999;1(6):21-32.

Premonitory/

Prodrome

Aura Mild Moderate to Severe

HAPostdrome

Pre-HA Post-HAHeadache

Time

Inte

nsity

Activation of the TNC May Result in Referred Pain that Could be Perceived Anywhere along the Trigeminocervical Network

Syndrome of Migraine: More than Pain

• Neurologic

• Gastrointestinal

• Autonomic

• Musculoskeletal

• Mood

• Pain

Migraine With Aura

• At least 2 attacks with at least 3 of the following – Fully reversible visual, sensory, or speech symptoms– At least 1 aura symptom that develops gradually over 5 minutes

and/or different aura symptoms occuring in succession over 5 minutes

– Each aura symptom lasts 5 minutes and no more then 60 minutes

– Headache fulfills criteria for migraine without aura• Headache begins during aura or follows aura within 60

minutes• Not attributed to another disorder

Headache Classification Committee of the International Headache Society. Cephalalgia. 2004;24(suppl 1):24-25.

Cortical Spreading DepressionFortification spectra

About 15-18 % of migraine patients have aura

STRATEGIES FOR MIGRAINE TREATMENT

Preemptive treatmentMigraine triggertime-limited and

predictable

Preemptive treatmentMigraine triggertime-limited and

predictable

Preventivetreatment

Decrease inmigraine frequency

warranted

Preventivetreatment

Decrease inmigraine frequency

warranted

Acutetreatment

To stop pain and prevent progression

Acutetreatment

To stop pain and prevent progression

Silberstein SD. Cephalalgia. 1997.

Establish diagnosisSet realistic goals

Educate patients Individualize care

Acute Migraine Medications• Nonspecific

– Simple Analgesics– NSAIDS– Combination analgesics– Opioids– Corticosteroids

• Adjunctive therapies– Antiemetics/dopamine antagonists

• Specific– Ergotamine/Dihydroergotamine– Triptans

Migraine-Specific Treatment Choices• Sumatriptan (Imitrex)

– Tablet (25, 50,100mg)– Injection (6mg, 4 mg stat

dose)– Single Dose Vial 6mg/0.5cc– Nasal Spray (5, 20mg)– Needleless injection (Sumavel

Dose Pro 6mg)• sumatriptan 85 mg and naproxen

sodium 500 mg (Treximet)• Zolmitriptan (Zomig)

– Tablet (2.5, 5mg)– ZMT (2.5, 5mg)– Nasal Spray 5.0 mg

• Naratriptan (Amerge)– Tablet (1, 2.5mg)

• Rizatriptan (Maxalt)– Tablet (5, 10mg)– ODT (5, 10mg)

• Almotriptan (Axert)– Tablet (6.25,12.5mg)

• Frovatriptan (Frova) (Relpax)– Tablet 2.5mg

• Eletriptan– Tablet (20,40mg)

• DHE-45 (dihydroergotamine mesylate) 4mg/cc injectable

• Migranal Nasal Spray 4mg/cc

Triptan Pharmacology

Tmax (h) Biologic Meta- t1/2 Before During Activity bolism

Drug (h) Attack Attack (%)

Sumatriptan 2 2 2.5 15 Mao-A, renal

Zolmitriptan 3 2 2.5 40 Cyp1A2, Mao-A

Naratriptan 6 2-3 3-4 70 Renal, Cyp1A2

Rizatriptan 2 1-1.5 1-1.5 42 Mao-A, renal

Eletriptan 4 1 2.8 50 Cyp3A4

Frovatriptan 25 3 3 30 Renal, Cyp1A2

Almotriptan 3.5 1.5-3 1.5-3 70 Cyp2d6, 3A4, Mao-A ,renal

Migraine Management in the Office

• Anticipate the needs of your patients to avoid costly and unpleasant urgent office or emergency department visits

• Provide a written or easily referenced plan for urgent care to your patients

• Re-assess and modify treatment plans as needed

Management Issues at First Visit

• Initial therapy– Match treatment needs to attack profile, associated

symptoms and level of disability (stratify the care)– Explain recurrence

• Back-up therapy– If initial treatment fails

• Rescue therapy• Education

– Treat early and optimally, lifestyle changes, avoid triggers

Escalation of Migraine PainOptimal Delivery

Time

Intensity Fast

Slow

Rescue therapy

• Patient has already used oral and usual medication

• Injectable treatment used most often– Severe pain and later in the headache– Gastroparesis, nausea or vomiting

• Both patient and physician desire rapid relief– Need resources for sicker patients– Need the room

Urgent Care Delivery: The Outpatient ClinicSome Things to Consider

• Transportation– Drugs may cause sedation or cognitive slowing

• Timing– Patient observation

• Staffing– Avoid being rushed-establish cut-off times for calls

• Severity of Symptoms– Rehydration or electrolyte imbalance may preclude

outpatient delivery

Outpatient Treatment Protocols

• Ask about medication allergy or drug hypersensitivity• Recent medication history (everything)• Be aware of maximum daily dosing to avoid toxicity

– Maximum daily dose of sumatriptan is 200 mg orally; 12 mg SQ; 20 mg nasal spray

– Maximum daily dose of DHE-45® is 3 mg– Use rational polypharmacy

• Respect half-lives of medication and drug interactions

Outpatient Treatment ProtocolsA combination approach

• Treatment with injectable anti-nausea medication– Dopamine antagonist if sedation is not an issue– Ondansetron if sedation is to be avoided

• Treatment with a migraine specific therapy– Subcutaneous sumatriptan– DHE-45®

• Treatment with injectable NSAID (especially if allodynia is present)– Ketorolac IM

Jakubowski M, Levy D, Goor-Areh I. et al. Headache 2005;45:850-861.

Neuroleptics (D2 receptor antagonists)

• Phenothiazines– Prochlorperazine, chlorpromazine, promethazine

• Butyrophenones– Droperidol, haloperidol

• Metoclopromide• Anti-adrenergic, anticholinergic, antiseritonergic,

antihistaminic effects– Sedation, drowsiness, EPS– Prevent EPS (dystonia and akasthesia) by premedicating

with an anticholinergic

Dopamine Antagonists

Medication Delivery and Dose Maximum Daily Dose

Chlorpromazine 12.5 mg-25 mg IM/IV 300 mg

Droperidol 0.625 mg-2.5 mg IV 10mg

Prochlorperazine 5-10 mg IM/IV 40 mg

Promethazine 12.5-25 mg IM/IV (AE w/IM) 100 mg

Metoclopromide 5-10 mg IM/IV 60 mg

Guidelines for InitiatingMigraine Prevention

• Frequency of headache greater than 4-6 per month, disability more than 2-3 days per month or that significantly interferes with quality of life

• Use of acute medication more than 2-3 times per week on average or escalating use

• Acute medications contraindicated, not tolerated, or ineffective

• Presence of uncommon migraine conditions– Hemiplegic or basilar migraine– Migraine with prolonged aura or migrainous infarction

• Patient preference

Source: AAFP/ACP-ASIM Recommendations.

Migraine Prevention: Medications

• Antidepressants– TCAs, SSRIs, MAOIs– Amitriptyline, nortriptyline

• Cardiovascular medications– Propranolol*– Timolol*– Verapamil

• Antiepileptic drugs (AEDs) – Divalproex*– Gabapentin– Topiramate*

– Zonisamide– Other

• NSAIDs• 5-HT antagonists

– Methysergide*• Other

– Riboflavin (B2)– Feverfew– Magnesium (Mg++)– Botulinum toxin– Petasites– ACE inhibitor– Angiotensin II antagonist– Coenzyme Q

TCAs=tricyclic antidepressants; SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxidase inhibitors; NSAIDs=nonsteroidal anti-inflammatory drugs; ACE=angiotensin-converting enzyme. *Currently holds FDA indication for migraine prevention.

Common Comorbidities

• Comorbid conditions often found in migraineurs include– Depression– Anxiety– Social phobias– Bipolar disorder– Irritable bowel syndrome– Sleep disorders

Migraine Comorbidity May Assist With Selection of Preventive Agent

Comorbidity– Anxiety– Bipolar– Depression – Epilepsy– Insomnia– MVP– Raynaud’s

Agent– SSRI/SNRI, AED– AED, SSRI/SNRI– TCA– AED– TCA– b-blocker– Calcium blockerAED=antiepileptic (anticonvulsant) drug; MVP=mitral valve prolapse;

SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin norepinephrine reuptake inhibitor; TCA=tricyclic antidepressant

Lipton R, Silberstein S. Clinician. 2001;19:1-26.

Other Types of Primary Headache • Cluster headache

– Occurs in episodes, or “clusters” – Brief, severe pain around 1 eye lasting 15 min to 3

hours– Up to 8 times per day, often waking patient from

sleep– Pacing headache

• Tension-type headache– Bilateral pressure, vice-like pain of mild to moderate

intensity– Rarely accompanied by associated symptoms

Silberstein SD et al. Wolff’s Headache and Other Head Pain 2001:6-26

Treatment of Cluster Headache• Acute therapy

– Oxygen 100% for 10-12 minutes at 8L/miin via tight-fitting mask

– Imitrex Injectable 4-6 mg SQ• Short-term prevention

– Triptan or ergot at bedtime• Prevention for episodic or chronic

– Two preventives with rapid induction• AED e.g. valproic acid or topiramate• Calcium channel blocker e.g. verapamil ( can go up to 480 mg)

– Corticosteroids

4.4 Primary headache associated with sexual activity

• 4.4.1 Preorgasmic headache– A. Dull ache in the head and neck associated with

awareness of neck and/or jaw muscle contraction and fulfilling criteria B.

– B. Occurs during sexual activity and increases with sexual excitement.

– C. Not attributed to another disorder• 4.4.2 Orgasmic headache

– A. Sudden severe (explosive) headache fulfilling criteria B.– B. Occurs at orgasm.– C. Not attributed to another disorder

ICHD-II Cephalalgia 2004; 24 (Supplement 1).

Case History

• 38 year old woman with 25 year h/o episodic headache• Gradual increase in frequency and for the last 6-7 years taking

Excedrin Migraine initially 2 tab q 6 h, then q 5h, now q 4 h (10 tabs/day)

• During pregnancy switched to Excedrin Tension, now mixes them. May take Excedrin PM to sleep

• Rescues with Fiorinal 2 or 3 tab (40/mo). Occasional ER visit• Wakes up with suboccipital headache (3/10) which is

constant, becoming unilateral with no predominant side, severe pain (10/10) and nausea about twice/mo for 2 d

• Interferes with taking care of her 6 year old and work• Prior neurologist tried sumatriptan, topirimate and

amitriptyline

Take 2 tablets every 4 hours until you are addicted.

Syndrome of Medication Overuse Headache (MOH)

• Occurs in patients with pre-existing migraine/pain• Waking with early morning headache• Pattern of headaches and overuse of analgesics in

predictable and escalating frequency• Prevention: limit frequency and dose of meds• Treatment: refractory to otherwise appropriate

therapy– withdrawal therapy– restriction of monthly doses for acute treatment

Medications With Risk of MOH or Rebound HA

Adapted from Smith TR et al. Drugs. 2004;64:2503-2514.

High Moderate to Low

Acetaminophen, aspirin, caffeineButalbital-containing combinationsShort-acting opioidsShort-acting NSAIDsDecongestants

Dihydroergotamine mesylateLong-acting NSAIDsSimple analgesicsLong-acting opioidsShort-acting NSAIDsTriptans

Principles of Medication Overuse Headache (MOH) Therapy

• Taper medications most likely to cause MOH/rebound • Substitute acute medications that are less likely to cause

MOH/rebound• Bridging program during withdrawal

– parenteral dihydroergotamine mesylate– low-dose tizanidine with long-acting NSAIDs – daily doses of a triptan for up to 10 days– short course of steroids, long-acting NSAIDs

• Preventive MedicationCautions:

– opiate and barbiturate abstinence syndromes– increasing headache during withdrawal period

Maizels M. Am Fam Physician. 2004;70:2299-2306.

Menstrual Migraine Frequency

0

5

10

15

20

25

30

35

34 29 24 19 14 9 4 2 7 12 17 22 27 32

Used with permission from Headache in Clinical Practice. Copyright © 1998, 2002 Martin Dunitz Ltd.

Day of cycle

No.

of a

ttac

ks

76

Migraine in women (n=55)

Day 1 = first day of bleeding

Menstrually Related Migraine (MRM) Occurs Days -2 to +3

• Approximately 60% of women who experience migraine relate the frequency of their attacks to the menstrual cycle

• Pure menstrual migraine occurs from days -2 to +3 of menstruation in at least 2 out of 3 menstrual cycles

• Menstrually related migraine always occurs • on days -2 to +3 in at least 2 out of 3 menstrual

cycles, as well as other times of the cycle

Allais G, Benedetto C. Neurol Sci. 2004;25 (suppl 3):S229-S231.

Hormone Levels During Menstrual Cycle

Adapted from Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2nd Ed. New York, NY: Martin Dunitz; 2002:102

Follicular phase Luteal phase

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29

Day of cycle (day 0 is start of blood flow)

Ho

rmo

ne

le

ve

ls t

hro

ug

ho

ut

cy

cle

Endocrine cycle

LH

FSH

E2

POvulation

HORMONAL FLUCTUATIONS DURING THE MENSTRUAL CYCLE

Case Study: Menstrual Migraine Over Time

• 23 year old nulliparous female• History of true menstrual migraine without

aura since menarche• Headaches changes 6 months ago with

administration of oral contraceptives• Now migraines present with aura and

weakness never experienced before• Concerns with oral contraceptives or alternate

etiology

Migraine as a Risk Factor for Stroke (Migraine Coexistent with Stroke)

• Stroke risk in young (less than 45 years of age) female population is generally very low– estimated to be between 5 and 10 per 100,000 woman-years

• However, there is increased stroke risk (odds ratio) in women migraineurs under age 45: Odds Ratio (OR)

– Migraine 3– Migraine with aura 6– Migraine plus OC’s 5 - 17– Migraine plus OC’s plus smoking 34

• Relative risk seems high, but absolute risk in migraineurs is low: – 17 to 19 in 100,000

• There is no evidence that migraine is a risk factor for stroke in women over age 45

MacGregor EA, de Lignieres B. Cephalalgia 2000; 20:157-163.IHS Task Force on Combined OC and HRT. Bousser MG et al. Cephalalgia 2000; 20:155-156.

Migraine-related Symptoms That May Require Further Evaluation and/or Cessation of Oral Contraceptives

• New persistent headache• New onset of migraine with aura• Increased headache frequency or intensity• Unusual or prolonged aura symptoms

IHS Task Force on Combined OC and HRT. Bousser MG et al. Cephalalgia 2000; 20:155-156.

Summary of Medication Efficacy for Urgent Care

Droperid

ol

Sumatr

iptan

Proclo

rperaz

ine

metoclo

promide IV DHE

Chlorpro

mazine

Ketoro

lac IV

Meperid

ine

Meto

clopro

mide IM

Mag

nesium IV

Ketoro

lac IM

Valpro

ate0

102030405060708090

Percent Patients with Pain Relief

%

Weighted averages of percentages of pain relief for all medications for which there were at least 2 randomized 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: Opioids, NSAIDs, Steroids, and Post-Discharge Medications. Headache 2012;52:467-482

8278 77

70 67 65

60 58

45

4337

32

Droperid

ol

Sumatr

iptan

Proclo

rperaz

ine

Meto

clopro

mide IV DHE

Chlorpro

mazine

Meperid

ine

Meto

clopro

mide IM

magnesiu

m IV

Ketoro

lac IM

0

10

20

30

40

50

60

Percent Patients with Pain Freedom

%

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

40 35

53

41

21

53

14

36

22

30

Summary

• Prochlorperazine and metoclopromide are the most frequently studied medications used in the ED with efficacy superior to placebo

• Triptans and DHE are equivalent to the dopamine antagonists for migraine pain relief

• Opioids are superior to placebo in efficacy• Steroid use can decrease headache recurrence

after discharge.

Conclusions• Based on weighted averages of percentage pain relief for medications

studied in at least 2 randomized single agent trials:– Recommend combination of:

• Droperidol or proclorperazine IV (77-82% pain relief)• Sumatriptan 6 mg SQ or DHE IV (67-78% pain relief)• Ketorolac 30 mg IV or dexamethasone 6 mg IV (69-78% pain relief)

• Based on weighted averages of percentage pain free for medications studied in at least two randomized trials with drugs used as single agents: – Recommend combination of:

• Proclorperazine IV or chlorpromazine IV (53% pain free)• Meperidine IM, sumatriptan SQ or magnesium IV (30-36% pain

free)• IV is the preferred route of administration and recurrence many be

decreased by the addition of dexamethasone

Thank you!