wapa winter conference 2013 headache review sylvia lucas md, phd clinical professor of neurology and...
TRANSCRIPT
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!