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Migraine Pharmacotherapy
Chaouki K. Khoury, M.D., M.S.
Assistant Professor
Residency Program Director
Department of Neurology
Oklahoma University Health Sciences Center
4th Annual Advanced Pharmacology Conference
Oklahoma Association of Clinical Nurse Specialists
4/15/2011
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Disclosures
• I have no financial relationships to disclose
• I will be discussing non FDA-approved
therapies
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Objectives
1)
Delineate the different migraine treatment strategies
2)
Discuss bio-behavioral interventions
3)
List oral abortive therapies to be used on an outpatient
basis
4)
List parenteral abortive medications to be used in the
Emergency Department or in the inpatient setting
5)
List commonly used prophylactic therapies
6)
Explain briefly the concept of prophylactic treatment
mechanism of action
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Sources of Head Pain
• Intracranial structures:
• Cerebral and dural arteries and veins
• Dura matter at base of skull
• Venous sinuses
• Extracranial structures:
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Cervical roots and nerves (C1, C2, C3)
Cranial nerves
Extracranial arteries
Extraocular & cranial muscles (frontalis, masseters,
neck extensors)
• Paranasal sinuses
• Periosteum
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Fenichel GM. Clinical pediatric neurology: a signs and symptoms approach. 5 th ed. pp.77-78
Referred Pain
• Supratentorial blood vessels refer pain to:
• eyes and forehead (V1)
• temples (V2, V3)
• Infratentorial blood vessels refer pain to:
• occiput and neck (C1, C2, C3)
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Approach to the patient with Headaches
• Main purpose is to differentiate:
• Headaches that are only painful
• Headaches that are painful and harmful
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Secondary Headaches
• Cervicogenic headache (whiplash and other neck injuries)
• Dialysis headache
• Drug-induced headache
(illicit drugs, prescription drugs, food-additives, caffeine)
• Eyestrain headache
• Hypertension headache
• Medication Overuse Headache (MOH)
• Post-ictal headache
• Posttraumatic headache
• Sinusitis headache
• TMJ syndrome
• Vasculitis-induced headache
(CTD, Hypersensitivity, Infection-induced)
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Fenichel GM. Clinical pediatric neurology: a signs and symptoms approach. 5th ed. pp.84-88
Primary Headaches: ICHD-II*
• Migraine
• Tension-type headache
• Cluster headache and other trigeminal
autonomic cephalalgias
• Other primary headaches
* Headache Classification Subcommittee of the International Headache Society. Cephalalgia. 2004;24 Suppl 1:9-160.
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Treatment strategies
1. Bio-behavioral and other non-pharmacologic
interventions (behavioral medicine techniques,
manipulation, acupuncture, physical therapy)
2. Abortive therapy
3. Prophylactic therapy
1. Pharmacologic agents
2. Neutriceuticals (vitamins, minerals, supplements, herbs):
e.g., B-2, Mg, petasites, melatonin, co-Q10
Rapoport AM. J Headache Pain. 2006 Oct;7(5):355-9
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Rapoport AM. J Headache Pain. 2006 Oct;7(5):355-9.
Abortive Therapy:
Outpatient
4th Annual Advanced Pharmacology Conference
Oklahoma Association of Clinical Nurse Specialists
4/15/2011
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Abortive Therapy: Classes
a) Non-specific analgesic therapy:
• Acetaminophen
• NSAIDs: aspirin, ibuprofen, naproxen, indomethacin, etc.
• Non-narcotic pain medication:
caffeine, tramadol, dichloralphenazone
• Narcotics
b) Semi-specific medications:
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Isomethoptene
Butalbital
Dopamine agonists: anti-emetics, anti-psychotics
Anti-histaminergic: hydroxyzine
c) Specific abortive medications
• Triptans
• Ergot derivatives: ergotamine, D.H.E.
Khoury CK & Couch JR. Drug Design, Development and Therapy. 2010:4 9–17.
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Simple Analgesics
• Acetaminophen 1000 mg (15 mg/Kg) q8h PRN
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Ibuprofen 800 mg (10 mg/Kg) q8h PRN
Naproxen sodium (Aleve®) 550 mg BID PRN
Naproxen (Naprosyn®) 500 mg BID PRN
Ketorolac (Toradol®) 30 mg first dose, then 15 mg q8h PRN
Other NSAIDs
• Caffeine 150-500 mg q8h PRN
• Tramadol (Ultram®) 100-200 mg q6-12h PRN
Evers S et al. EFNS guideline on the drug treatment of migraine. Eur J of Neurol. 2009;16(9):968–981.
AAN and CNS clinical practice guidelines for Child Neurology. 2005-2006 ed.
Damen L et al. Pediatrics. 2005 Aug;116(2):e295-302.
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Dopamine antagonists: antiemetics
• Promethazine hydrochloride (Phenergan) 12.5-50 mg q8h PRN
• Metoclopramide hydrochloride (Reglan®) 10 mg (0.15 mg/Kg) q8h PRN
• Prochlorperazine (Compazine®) 10 mg (0.15 mg/Kg) q8h PRN
Review of ED rx of acute migraine in children (5-17y; n=382) in Canada in
2003/2004:1
• Dopamine antagonists (metoclopramide and prochlorperazine) were used in
20.7% of children overall
• More commonly used in pediatric EDs
Systematic review of medication trials in children (<18 y) through 2004:2
• Intravenous prochlorperazine more effective than intravenous ketorolac
1Richer
L et al. Headache. 2007 May;47(5):703-10.
2Damen
L et al. Pediatrics. 2005 Aug;116(2):e295-302.
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Combination medications
• Basic concept:
• Non-specific analgesic
(acetaminophen, NSAID, dichlorphenazone)
• Caffeine
• Semi-specific migraine medication
• Available as:
• OTC: Excedrin, Esgic, BC powder, Cafergot
• Pre-combined prescription: Midrin, Fiorinal, Fioricet
• Separate prescriptions combined together1
1 Ghelardini
C et al. J Pain. 2004 Oct;5(8):413-9.
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Triptans (5-HT1B/1D agonists)
Rapid onset, short half-life:
• Sumatriptan (Imitrex®)
• Zolmitriptan (Zomig®)
• Rizatriptan (Maxalt®)
• Eletriptan (Relpax®)
1993 (Europe 1991)
Nov 1997
Jun 1998
Dec 2002
Slow onset, short half-life:
• Almotriptan (Axert®)
May 2001
Slow onset, long half-life:
• Naratriptan (Amerge®)
• Frovatriptan (Frova®)
Feb 1998
Nov 2001
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A closer look at the triptans:
• The effectiveness of the triptans seems to be
more similar than different; however, each
patient might have one triptan that works
best for him/her1
• Despite the theoretical contraindication of
triptans in hemiplegic migraine, retrospective
studies seem to refute such a risk2
1 Rapoport AM.
2 Artto
J Headache Pain. 2006 Oct;7(5):355-9.
V et al. Eur J Neurol. 2007 Sep;14(9):1053-6.
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A closer look at the triptans:
Sumatriptan/naproxen sodium combination (Treximet®)
• Triptans work best when given early in the course of a migraine attack,
and once central sensitization sets in, they tend to fail to abort the
attack1
• Indomethacin alone or in combination with prochlorperazine and
caffeine2 as well as other COX1/COX2 inhibitors3 are able to inhibit
inflammation associated with central sensitization, and hence are still
able to abort a migraine attack once allodynia sets in
• Therefore, a combination of a triptan and a COX1/COX2 inhibitor should
be considered; studies have shown the tolerability as well as the
superior effectiveness of such combination over either medication alone4
1 Burstein
R and Jakubowski M. Ann Neurol. 2004 Jan;55(1):27-36.
C et al. J Pain. 2004 Oct;5(8):413-9.
3 Jakubowski M et al. Headache. 2005 Jul-Aug;45(7):850-61.
4 Smith TR et al. Headache. 2005 Sep;45(8):983-91.
2 Ghelardini
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Corticosteroids
• Oral dexamethasone (4 mg) can also be
used on an outpatient basis as an
adjunct medication. It still decreases the
rate of recurrence further, even in
patients who are already treated with a
triptan and a NSAID.
Krymchantowski AV, Barbosa JS. Arq Neuropsiquiatr. 2001 Sep;59(3-B):708-11.
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Abortive Therapy:
Parenteral
4th Annual Advanced Pharmacology Conference
Oklahoma Association of Clinical Nurse Specialists
4/15/2011
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1- IV hydration
• Normal saline IV bolus 20 mL/Kg
• Then continue at 1.5 times maintenance
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2- Any of the following medication regimens
a) IV valproic acid (Depacon®)
b) IV antiemetic
(usually combined with IV ketorolac & IV caffeine)
c) IV magnesium sulfate
d) IV corticosteroids
(methylprednisolone, dexamethasone)
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a) Intravenous Valproic Acid (Depacon®)
• 15-20 mg/Kg (up to 1000mg) at 50 mg/min
• May administer an additional ½ dose in 30 minutes
if headache persists
Reiter PD et al. Headache. 2005 Jul-Aug;45(7):899-903.
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b) Antiemetics
Main Side Effects: sedation, akathisia, dystonic reactions
1. IV promethazine (Phenergan®) 12.5 – 50 mg IV over 15 minutes
May repeat in 4 hrs if headache persists up to 100mg/24 hrs
2. IV metoclopramide (Reglan®) 10 mg (0.15 mg/kg) IV1
3. IV procholrperazine (Compazine®) 10 mg (0.15 mg/kg)2
4. IV3 or IM4 droperidol (Inapsine®) 2.5 mg (0.01-0.015 mg/kg max 1.25 mg)
Repeat in 30 minutes if headache persists (max 3 doses); the patient
should then be given benztropine mesylate (Cogentin®) 1 mg (0.02-0.05
mg/kg/dose) PO BID x 3 days to avoid developing akathisia5
1 Tek DS, et al. Ann Emerg Med 1990; 19:1083-1087.
2 Brousseau DC, et al. Ann Emerg Med. 2004 Feb;43(2):256-62.
3 Gan TJ, et al. , Anesth Analg, 2007, 105(6):1615-28.
4 Richman PB, et al. American Journal of Emergency Medicine. 20(1):39-42, 2002.
5 Wang SJ, et al. Headache 1997; 37:377-382.
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b) Antiemetics efficacy
• Calcium carbasalate + metoclopramide was superior
to oral dihydroergotamine in improving pain and
other migraine symptoms in a randomized, doubleblind, cross-over study (n=155)4
• 10 mg prochlorperazine IV was superior to 500 mg
valproic acid IV2 and to 10mg metoclopramide IV3 in
randomized, prospective, double-blind trials (n=40 &
70, respectively)
1 Edwards KR. Headache. 2001 Nov-Dec;41(10):976-80.
2 Tanen DA et al. Ann Emerg Med. 2003 Jun;41(6):847-53.
3 Coppola M et al. Ann Emerg Med. 1995 Nov;26(5):541-6.
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c) Intravenous Magnesium Sulfate
• 1 gram (30 mg/kg) infused IV over 15 minutes
Repeat 30 minutes later if headache persists
• Results remained conflicting until a double-blind,
randomized placebo-controlled trial evaluated it in
migraine with aura, separately from migraine
without aura
• Statistical benefit found only in migraine with aura
Bigal ME et al. Cephalalgia. 2002 Jun;22(5):345-53.
Mauskop A, et al. Headache 1996;36:154-160
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d) Intravenous Corticosteroids
• Dexamethasone (Decadron®) 8 mg (0.1 mg/kg) IM
or IV times one1
• Dexamethasone (Decadron®) 24 mg IV2
Decreased recurrence rate of severe attacks after
successful treatment in the ER: 18% vs. 45%
(OR 0.28; 95% CI, 0.11 to 0.69; p=0.005)
This supports that there is an inflammatory
component to migraine that needs to be treated too
• Methylprednisolone 1 g (30 mg/kg) IV times one
1 Gallagher RM. Headache 1986;26:73-74.
2 Innes GD et al. CJEM. 1999 Apr;1(1):26-33.
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3- Dihydroergotamine
• Raskin protocol1
• Continuous infusion of DHE with metoclopramide is similar
in effectiveness, speed of action, and side effects profile to
repetitive dosing DHE and metoclopramide (retrospective
analysis; n = 171).2
• IM DHE and metoclopramide showed a trend to be superior
to IV valproic acid (without statistical significance) in an
open-label study (n=40).3
1 Raskin NH. Headache 1990 ;sup 2:550-3
2 Charles JA, Jotkowitz S. J Headache Pain. 2005 Feb;6(1):51-4.
3 Linder SL. Headache. 1994 Nov-Dec;34(10):578-80.
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4- Antipsychotics:
haloperidol (Haldol®)
• Pretreat with 1 mg PO or IV or IM benztropine mesylate
(Cogentin®)
• 5mg haloperidol (Haldol®) IV was effective in a small (n=40)
randomized, double-blinded, placebo-controlled study in relieving
migraine-associated pain, even when other medications have
failed. Relapses were also rare, but the main limitation to the use
of haloperidol in some patients was its side effects.1 Haloperidol
also showed superiority to dexamethasone in another small openlabel study (n=29).2
• Less sedation than chlorpromazine (Thorazine®) or
prochlorpromazine (Compazine®) and does not produce
orthostatic hypotension3
1 Honkaniemi
J et al. Headache. 2006 May;46(5):781-7.
PH et al. Arq Neuropsiquiatr. 2004 Jun;62(2B):513-8.
3 Fisher H. J Emerg Med 1995; 13:119-122
2 Monzillo
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4- Antipsychotics:
chlorpromazine (Thorazine®)
•
Consider pretreatment with 1 mg PO or IV or IM benztropine mesylate
(Cogentin®)  may worsen anticholinergic symptoms
i.
Chlorpromazine 12.5 mg IV
May repeat in 20 minute intervals up to 3 times (max dose of 37.5 mg)1
ii. Chlorpromazine 0.1 mg/kg IV at a rate of 1 mg/min
May repeat twice at 15-30 minute intervals (max dose not to exceed 37.5
mg)2
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Side effects: hypotension, dizziness, sedation, burning at IV site, dry mouth,
nasal congestion, extrapyramidal reactions
Significant sedation or orthostatic hypotension may warrant several hours –
overnight observation
iii. Chlorpromazine 1 mg/kg IM3
•
Slower onset of action than IV, same side effects
1 Bell R, et al. Ann Emerg Med 1990; 19:1079-1082
2 Lane PL, et al. Am Emerg Med 1989; 18:360-365
3 McEwen, et al. Ann Emerg Med 1987; 16:758-763.
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What about Opioids
• They have not been demonstrated to be
superior to other abortive treatment in the
ER setting.1
• However, they may have a role in a select
subgroup of patients w/ chronic daily
headache for either prophylaxis or
augmentation therapy during an acute
attack.2
1 Wasay M et al. J Headache Pain. 2006 Dec;7(6):413-5.
2 Ziegler DK. Neurol Clin. 1997 Feb;15(1):199-207.
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Prophylactic Therapy
4th Annual Advanced Pharmacology Conference
Oklahoma Association of Clinical Nurse Specialists
4/15/2011
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FDA approved medications
• Methysergide (discontinued)
• Propranonol
• Timolol
• Valproate
• Topiramate
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Migraine Prophylactic Therapy:
The evidence
Recent reviews of pediatric migraine prophylaxis seem to all point to:
• Drugs w/ most supportive studies w/ respect to efficacy:
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Drugs w/ likely efficacy and promising initial data:
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Pizotifen
Nimodipine
Drugs lacking significant data:
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Propranolol
Trazodone
Drugs w/ conflicting data but likely ineffective:
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Topiramate
Valproic acid
Amitriptyline
Cyproheptadine
Drugs w/ conflicting data but likely effective:
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Flunarizine
ACE-inhibitors & ARB
Gabapentin
Lamotrigine
Levetiracetam
Venlafaxine
Zonisamide
Drugs probably ineffective:
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Clonidine
Eiland LS et al. Ann Pharmacother. 2007 Jul;41(7):1181-90.
Balottin U, Termine C. Expert Opin Pharmacother. 2007 Apr;8(6):731-44.
Hämäläinen ML. CNS Drugs. 2006;20(10):813-20.
Lewis DW, Winner P. NeuroRx. 2006 Apr;3(2):181-91.
Hershey AD, Winner PK. J Am Osteopath Assoc. 2005 Apr;105(4 Suppl 2):2S-8S.
Lewis DW et al. Headache. 2004 Mar;44(3):230-7.
Cuvellier JC et al. Arch Pediatr. 2004 May;11(5):449-55.
Lewis DW. Curr Opin Pediatr. 2004 Dec;16(6):628-36.
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How do prophylactic medications work?
Let’s look at select prophylactic classes
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Calcium-channel blockers:
↓ Hyperexcitability
Regulate deficient calcium channels
(DMSG, 1998)
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Betablockers:
↓ NE
↓ DA
↓ Hyperexcitability
Decrease Central Catecholamines
(DMSG, 1998)
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Tricyclic Antidepressants:
↓ Pain Transmission
↑ 5HT
Centrally Modulate Pain
(DMSG, 1998)
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Betablockers
Reduction of
NE and DA
(Schoenen et al, 1986)
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Other Prophylactic Interventions:
1. Botulinum neurotoxin A: In a
randomized double-blind, placebocontrolled study, it was found to be
effective in a subgroup of chronic
migraineurs who are not on
prophylactic medicine (64% of total
sample size).1
2. Sleep apnea treatment
1 Dodick DW et al. Headache. 2005 Apr;45(4):315-24.
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Neutriceuticals
• Magnesium gluconate tablets
Start 200 mg BID and increase to 400 mg BID in 1 week
• Riboflavin tablets
Start 200 mg BID (which is the target dose)
• Butterbur (Petasites 75mg)
Start 50 mg TID (which is the target dose)
• Coenzyme Q10
Start 100 mg TID (which is the target dose)
• Melatonin
Start 3 mg QHS and increase by 3 mg weekly up to 15 mg QHS
Evans RW, et al. Headache. 2006 Jan;46(1):160-4.
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Thank you
4th Annual Advanced Pharmacology Conference
Oklahoma Association of Clinical Nurse Specialists
4/15/2011
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