HOW TO SELECT MIGRAINE HOW TO SELECT MIGRAINE  PREVENTIVES Financial Disclosure

1/31/2014
Judy Lane, MD
The Head Pain Center
HOW TO SELECT MIGRAINE HOW
TO SELECT MIGRAINE
PREVENTIVES
Financial Disclosure
 Consulting Fees/Honoraria from Allergan and Impax
 Speakers Bureau for Nautilus
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1/31/2014
Learning Objectives
 Describe three possible therapeutic mechanisms of oral preventive agents
 Cite rational medication combinations for migraine prevention
 Summarize current thoughts about lessening tachyphylaxis from preventive medications
Introduction
 First ( and only) preventive introduced specifically for migraine: Methysergide, 1962
 Underutilized (20% use but 38% are appropriate), doesn’t include nutraceuticals
and off‐label use
 Mostly off‐label use
Mostly off label use
 ? Reduce transformation
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When to Use a Preventive
 3+ Headache episodes per month
 Dysfunction interfering with quality of life
 Acute medications inadequate
 Patient preference
 Should every patient receive natural preventives?
Principles of Preventive Medications
 Start low, go slow
 Adequate trial: 2‐3 months
 Consider co‐morbidity
 Avoid MOH
 Monitor for drugs that may interfere
 Rational polypharmacy: for co‐morbidity, up to 6 months before maximal improvement
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Possible Therapeutic Mechanisms
 Stabilize excitable CNS
 Enhance antinociceptive pathways
 Inhibit peripheral and central activation
 Inhibit cortical spreading depression
Dr…, What is your Favorite Preventive? 4
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Preventives FDA Approved  Methysergide
 Propranolol
 Timolol
 Divalproex sodium, DR and ER
 Topiramate
 Botulinum A (chronic migraine)
Efficacy based on Clinical Trials
Level A
Level B
 Metoprolol
 Amitriptyline
 Propranolol
 Venlafaxine
 Topiramate
 Atenolol
 Sodium valproate
 Nadolol
 Divalproex sodium
 Magnesium
 Petasites
 Riboflavin
 Feverfew
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Efficacy based on Clinical Trials
Level C
Other
 Coenzyme‐ Q 10
 Lisinopril
 Nortriptyline
 Candesartan
 Gabapentin
 Memantine
 Estrogen
 Verapamil
 Nicardipine
 Nimodipine
 Cyproheptadine
Useful Information
 Family history: response to medications
 What has worked in the past?
 Were prior trials done in state of MOH?
 Time of day most vulnerable
 Are migraines nocturnal?
 What does the patient want to try? Alternatives vs prescriptions.
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Clinical Pearls
 Optimize dosing : time of day, dividing
 Follow with headache calendar
Monotherapy based on Co‐
morbidity
 Anxiety/Depression/Bipolar
 Sleep disorders
 Fibromyalgia
 Epilepsy
 Stroke/Cardiovascular
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Monotherapy
 Simplified
 Cheaper
 Minimal side effects
 Less drug interaction
Consider Rational Combinations
 Refractory migraine
 Strong family history
 Early age of onset/ disease modifying?
 Disability
 Tachyphylaxis
 Goal of “ Alternatives only”
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Two Studies of Combination Therapy
 #1. 52 RM compared beta blocker alone x 2 months, then VPA alone x 2 months, then combination
 Combo: > ½ with 50% fewer headache days
 #2. 58 patients failed both beta blocker and topiramate alone.
alone
 Combo: 60% > 50% less frequent with combo, 17% didn’t tolerate
Rational combinations
 Topiramate
 Topiramate
 SSRI ( first‐line therapy for depression in 2007)
 CCB
 Memantine
 Magnesium
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“This triptan is magic!”
Think about an SSRI
Think about a daily long‐
acting triptan
Migraine with Aura
 Topiramate
 Calcium channel blockers
 Magnesium (glutamate blocker)
 Lamontrigine
 ? Memantine (glutamate implicated in CSD)
 Avoid BBs: case reports of prolonged aura and possible ischemic stroke
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Hemiplegic Migraine
 CCBs ( associated with calcium channel 



mutations)
Magnesium
Riboflavin
Aspirin @ low dose
Coenzyme Q
Headache Worsened by Triptan
Use
 Vasospasm?
 Think about a CCB
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Topiramate Use: The Big Gun
 Start low, go slow
 When to divide the dose
 Tingling reversed with potassium rich foods
 BC issue
 SSRIs good in combination
 Interferes with folate/serotonin synthesis
 Memantine good in combination
Topiramate: Cognitive  Cognitive side effects: verbal fluency, 



psychomotor speed, working memory, h
d
k
processing speed More sx at doses > 96mg (15% and 24%)
Higher frequency with psychiatric history Perhaps due to simultaneous effects on multiple channels; GABAergic‐> attention and vigilance, Antiglutamatergic‐> memory and learning
Weeks to normalize (Martin; Ojemann)
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Botulinum Toxin A
 Time to effect first series: 4 weeks
 Commit to at least 2 series’
 10 % did not respond until third series
 12 week intervals
 Doesn’t always work during MOH
 Polypharmacy
DHE is the Only Effective Medication
 Methergine
 Methysergide
 TCA
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Methergine/Methysergide
 Informed consent
 Fibrosis: retroperitoneal, pleuropulmonary, 




cardiac valve thickening
Dosing
Use of DHE abortively
Use of holiday
fh ld
Imaging
Blood studies
New Information/Duloxetine


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

Wm. Young: Prospective study
22 completers
Nondepressed individuals
Episodic migraine
Mean dose 110 mg
52% had 50% or greater decrease in headache days
 Recommended higher dose: ie, 120 mg rather than 60mg
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Memantine Preventively
 Bigal, Rapoport et al
 Refractory migraine or transformed migraine
 Antagonist at NMDA receptors, blocks excessive activity but not normal function
 28 patients, 3 months, not placebo controlled
 Endpoints: days with headache reduced(22‐>16), d ith days with severe pain reduced (7.8 ‐>3.2), less i d d ( 8 ) l disability at 3 months ( 36.6 vs 54.9)
 37% side effects (most mild), 5.5% terminated
 Add‐on utility, especially for topiramate
Use of Oral Contraceptives
 Particular importance in MRM who require 




contraception
Comorbid endometriosis , dysmenorrheaas, polycystic ovarian syndrome
Continuous vs cycling off monthly
Review other risk factors
1/3, 1/3, 1/3
Monitor for new aura or worsening
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Pregnancy
 Early = all or none, SAB, embryo toxicity
 Teratogenesis 31 days‐> 10 weeks after last menses
 Later use: growth retardation, effects on maternal uterine contraction, drug withdrawal
 Most Category B or C
g y
 Magnesium: category B, riboflavin: category A
 CCBs and Propranolol : category C
 Amitriptyline: category C or D
Pediatrics/Adolescence
 Petodolex
 Botulinum toxin
 Topiramate
 SSRIs
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Tachyphylaxis: Mechanisms
 Pharmacokinetics/Pharmacodynamics/Cross 




Tolerance/Behavioral tolerance
Placebo effects
Natural change in disease
Disease progression: genetic, TBI,obesity, MOH, sleep disorder, work stress
p
,
Inadequate recall
Drug delivery/ Poor adherence
Ways to Deal with Tachyphylaxis
 1‐8% per literature
 Increase medication dose
 Drug holiday
 Rational combinations/Treat multiple migraine mechanisms
 Retry, especially if prior MOH
ll f
 Behavioral/environmental treatments
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Common Meds that Exacerbate Migraine
 Zolpidem( 7‐19%)
 Eszopiclone( 13‐21%)
 Hycosamine (< 1%)
 Nifedipine (10‐23%)
 Omeprozole ( 7%)
 Ranitidine (3%)
 Buproprion ( 25‐30)
 Milnacipran(18%)
Length of Preventive Treatment
 Wober: 64 patients discontinued meds used up to 6 months: 75% relapsed
 Repeating same preventive less successful
 Pascual: 80 patients discontinued topiramate: after 6 months, 50% worse
topiramate
after 6 months 50% worse
 Recommended at least 1 year on preventive meds
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Summary
Be creative
Be
creative
Treat co‐morbidity
Decrease dose over time
Don’t discontinue too quickly one med at a time
quickly, one med at a time, one month interval
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