preventive treatment of migraine · frequent headaches failure, contraindication to, or troublesome...
TRANSCRIPT
Preventive treatment of
migrainemigraine
Rebecca Burch, MD
Brigham and Women’s Faulkner Hospital
Harvard Medical School
Boston, MA
Disclosures
� No disclosures
� Many preventive treatments for migraine are not FDA-approvedare not FDA-approved
Objectives
� Recognize when preventive treatment for migraine should be offered
Identify top tier migraine preventive � Identify top tier migraine preventive medications
� List treatment principles that increase the success of preventive migraine treatment
A Case
� A 36 year old woman has had migraines
since her teens, slowly increasing in frequency
� Now 14 days/month, each lasting 1-2 days
� Headaches respond to naratriptan, naproxen, and metoclopramide� Treating 12 days/month
� Missed work twice in the last month
� No other medical issues, no other medications
When should prevention be
considered?
� Frequent headaches
Ramadan NM, et al. Evidenced-based guidelines for migraine headache in the primary care setting:
pharmacological management for prevention of migraine. http//www.neurology.org.
Silberstein SD & Goadsby PJ. Cephalalgia 2002;22:491–512.
ARS # 1
� At what frequency of headache would you recommend starting prevention?
� A. 2 headaches per month
� B. 4 headaches per month� B. 4 headaches per month
� C. 15 headache days per month
� D. Daily headache
� E. Completely depends on patient preference
Attack Frequency at Baseline
Predicts CDH at Follow-Up
IntermediateIntermediate
(105 to 179)(105 to 179)
0.20.2
0.30.3
PredictedPredicted
11--yearyear
*Top line predicted incidence of intermediate frequent headaches (105 to 179 days/year) *Top line predicted incidence of intermediate frequent headaches (105 to 179 days/year)
Bottom line shows predicted incidence of CDH (180+ days/year). Bottom line shows predicted incidence of CDH (180+ days/year).
CDH (180+)CDH (180+)
22 2424 5252 104104
00
0.10.1
Baseline Headache FrequencyBaseline Headache Frequency
11--yearyear
IncidenceIncidence
Scher AI et al. Pain. 2003;106:81-89..
When should prevention be
considered?
� Frequent headaches
� Failure, contraindication to, or troublesome side-effects from acute medications
Overuse of acute medications � Overuse of acute medications
� Special situations
� e.g. headaches with profound disability or
consequences
Ramadan NM, et al. Evidence-based guidelines for migraine headache in the primary care setting:
pharmacological management for prevention of migraine. http//www.neurology.org.
Silberstein SD & Goadsby PJ. Cephalalgia 2002;22:491–512.
Preventive treatment goals
� Decrease attack frequency, intensity, duration
� Improve responsiveness to acute treatment
� Improve function
� Reduce need for acute treatment
� Not “no headaches”
Treatment principles
� “Start low, go slow”
� Choose treatments based on comorbidity and side effectsand side effects
� Quantify treatment effects
� Patient buy-in is essential
Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.
Adherence is poor
Figure 2. Rate of adherence to Oral Migraine Preventive Medications, by class, among US insured patients with chronic migraine.
Hepp Z et al. Cephalalgia 2014;0333102414547138
Patient preference
72
60
80
100
Percentage
12
63 3 2 2
0
20
40
Efficacy Speed of onset
Absence of side effects
Out of pocket
expense
Formulation of therapy
Type of treatment
Dosing frequency
Percentage (n=250)
Most important aspect of migraine preventive treatment to
patients in 2 headache clinicsPeres MF, Headache 2007
Classes of Migraine Preventives
� Antiepileptic drugs
� Antidepressants
� Beta-adrenergic blockers
� Calcium channel antagonists� Calcium channel antagonists
� Serotonin (5-HT) antagonists
� Neurotoxins (eg, onabotulinumtoxinA)
� ACEI/ARBs
� Vitamins, herbs, minerals
Suppression of cortical spreading depression in migraine prophylaxis
Annals of Neurology
Volume 59, Issue 4, pages 652-661, 31 JAN 2006 DOI: 10.1002/ana.20778
http://onlinelibrary.wiley.com/doi/10.1002/ana.20778/full#fig1
CSDs after KCl administration
Back to our case: What treatment
should we start? (ARS 2)
� A. A beta blocker (propranolol/metoprolol)
� B. An AED (Topiramate/valproate)
� C. A tricyclic antidepressant (amitriptyline)
� D. Magnesium
� E. Something else
2012 AAN/AHS Guidelines
Level A Drugs: “should be offered”
� ≥ 2 RCTs showing efficacy. 6 treatments:
� Beta-blockers: � Metoprolol, propranolol and timolol
� AEDs: � Topiramate and divalproex/sodium valproate
� Butterbur� Some developing safety concerns
2012 AAN/AHS Guidelines
Level B Drugs: “should be considered”
� 1 RCT or ≥ 2 less rigorous studies. 10 treatments
� Includes amitriptyline, feverfew, several NSAIDs, riboflavin (Vit B2) and venlafaxine
2012 AAN/AHS Guidelines
Level C Drugs: “may be considered”
� A single less rigorous study. 11 treatments
� New: lisinopril and candesartan
� Includes Clonidine, carbamazepine, coenzyme Q10
2012 AAN/AHS Guidelines
Level U Drugs
� “Insufficient data to support or refute…”i.e. methodologic shortcomings or conflicting study results
� 14 drugs� 14 drugs
� Includes: gabapentin, verapamil, indomethacin, fluoxetine, proptriptylineand acetazolamide.
2012 AAN/AHS Guidelines
Ineffective: “should not be offered or
considered”
� “possibly or probably ineffective”
Includes: lamotrigine, montelukast, � Includes: lamotrigine, montelukast, oxcarbazepine and telmisartan.
Common Preventive MedicationsEvidence
Level
Medication
���� = FDA
Indication
Usual Daily
Dose
Comments
B Atenolol 50-100 mg
A Propranolol � 80-240 mg
A Metoprolol 50-150 mg
U Verapamil 180-480 mg Downgraded, favorable AE
profileprofile
A Divalproex
sodium�
250-1500 mg FDA pregnancy category X
U Gabapentin 300-1800 mg Downgraded, favorable AE
profile
A Topiramate� 25-150 mg FDA pregnancy category D
B Amitriptyline 10-150 mg Downgraded but strong clinical
impression of benefit
B Venlafaxine 37.5-150 mg Well tolerated, not sedating
C Cyproheptadine 2-8 mg Pediatric population, sedating
Rizzoli, P. Acute and Preventive Treatment of Migraine, Continuum Neurol 2012;18(4):764-82
AAN/AHS Canadian EFNS
Search dates Through 5/09 Through 6/11 Through 1/09
Inclusion
criteria
“…randomized adult
patients with
migraine to agent
under study or
comparator”
“prospective,
randomized,
controlled trials…”
“Papers published in
English or German..a
review book..the
German treatment
recommendations…”
Methods of Level of evidence A, Level of evidence Grade A, B, C
Comparison to other guidelines
Methods of
classification
Level of evidence A,
B , C, U
A: established
efficacy, should be
offered;
B: Probably
effective, should be
considered;
C: Possibly
effective, may be
considered.
U: uncertain,
insufficient
Level of evidence
rated high,
moderate, low, or
very low;
Then graded
strong or weak
based on balance
of benefits and
harms
Grade A, B, C
(drugs of first choice,
drugs of second
choice, drugs of third
choice) based on
evidence base and
expert opinion
Comparison to other guidelines
� Areas of agreement: Highest level in all 3 guidelines:
� Divalproex
� Metoprolol� Metoprolol
� Propranolol
� Topiramate
But wait…
� AHRQ has commissioned a systematic review of the evidence for preventive migraine treatment
� They reach completely different � They reach completely different conclusions
� They emphasize the overall benefits of ACEIs and ARBS…mostly driven by quality scores for individual studies and benign side effect profile
Shamliyan TA, Choi JY, Ramakrishnan R, Biggs Miller J, Wang SY, Taylor FR, Kane RL. Preventive pharmacologic
treatments for episodic migraine in adults. Journal of General Internal Medicine 2013
Back to our case (ARS #3)
� Our patient calls back a month later to say that there is no change in her headaches
� What would you do?
A. Remind her that preventive drugs can take � A. Remind her that preventive drugs can take
2-3 months to show benefit
� B. Increase the dose of propranolol
� C. Add a small dose of topiramate to the
propranolol
� D. Switch from propranolol to another drug
What is an adequate trial of
prevention?
� Duration 2 -3 months
� Dose At target dose
� Monitoring Tracked with diary or calendar
Topiramate PropranololAnnals of Neurology Volume 59, Issue 4,
pages 652-661, 31 JAN 2006
Do patients recall headaches
accurately?
� Patient recall of headache frequency vsdiary:
� Frequency recall accurate over a 4 week
period period
� Patients recalled a higher intensity of
headaches than diaries showed
� It seems unlikely that patient recall of headaches that occurred in the distant past is accurate
McKenzie JA, et a. Headache. 2009 May;49(5):669-72.
Optimize Preventive Therapy With
Objective Evidence
� Frequency
� Severity
� Medication use
If you want to get more detailed:� If you want to get more detailed:
� Disability measurements (e.g. MIDAS)
� Quality of life
� Missed work time/ED visits
Our patient…
� Trials of amitriptyline, topiramate, propranolol, and feverfew all ineffective
Headache frequency increased to 18-20 � Headache frequency increased to 18-20 days/month
� What now?
Chronic Migraine
� Headache > 15 days/month
� Lasts > 4 hours/day
� 8 headaches are migrainous
� Only 1 FDA approved treatment
� Onabotulinum toxin A
� Topiramate has some evidence but is not FDA
approved
Onabotulinum toxin A
Dose and Sites
� The recommended dose for treating chronic migraine is 155 Units IM as 0.1 mL(5 Units) per site
� The recommended retreatment schedule � The recommended retreatment schedule is every 12 weeks.
http://www.allergan.com
/assets/pdf/botox_pi.pdf
Preventive conundrums
� How long should we treat?
� How distinct are preventive and acute treatments, really?
How much improvement is attributable to � How much improvement is attributable to regression to the mean?
� How should future preventive treatments be tested?
Summary
� Prevention is an underused intervention
� Many options are available
� If at first you don’t succeed…
Thank you!