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!

� rburch@partners.org