Refractory HeadacheChallenges and Strategies

David W. Dodick, M.D.

Department of Neurology

Mayo Clinic

Phoenix Arizona USA

Headache Masters School, Tokyo 2013

• Definition of refractory/intractability depends on:

• Who you are: primary care physician, neurologist,

headache specialist

• Where you are: availability of people (other

disciplines), resources (health system), therapeutic

options

• What your/patient expectations are: cure, improved

function, quality of life

Headache 2010;50:1499-1506

SATISFACTION =EXPECTATIONS

REALITY

--------

1. We missed something

a. Wrong diagnosis

b. Exacerbating factor

c. Inadequate treatment

2. Patients is refractory

WHY HEADACHE MAY BE REFRACTORY

SECONDARY DIAGNOSIS IS MISSED

Lifetime

migraine

prevalence

43%♀ and

18%♂

Reason 1: Many patients with Secondary Headache Will Have History of Primary Headache Disorder

Lifetime TTH

78% (♀>♂)

Frequency and duration 5 attacks lasting 4-72 hours

Pain criteria: 2 of the following 4

Unilateral

Pulsating

Moderate or severe intensity

Aggravation by routine physical activity

Associated symptoms: 1 of the following

Nausea and/or vomiting

Photophobia and phonophobia

Not attributable to another disorder

Often

forgotten

Lack

specificity

Reason 2: Many Patients with Secondary Headache will have Migraine or Tension-type Phenotype

77% of patients with headache

secondary to brain tumor

meet ICHD criteria for tension-

type headache (Forsythe and

Posner Neurology 1992)

New-onset chronic tension-type

headache is a diagnosis of

exclusion

Systemic symptoms (fever, weight loss) or

Secondary risk factors (HIV, cancer)

Neurologic symptoms (or signs)

Onset: abrupt, peak <1 min

Older: >50 (GCA; glaucoma, cardiac cephalgia )

Previous headache history (new or change in pattern/progression)

Postural (worse in upright/supine position)

Precipitated by Valsalva (exertion)

Pulsatile tinnitus (diplopia, transient visual obscurations)

Reason 3: Warning symptoms not elicitedSNOOP4 Red Flags

Dodick DW. Seminars in Neurology 2010;30(1):74-81

Reason 4: Relying on CT to rule out secondary causes of headache

Reason 4: Wrong Imaging Test! Secondary causes of headache missed on CT Head

o Pressure

• CSF Leak (SIH)

• Intracranial hypertension

o Infections

• Meningoencephalitis

• Cerebritis and brain abscess

o Neoplastic disease

• Parenchymal and extra

axial neoplasms (especially

posterior fossa)

• Meningeal carcinomatosis

• Metastatic brain tumors

• Pituitary lesions

PIN the secondary diagnosisSIH=spontaneous intracranial hypotension

Reason 5: Wrong Imaging TestVascular imaging not performed

WHY HEADACHE MAY BE REFRACTORY

PRIMARY DIAGNOSIS IS MISSED

Only 45%

see an HCP

Only 39%

diagnosed by

an HCP

Of 775

patients

meeting EM

criteria

Only 26%

receive

treatment

Only 41%

see an HCP

Only 11%

diagnosed by

an HCP

Of 1254

patients

meeting CM

criteria

Only 4.5%

receive

treatment

Diagnosis of Migraine (EM/CM) in US Practices

Only 10% of HCP consult a neurologist and

4% consult a specialist

Lipton RB, et al. Headache 2013;51:81-92. Dodick DW, Headache 2016;56:821-834

Diagnosis of primary headache disorder

• Know the criteria for migraine, tension-type, and cluster headache

• Use a systematic approach to history taking

• Location (if unilateral, is it side-locked)

• Cranial autonomic features

• Diurnal variation (nocturnal, awakening)

• Frequency and duration of individual episodes

• Monthly Frequency of headache days

• Remitting or unremitting pain

Why is Migraine Frequently Mistaken For Tension-Type Headache (TTH)?

• Guilt by location: Neck pain (75%) and

bilateral headache (40%)

• Guilt by association: Stress (as trigger)

comorbid anxiety/depression

• TTH overrides probable migraine

(ICHD needs refinement; TTH should

have no associated symptoms)

Why is Migraine Frequently Mistaken for Sinus Headache?

• Pain often located over sinuses

• Migraine often triggered by

weather changes

• Tearing/nasal congestion

common (up to 50%)

• Resolution attributed to sinus

medication

1. We missed something

a. Wrong diagnosis

b. Exacerbating factor

c. Inadequate treatment

2. Patients is refractory

Exacerbating factors

• Medications (e.g. dipyridamole, SSRI)

• Acute medication overuse

• Estrogen (COC, HRT, menopause)

• Dietary or lifestyle factors

• Occupational or environmental

• Comorbid illness/condition (psychiatric, obesity, obstructive sleep apnea)

1. We missed something

a. Wrong diagnosis

b. Exacerbating factor

c. Inadequate treatment

2. Patients is refractory

WHY HEADACHE MAY BE REFRACTORY

PHARMACOTHERAPY IS INADEQUATE

©2013 MFMER | slide-22

Acute Treatment ‘Fails’

Recurrence, partial or inconsistent response• Early Rx (while pain is mild)• Increase dose• Combination Rx (triptan+NSAID)

• Switch drug or route of administration

Overuse• Establish use limits• Consider prevention

Becker WB. Continuum 2015;21:953-972

WHY HEADACHE MAY BE REFRACTORY

COMPLIANCE

©2013 MFMER | slide-24

19%

21%

31%29%

33%

23%

36%

24%

29%

24%

32%

28%

16%

20%

26%

10% 10%

17%

14%

17%

10%

19%

13%

18%

12%

21%

16%

8%

11%

14%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Amitr

ipty

line

N=1,

164

Nor

trip

tylin

e N=

653

Cita

lopr

am N

=1,1

50

Sert

ralin

e N=

622

Fluo

xetin

e N=

421

Paro

xetin

e N=

190

Venl

afax

ine

N=27

7

Prop

rano

lol N

=699

Met

opro

lol N

=395

Nad

olol

N=1

10

Aten

olol

N=1

95

Topi

ram

ate

N=2,

604

Gaba

pent

in N

=860

Diva

lpro

ex N

=292

Tota

l N=9

,632

Antidepressants Beta Blockers Anticonvulsants AllClasses

Prop

ortio

n of

Pat

ient

s Per

siste

nt Persistent At 6 Months Persistent at 12 Months

Hepp Z, et al. Cephalalgia 2015;35:478-488

86% discontinue at

12 months

Improving compliance

• Start very low, go very slow (e.g. topiramate 15mg q2 wks)

• Combination therapy

• One drug for two diseases not always optimal (e.g. tricyclic in patient with migraine and depression)

• Minimize dose/side effects; maximize efficacy with different MOA

• Beware the claim of ‘tachyphylaxis’

• Always have side effect discussion

• Always set expectations for efficacy

Dodick DW, Silberstein SD. Practical Neurology 2007;46:1-13

Preventive medication side effects

• Expect them

• Many attenuate/resolve over time

• Some may be attenuated (selenium for divalproex induced

hair loss (200-400ug) potassium for topiramate induced

paresthesias (20-40mEq/day)

-14

-12

-10

-8

-6

-4

-2

00 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Head

ach

e D

ays/2

8 D

ays

p<0.001p<0.001

p<0.001

p<0.001

p<0.001

Week 24

Primary Endpoint

p<0.001

p<0.001p=0.008

p=0.01p=0.007

p=0.019

p=0.047

p=0.011

p=0.019

Head

ach

e D

ays/2

8 D

ays

(Mean

Ch

an

ge F

rom

Base

lin

e)

Week:

Efficacy is cumulative and takes time

Onset of effect Maximal effect

◄ January ~ February 2012 ~ March ►

Sun Mon Tue Wed Thu Fri Sat

1 2 3 4

5 6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 23 24 25

26 27 28 29 Severe

Moderate

Mild

Effective prevention may be reduction in severity and not frequency

◄ January ~ February 2012 ~ March ►

Sun Mon Tue Wed Thu Fri Sat

1 2 3 4

5 6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 23 24 25

26 27 28 29 Severe

Moderate

Mild

Effective prevention may be reduction in severity and not frequency

WHY HEADACHE MAY BE REFRACTORY

PHARMACOLOGIC RANGE OF OPTIONS NOT EXPLORED

©2013 MFMER | slide-31

Migraine Preventive Medications

(Guidelines and Beyond)

Silberstein et al., Neurology 2012Holland et al., Neurology 2012Silberstein SD. Continuum 2015;21:973-989

Others:• Memantine

• Lisinopril

• Candesartan

• Amiloride

• Duloxetine

• Zonisamide

• Simvastatin + vitamin D

• Verapamil

• Flunarizine

Onabotulinumtoxin A*

* For chronic migraine

Blumenfeld A. et al. Headache 2010;50:1406-1418)

155 Units-31 injection sites

Injection Therapy

Blumenfeld A, et al. Headache 2013;53:437-446)

Injection Therapy: Trigger Point Injections

Robbins M., et al. Headache 2014;54:1441-1459

NON-INVASIVE NEUROMODULATION THERAPIES

Supraorbital nerve stimulation

Single pulse TMSVagal nerve stimulation

Refractory Headache: Infusion Center and Inpatient Treatment Protocols

• Repetitive IV infusions for 3-5 days

• Dihydroergotamine 0.5 - 1.0mg plus

antiemetic

• Divalproex sodium 6.4 mg / kg

• Methylprednisolone 250-500mg or

Dexamethasone 4-8mg Q12h

• Magnesium sulfate 1gram q 24h

• Ketorolac 30mg Q12-24h

• Diphenhydramine 50mg

• Lorazepam 0.5mg

WHY HEADACHE MAY BE REFRACTORY

NON-PHARMACOLOGIC RANGE OF OPTIONS NOT EXPLORED

©2013 MFMER | slide-38

Complementary and Alternative Medicine

200mg bid

Level B300 mg

Level B

3-25mg

300mg daily

Level C

0.2-0.6mg

Level B

Silberstein et al., Neurology 2012Holland et al., Neurology 2012

Multidisciplinary integrated headache care

PsychiatryPsychology

CBT/BiofeedbackNeurology

Sleep physiologyPMRAcupuncture

Women’s Health Specialist

Integrative medicine specialist(meditation, yoga,

message)

Headache nurse specialist

Exercise physiologyDietician

WHY HEADACHE MAY BE REFRACTORY

HEADACHE/PATIENT IS TRULYREFRACTORY

©2013 MFMER | slide-41

• Primary Goal: Restore function when pain cannot be eliminated

• Requires willingness to withdraw from opioids or other analgesics

• Develop treatment goals that include an active lifestyle

• Behavioral strategies of goal setting, paced activity, improved

physical conditioning, decreased pain avoidance, stress

management

Bruce B., et al. Curr Pain Head Reports 2009;13:67-72

Typical patient

• Significant functional decline, extremely debilitated, unable to be

employed or function in home setting

• Medication overuse, demoralization, depression, anxiety

• High medical utilizers: failed medication trials, surgery, injections,

implantable technology, extensive and varied physical therapy programs,

psychiatric and psychological care

Bruce B., et al. Curr Pain Head Reports 2009;13:67-72

Chronic Pain Rehabilitation3-week outpatient day or

inpatient treatment program

PsychiatryPsychology

Occupational therapists

Social Work

Vocational rehabilitationalPhysical therapists

PharmacistsChaplainsNursing

Chemical dependency counselors

Dietician

Bruce B., et al. Curr Pain Head Reports 2009;13:67-72

3-week intensive hospital-based

outpatient treatment program

N=195Mean duration = 10.8 years44% MOH52% major depression

Pain severity (p<0.001)

Depression (p<0.001)

Physical functioning (p<0.001)

General activity level (p<0.001)

House, work, social activities (p<0.001)

Interference of pain in life (p<0.001)

Pain catastrophizing (p<0.001)

Bruce B., et al. Curr Pain Head Reports 2009;13:67-72

1. We missed something

a. Wrong diagnosis

b. Exacerbating factor

c. Inadequate treatment

2. Patients is truly refractory

In my practice

>80%

Assuming appropriate expectations

<20%

ありがとうございました