Chronic Daily Headaches & Medication Overuse Headache

Diagnosis and Management

Dr Brendan Davies

North Midlands Regional Headache Clinic

University Hospital of North Staffordshire

4th Biennial Hull-BASH Headache Meeting

Jan 20th 2011

Frequent Headaches (or Chronic Daily headache)

A headache syndrome (not a diagnosis) characterised by

Headache present on more than 15 days per month for at least 3 months

duration = >180 days per year,

~ 50% of the time!

4-5% of the general population

30-80% of clinic populations

Several possible causes

Chronic daily headache prevalenceUSA, Spain, Greece, Italy, China

Population studies - 4%-5%

Women > Men

(Adapted from Castillo et al., 1999 and Guitera et al., 1999)

Recognition of the Problem is the first step !!

Chronic Daily headache - Subtypes

Primary Headache disorders

Secondary Headache disorders

Paroxysmal Headache

Attack Duration < 4 hours +/or

Discrete episodes

Long lasting Headache

Daily or near daily headache

Duration > 4 hours per day

Chronic MigraineChronic

Tension-type headache

New Daily Persistent headache

Hemicrania Continua

Adapted from Silberstein et al., Neurology (1996) 47: 871-

With or withoutmedication overuse

The FrHE Study

Case control and cohort analyses identifiedIndependent risk factors for CDH

Not readily modifiable Potentially modifiableMigraine Attack frequencyFemale Gender ObesityLow education/socioeconomic status Medication overuseHead injury Stressful life events

Snoring (sleep apnea, sleep disturbance)

FrHE=Frequent Headache Epidemiology StudyScher AI et al. Pain. 2003;106:81-89.

The Scope of the Problem Primary CDH Epidemiology

Pascual, Colas and Castillo. Current Pain & Headache Reports 2001

Prevalence Population HA Clinic– New Daily Persistent Headache 0.1% 20%

– Chronic Migraine* 2% 20-60%

– Chronic Tension Type headache 2-3% 10-20%

– Hemicrania Continua ? ?

– With associated Medication Overuse 0.5-1% 30 < 80%

USA & European studies

* = previous term Transformed in some studies

Consultations for headache with emergency healthcare practitioners: chronic vs episodic migraine

Varon SF et al. Poster 14th International Headache Congress, 2009, USA.

Taiwan

0 5% 10% 15% 20%

Proportion of patients consulting an emergencyhealthcare professional in the last 3 months

25%

6.212.5

Austrialia10.4

10.9

Spain14.7

23.2

7.05.5

France2.3

1.8

UK3.4

14.0

Germany4.8

7.7

Canada3.5

5.5

US3.5

5.8

Pooled5.4

9.0 Episodic migraine

Chronic migraine

Italy

How does Chronic Daily Headache start ?

Time

Evolving CDH

Time

NDPH

Headache Free before daily headache

De novo (Acute?) headache onset

Hea

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seve

rity

New Daily Persistent Headache (NDPH) The IHS (2004) Definition

• A daily headache with onset over < 3 days• Unremitting from onset & persistent > 3 months• No Secondary cause

• 2 of: Bilateral headachePressure/ tight (Non-pulsating)Mild-moderateNot worsened by physical activity

<1 of: Photophobia, phonophobia & mild nausea

New Daily Persistent Headache“De novo headache” or “CDH with acute onset”

A more useful concept ?

– A “ a headache syndrome” needing investigation to exclude secondary causes that guide specific treatments

– A new headache problem having previously been “Headache free” implies a potentially new pathophysiological process ?

– Highlights the need to consider/exclude a possible 2° headache disorders (NDPH mimics) before diagnosis

New Daily Persistent Headache

Primary NDPH Secondary Causes of NDPH

Migrainous typeFeatureless (Tension type)

Low CSF Volume Headache* Raised Intracranial Pressure Headache

CVST*Chronic MeningitisGiant Cell Arteritis

Post-Traumatic & Post-MeningitisMetabolic e.g. Hypercapnia, CO

SAH (Sudden onset)*Arterial dissection*

* All may have abrupt onset

A daily unremitting headache syndrome• Initial onset over < 3 days

• Persistent for > 3/12

NDPH - Clinical Features• “Classically” - Patient remembers the day & date the

headache started & the circumstances

• Prompts investigation for secondary causes?

• Not usually Unilateral – Think of alternatives– TACs & Hemicrania Continua if ANS symptoms– Temporal Arteritis, Intracranial lesions in elderly etc– Cervicogenic headache?

• 1○ NDPH– “Feature-Full” Migrainous or “FeatureLess” TTH

• “Benign vs. Refractory forms”

Diagnostic Studies in NDPH if Suspected Low CSF volume/pressure

• Always ask about effect of posture & otological symptoms?

• CT Brain Normal !! “Beware” Bilateral Subdurals?

• CSF Pressure < 60mm H20 ? (but can be normal!)– Normal glucose but may - WCC, Protein, RBC

• Gd-DTPA is investigation

of choice– Diffuse linear Non-nodular

Pachymeningeal enhancement– Tonsillar descent & Brain sagging– Bilateral subdural

Recognition of MigraineThe IHS criteria 2004 > 90% specificity

5 Headache attacks lasting 4 < 72 hours

• with at least 2 of:– Unilateral– Pulsating– Moderate or severe– Worsened by +/or avoidance

of physical activity

• and at least 1 of– Nausea +/or vomiting Light sensitivity Noise sensitivity

IHCD II Classification 2004 Cephalagia Vol 24; Suppl 1

Chronic migraine development

• Infrequent episodic migraine “transforms” into frequent migraine

• With or without medication overuse• Analgesics overused by 65%

Time months/years

H/A

in

ten

sit

y

0

10

Migraine attack

Background daily headache

& migraine attack

Overusing painkillers?

Chronic MigraineThe IHS 2006 Revised Classification

previously Triptan/Ergot responsive?

Headache on > 15 days month

with features of Migraine type headache

On > 8 days / month*

for > 3 months without other cause

of headache

With or without Analgesic Medication Overuse Headache?

*ICHD-2 = Previously >15

• 1 year longitudinal follow-up study – 450 headache sufferers (Migraine +/- Tension type)

14% developed CDH from an initial intermittent pattern (mean 7 days/month) baseline

• 1/3 were not overusing medicationOdds Ratio

• Factors implicated: High initial headache frequency 20.1Medication Overuse 19.1Moderate initial HA frequency 6.2

Tips for recognising Chronic Migraine

• History of episodic headache in earlier life?

• Insidious onset of frequent or daily headache

• “Background headache with worsening”

• Worse Headache episodes– Migrainous– Often triggered by recognised by migraine triggers– May be triptan responsive

• Family history of migraine?

• & No “red flag” features

Chronic Migraine Comorbidities

Thanks to Dr David Kernick for graphic

• Mental Health Disorders Zwart et al., 2003; Buse et al., 2010

– Depression– Generalised Anxiety Disorder– Bipolar disorder

• Chronic Musculoskeletal painHagen et al., 2002; Buse et al., 2010

• Restless Legs Syndrome & Sleep DisodersRhode et al., 2007; Chen et al., 2010

Clinical trial data forpreventive pharmacotherapy in “chronic migraine”

Evidence for use in chronic migraine

Anticonvulsants:ValproateTopiramateGabapentin

Small double-blind, placebo-controlled trials in CM1,2

Double-blind, placebo-controlled trials in CM3,4

One double-blind, placebo-controlled trial in CDH5

Botox Double-blind, placebo-controlled trials in CM 10-12

Antidepressants: Amitriptyline Fluoxetine

Small open-label trial in TM6

Small double-blind treatment, placebo-controlled trial in CDH7

Alpha-2-adrenergic agonist:Tizandine

Small double-blind treatment, placebo-controlled trial in CDH8

Glutamate NMDA Antagonists:Memantine

Small open-label trial9

Beta-blockers No evidence that they are effective in CM

Serotonergic modulators No evidence that they are effective in CM

Calcium channel blockers No evidence that they are effective in CM

ACE inhibitors and ARBs No evidence that they are effective in CM

1. Yurekli VA et al. J Headache Pain 2008;9:37–41.2. Bartolini M et al. Clin Neuropharmacol 2005;28:277–279. 3. Diener HC et al. Cephalalgia 2007;27:814–823.4. Silberstein SD et al. Headache 2007;47:170–180.

5. Spira PJ, Beran RG. Neurology 2003;61:1753–1759. 6. Krymchantowski AV et al. Headache 2002;45:510–514.7. Saper JR et al. Headache 1994;34:497–502. 8. Saper JR et al. Headache 2002;42:470–482.

9. Bigal M et al., Headache 2008; 48; 1337- 4210. Diener HC et al., Cephalalgia. 2010 Jul;30(7):804-1411. Aurora SK et al., Cephalalgia. 2010 Jul;30(7):793-80312. Dodick DW et al., Headache. 2010 Jun;50(6):921-36

Analgesic Medication Use

1-3 % of the population take analgesics on a regular basis

7% take analgesics at least 1x/wk

Medication Overuse Headache IHS 2004 & revised 2005 Classification

Chronic daily headache >15 days/month for >3 months

Regular intake for > 3 months of

And return to Pre-overuse pattern with cessation of Overuse

* 15 = consensus figure rather than evidence based

Triptan or ergot medication > 10 days / month

Opiate or Combination analgesics > 10 days / month

Simple Analgesics or combinations of above > 15 days month*

Medication Overuse Headache Clinical Features

• Characteristics may vary – Usually dull, generalised – Early morning worsening

Katsarvara et al, Drug Safety, 2001; 24: 921-927.

May differ depending on the drug being overused

Triptans Daily migrainous headache

Analgesics Diffuse featureless headache

Ergots Diffuse pulsating headache

Chronic Migraine and Medication Overuse headache (MOH)

• 45-70% sufferers of chronic primary headache experience

> 50% improvement in headache with analgesic withdrawalBigal et al., Cephalagia (2004) 24; 483-; Zeeberg et al, Neurology (2006) 66; 1894-

“In the absence of data it is generally accepted that patients are refractory to prophylactic medication while overusing analgesic medications and that they become responsive after analgesic medication withdrawal”

Does medication overuse matter?Topiramate in Chronic Migraine

(* P < 0.02; ** P < 0.03)

*

Red

uctio

n in

hea

dach

e da

ys

0.2

0.8

-3.5 -3.5-4

-3

-2

-1

0

1

2 placebo topiramate 100mg/day

n = 27 32 23 23

**

Medication overuse

Does Medication Overuse always reduce efficacy ?

PREEMPT pooled efficacy of BOTOX® in medication overuse subgroup* at week 24

*Of the total pooled PREEMPT population, 64.8% and 66.1% of BOTOX® and placebo groups, respectively, overused acute headache pain medication (simple analgesics, ergotamine/DHE, triptans, opioids, combination of analgesics or any combination of the preceding classes).

†Headache days are reported as headache days per 28 days; change in frequency of headache days was the primary endpoint of the pooled analysis. ‡p<0.001.

Nu

mb

er o

f d

ays

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Migraine daysModerate/severeheadache days

-6

-8.1‡

-5.7

-7.7‡

-6.2

-8.2‡

BOTOX® (n=445)

Placebo (n=459)

Imp

rove

men

t

Headache days/mth†

Change in frequency from baseline

Silberstein SD et al. IHC 2009. Dodick DW et al., Headache. 2010 Jun;50(6):921-36

• Tertiary referral centre study – n=175– Refractory CDH population with MOH

• 55% with migraine

– Previously refractory to 1-5 migraine preventatives

– 30 - 40% of individuals became responsive to Migraine preventatives post MOH treatment

• (8 month mean follow-up)

Analgesic Overuse Cessation improves Headache frequency & Drug responsiveness

Chronic Migraine & Medication Overuse Headache“Management controversies?”

What is the most effective strategy for initial MOH management?

MOH can be effectively managed initially as an OPD in most cases

85% responders/ 2/3 reduction in headache frequency

Rebound Headache & “Pain killer rebound symptoms”

(Katsarava et al, Neurology, 2002)

• Headache gets worse before better • in at least 70%

• Withdrawal symptoms– Nausea, vomiting– Autonomic activation

– Sleep disturbance & agitation

• Mean Duration & severity determined by overused drug class

• Triptans 4 days (85%)• Ergots 7 days

(57%)• Analgesics 9-10 days +

( 23%)

Headache intensity worsens at day 2-4 before improvement

Pilot DB RC n = 18 only

Prednisolone 100mg 5 days in MOH

50% in moderate-severe rebound headache in 1st 72 hrs compared with placebo

DB RCT n = 100 (65 with CM)

Prednisolone 60mg taper over 6 days in MOH

No effect on withdrawal headache in placebo vs. active treatment group

Dose response?

Sample size?

Triptan only MOH?

Prednisolone for Medication Overuse

withdrawal headache?

The “Stop - Start Strategy”in MOH

• OPD Based MOH withdrawal

• Abrupt GP supervised Analgesic withdrawal for 4 weeks when on established prophylaxis– Worse before better !!!– Written Support protocol & patient education

– Prednisolone Rescue option ?– Early follow-up – better outcome ?

• Start early new Migraine Drug Prophylaxis – When? What?

• Failed OPD withdrawal or no change in Headache – Review comorbidities again & Consider Inpatient strategy

Prognosis of MOH treatment Headache free +/or > 50% reduction in headache frequency

Short term• 20-85% @ 2-4 wks• 60-70% @ 6 months

Medium to long term• 35-60% @ 1 yr 50% @ 5 yrs

* Multiple observational studies

Withdrawal rates at 2 weeks

85%

57%

23%

Medication Overuse Headache

If 6-8 weeks afteracute analgesic medication withdrawal

there is no improvementThe initial diagnosis of

Medication Overuse Headache is not tenable

Review the Initial Diagnosis !

• 1st described 1984 –Sjaastad & Speirings

• Rare !!• 93+ cases in world

literature to 2001…..

• Female > males 2-3:1• Onset 4th & 5th decade• No obvious triggers

– c.f. Migraine

Hemicrania Continua“Women with constant Hemicrania tearing & nasal congestion”

• (Daily) mild-moderate Strictly side-locked unilateral pain• Mild-moderate background intensity with exacerbations

• Exacerbations associated with– Ipsilateral autonomic symptoms in up to ¾ patients

– Minimal or Absent autonomic symptoms in up to 1/3

– Photophobia, phonophobia & nausea in ~1/2

• Absolute headache response to Indometacin treatment– Mean oral dosage <150mg / day (ensure tried up to 225mg)

+/- “ blinded Indotest”Rare cause but very treatable cause of CDH/NDPH

Consider Indometacin trial in all with new onset side locked especially refractory hemicrania

A pragmatic approach to Long lasting Primary Chronic Daily headache diagnosis

Bigal ME, Lipton RB. J Headache Pain 2007;8:263–272.

Hemicrania continua

New Daily Persistent Headache

Chronic Migraine

Chronic Tension-Type Headache

Featureless holocranial Headaches with minimal

impairment

Continuous strictly unilateral pain with autonomic features

Clear onset as a daily syndrome

NO

Migraine or specific acute medications ≥8 days/month

Chronic Daily HeadacheLasting ≥4 hours per day

Associated symptoms

define the CDH syndrome

Need to know more about best practice in

Headache management

Join BASH !!

&

Go & buy this book !!!

Questions?

• Chronic Daily Headache is a symptom & not a diagnosis

• Accurate diagnosis determines both treatment choice & prognosis

• Medication Overuse is ubiquitous and must always be considered...........

• And more importantly properly addressed !!

BACKUP SLIDES

Chronic Refractory Migraine

What do I do?

& possible “Horizon” therapies?

Short term Chronic migraine prevention by greater occipital nerve blockade

Occipital nerve blockade (ONB) – 2% Lidocaine (2 ml) +/- 80 mg depo-medrone– Response rate: 50% for up to 1 month

Afridi et al. Pain 2006

Ashkenazi et al. JNNP 2007

– AEs• local discomfort• alopecia (1-2%)

Shields et al., Neurology 2004

Open label outcome data Tobin & Flitman Headache 2009

• 108 ONB patients• No benefit in 20%

In-Patient Management of Chronic Migraine +/- MOH

• When?– Failure of outpatient approach & significant impairment– Medication type +/or comorbidities

• How?– Inpatient Supportive care

• Hydration/drugs to combat withdrawal symptoms• iv Dihydroergotamine, i.v lidocaine• Steroids, Neuroleptics, Anti-emetics & Anxiolytics?

• Clonidine or lofexidine if opiates

• Identify & Treat Comorbidity

In-Patient Management of Medication Overuse Headache

• When?– Failure of outpatient approach– Medication type +/or comorbidities

• How?– Supportive care

• Hydration/drugs to combat withdrawal symptoms– Clonidine if opiates – Anti-emetics & Neuroleptics

• Iv Anti-nocioceptive drugs– i.v. Aspirin & iv Dihydroergotamine– i.v. AEDs

Intravenous Inpatient Therapies for Chronic Migraine at UHNS

iv Dihydroergotamine (DHE)• Central 5HT receptor agonist

– 5HT 1A, 1B, 1D & 5HT2A & 2C Receptors

– CGRP & Sub-P release blocked

– α-Adrenergic antagonist

– D1 &D2 receptor agonism

• USA since 1986

• Indications:– Status Migrainosis

– Chronic Migraine +/- MOH

– Refractory Chronic Cluster Headache

• USA -Open label data

• Data on iv DHE inpatients at UHNS• 42 patients audited 2007-8• Age 31-73 yrs• 5 day iv therapy course• Most had failed on >3 preventatives

Comparison of side effects at UHNS with USA

Evidence based treatment of Chronic migraine

Change From Baseline in Monthly (28-day) Rate of Migraine/Migrainous Days

Primary OutcomeMigraine/Migrainous Days

-7

-6

-5

-4

-3

-2

-1

0

Mean Change From Baseline

Mean baseline ± SD

-6.4 ± 5.8

-4.7 ± 6.1

P = 0.010

17.1 ± 5.4

Topiramate

17.0 ± 5.0

Placebo

N=153 for topiramate and placebo groups.P-value based on ANCOVA model including treatment and center as main effect, and baseline monthly migraine/migrainous or migraine days as covariates.

Population Therapeutic gain

= 1.7 days

Silberstein SD et al. Headache 2007;47:170–180.

Responder Rates

2937

63

5248

39

0

10

20

30

40

50

60

70

Topiramate (n = 153) Placebo (n = 153)

Patients (%)

≥30% ≥40% ≥50%

Percent Reduction in Mean Monthly Migraine/Migrainous Days(NB. - No adjustment for multiplicity)

P = 0.012

P = 0.093

P = 0.031

Silberstein SD et al. Headache 2007;47:170–180.

• 2 Trials: PREEMPT1 and PREEMPT 2• Phase 3, parallel-group, placebo-controlled studies of Botulinum toxin

A 155-195U in Chronic Migraine

1384 patients randomised (Botulinum toxin A 688, Placebo 696)31 injections per treatment session

Botulinum Toxin A in Chronic MigrainePREEMPT Studies

Diener HC et al., Cephalalgia. 2010 Jul;30(7):804-14Aurora SK et al., Cephalalgia. 2010 Jul;30(7):793-803Dodick DW et al., Headache. 2010 Jun;50(6):921-36

p<0.001

Botulinum Toxin A in Chronic MigrainePREEMPT 1 & 2 Studies pooled analysis

Mean change from baseline in frequency of headache days

Mean ± standard error. The double-blind phase included 688 subjects in the BOTOX® group and 696 in the placebo group.

Headache days at baseline: 19.9 BOTOX® group vs. 19.8 placebo group, p=0.498.

At Week 24

BOTOX® treated patients• Mean 8.4 fewer

headache days/month• vs. 6.6 with placebo

(p<0.001)1,2

Mea

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(day

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-day

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iod

) 52484440363228241612840

Study week

020 56

-2

-4

-6

-8

-10

-12

-14

BOTOX® (n=688)

Placebo (n=696)

p=0.019

p=0.047p=0.007

p=0.01p=0.008

p<0.001p<0.001

p<0.001p<0.001

p<0.001

Double-blind phase:BOTOX® vs. placebo

Open-label phase:All patients on BOTOX®

p<0.001

p=0.019 p=0.011

Dodick DW et al., Headache. 2010 Jun;50(6):921-36

Why Chronic Migraine and not Chronic tension type headache?

• Several cohort studies identified CDH with neurobiological features of Migraine – (not tension type !)Messinger et al., (1991), Pfaffenrath et al., (1993), Sanin et al (1994), Sandrini et al.,(1993)

• Silberstein & a new concepts in CDH classification - 1994– “Transformed Migraine” – evolving from an initial episodic pattern

Subjective classification ? Scientific basis ?

Natural history studies – supportive (Mathew et al., 1982, Sandrini et al, 1993)

“Positive “family history of Migraine in ¾ of patients

Response to Conventional anti-migraine preventatives (Lipton et al, 2000)

Biochemistry of Throbbing “Tension type” CDH & ↑CGRP (Ashina et al, 2000)