Approached to Headache and Update Management

Associated Professor Subsai KongsaengdaoRajavithi Hospital,

Thailand

1988 2004 2013

IHICHD-3

beta

Headache Classification

• Primary headaches• Secondary headaches• Cranial neuralgias,

central and primary facial pain and other headache

IHS ICHD –II, Cephalalgia Vol 24 (sup 1), 2004

Primary Headaches

Clinical diagnosis WHO-ICD10• Migraine G 43• Tension type headache G 44.2• Cluster headache G 44.0• Other primary headache G 44.8

WHO ICD 10 NA codes

Secondary HeadachesHeadache attribute to WHO-ICD10

• Head/neck trauma G 44.88• Cranial/cervical vascular dis. G 44.81• Nonvascular intracranial dis G 44.82• Substances or withdrawal G 44.83• Infection G 44.821/ 881• Disturbance of Homeostasis G 44.882• HEENT disorder G 44.884• Psychiatric disorder R 51

Cranial neuralgias, central and primary facial pain and other

headacheClinical diagnosis WHO-ICD10

• Cranial neuralgia G 44.847• External compression HA G 44.801• Cold induce HA G 44.802• Compression irritation of CN G 44.848• Post herpetic neuralgia G 44.847• Tolosa-Hunt syndrome G 44.850• Other R 51

Tension Type Headache (TTH)Previous used terms :• Tension headache• Muscle contraction headache• Psychomyogenic headache• Stress headache• Ordinary headache• Essential headache• Idiopathic headache• Psychogenic headache

Prevalence of common headache

22 Rasmussen BK. Epidemology of headache. Cephalalgia 1995;15:45–68.

Tension Type Headache

• One year prevalence 28-63% in male 34-86% in female 1

• Life time prevalence 69% in male 86% in female 1

• Disorder of CNS with probable sensitization of second-order TG neurons and some peripheral component

Rasmussen BK. Epidemology of headache. Cephalalgia 1995;15:45–68.

Tension Type Headache

Impact and cost• All migraineurs and 60% of CTTH patients

have a reduced capacity of work or other ADL

• In one year study, 27% of working day lost in MG pt and 82% of working day lost in CTTH patients

Rasmussen BK. Et al. Neurology 1992; 42 : 1225–31.

Tension Type Headache (TTH)Episodic tension type headache (<15d/mo, 30 min – 7d)Chronic tension type headache(>15d/mo, > 3 months/year)Headache has at least two of followings:

Bilateral locationPressing/ Tightening ( non pulsating ) qualityMild or moderate intensityNot aggravate by physical activity

Both of the followings:• No nausea or vomiting• No more than one of photophobia or phonophobia

Not attribute to another disorder

IHS ICHD –II, Cephalalgia Vol 24 (sup 1), 2004

Tension Type Headache (TTH)Episodic tension type headache (>15d/mo)

Infrequent Episodic TTH ( <1 day/mo)Frequent Episodic TTH ( >1, <15 days/mo)

Chronic tension type headache (>15d/mo, > 3 m/y)

TTH with or without pericranial tendernessProbable TTH

IHS ICHD –II, Cephalalgia Vol 24 (sup 1), 2004

IHS ClassificationMigraine

• Migraine without aura• Migraine with aura• Ophthalmoplegic • Retinal migraine • Childhood periodic syndromes that may be precursors

to or associated with migraine• Complications of migraine• Migrainous disorder not fulfilling the above criteria

Migraine without auraDiagnostic criteria

A. At least 5 attacks fulfilling B-DB. Headache lasting 4 to 72 hours

(untreated or unsuccessfully treated)C. Headache has at least two of the following

characteristics:1. Unilateral location2. Pulsating quality 3. Moderated or severe intensity (inhibits or prohibits daily activities)

4. Aggravation by walking stairs or similar routinephysical activity

Migraine without aura

Diagnostic criteria D. During headache, at least one of the

following 1. Nausea and/or vomiting2. Photophobia and phonophobia

E. No evidence of organic disease

Burdens of migraine

• Migraine prevalence is high• prevalence peaks at the time of

high productivity• Impair quality of life substantial

disability and significant economic cost

Pathophysiologyof Migraine

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Cortical spreding depression

Hypersensitive cortex

Cortical spreding depressionHypersensitive cortex

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation– Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Trigeminal Activation

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Neurogenic Inflamation

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Central Facilitation:Trigeminal Neucleus Caudalis

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Central sensitization due to :Supraspinal facilitation

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Central sensitization due to :Decreased Antinociceptive System activity

Migraine Mechanisms• Aura due to cortical spreading

depression in hypersensitive cortex• Headache generated by

– TG activation – Neurogenic inflammation– Central pain facilitation

• Central sensitization due to– Supra spinal Facilitation– Decreased anti-nociceptive system activity– Increased peripheral input

Central sensitization due to :Increased peripheral Input

Migraine and Channelopathy

• Familial hemiplegic migraine– CACNA1A : P/Q voltage gated Ca2+ channel– Several mutation

Mechanism of Refer Pain

Migraine mechanismsPeripheral Central

Sensitization SensitizationGlu, Sp, C-GRP, NA, NGF Glu, Sp

C fiber /A delta fiber

Aβ fiberTrigeminal ganglion Nucleus TG caudalis

Bk, PGs, HA, 5HT, H+

Adenosine, NO

Migraine mechanismsPeripheral Central

Sensitization SensitizationGlu, Sp, C-GRP, NA, NGF Glu, Sp

C fiber /A delta fiber

Aβ fiberTrigeminal ganglion Nucleus TG caudalis

Bk, PGs, HA, 5HT, H+

Adenosine, NO

Central pain facilitation

Common problems in HA clinic

• What is/are the cause(s) of Headache ?• How serious of my headache ?• Cancer or not vs Tumor or not?• I need CT scan or MRI or both !• How can you treat ?• Complete recovery or not ?• Expensive or not ?

Common problems in HA clinic

• What is/are the cause(s) of Headache ?• How serious of my headache ?• Cancer or not vs Tumor or not?• I need CT scan or MRI or both !• How can you treat ?• Complete recovery or not ?• Expensive or not ?

Common problems in HA clinic

• What is/are the cause(s) of Headache ?• How serious of my headache ?• Cancer or not vs Tumor or not?• I need CT scan or MRI or both !• How can you treat ?• Complete recovery or not ?• Expensive or not ?

Step 1

OR

Peter J Goadsby and Christopher BoesJ. Neurol. Neurosurg. Psychiatry 2002;72;2-5

Careful History Taking

Dangerous headache• Increase intracranial pressure ?• Sudden severe headache ?• Neuro-localizing sign ?• Night headache ?

Careful Physical examination

• Complete general physical examination• Complete neurological examination• Ophthalmoscopic examination• Pericranial palpation artery and nerve• Red eye • Visual impairment and diplopia• Stiffness of neck

Step 2

Migraine Non –Migraine HA

Episodic Chronic

Dangerousor 2 headache

Infrequent episodic

TTH

Freqent episodic

TTH<4 hr >4 hr

Common causes of chronic daily headache

Peter J Goadsby and Christopher BoesJ. Neurol. Neurosurg. Psychiatry 2002;72;2-5

Cluster HA and Trigeminal Autonomic cephalagia

• Cluster headache• Paroxysmal hemicrania• Short lasting unilateral neuralgiform

headache attacke with conjuctival injection and tearing (SUNCT)

• Probable CA, PH, SUNCT

IHS ICHD –II, Cephalalgia Vol 24 (sup 1), 2004

Cluster headache• 5 attacks fulfill followings :

– Severe orbital (temporal) 15-180 min (unRx)– Atleast one of followings:

• Ipsilateral conjunctival injection/tearing• Ipsilateral nasal congestion rhinorrhea• Ipsilateral eyelid edema• Ipsilateral forehead and facial swelling• Ipsilateral miosis/ ptosis• Restlessness/ agitation

– Attack EOD or up to 8 times /day– Not attribute to other disorders

IHS ICHD –II, Cephalalgia Vol 24 (sup 1), 2004

Paroxysmal hemicrania• 20 attacks fulfill followings :

– Severe orbital (temporal) 2-30 min (unRx)– Atleast one of followings:

• Ipsilateral conjunctival injection/tearing• Ipsilateral nasal congestion rhinorrhea• Ipsilateral eyelid edema• Ipsilateral forehead and facial swelling• Ipsilateral miosis/ ptosis

– Attack more than 5 times /day (half of time)– Completely prevent by indomethacine– Not attribute to other disorders

IHS ICHD –II, Cephalagia Vol 24 (sup 1), 2004

Episodic or Chronic in Cluster headache and Paroxysmal

hemicrania• Episodic :

– Attack occurred in period of 7 days to 1 year separated by at least 1month of symptom free

• Chronic :– Attack occurred in period > 1 year or

separated by at less than 1month of symptom free

IHS ICHD –II, Cephalagia Vol 24 (sup 1), 2004

SUNCT

• 5 attacks fulfill followings :– Stabbing/pulsating orbital (temporal) 5-240Sec– Ipsilateral conjunctival injection and tearing– Attack 3 -200 times /day– Not attribute to other disorders

IHS ICHD –II, Cephalagia Vol 24 (sup 1), 2004

Chronic daily headache

Peter J Goadsby and Christopher BoesJ. Neurol. Neurosurg. Psychiatry 2002;72;2-5

Treatment of migraine

• Acute treatment• Migraine prevention

Acute medications: efficacy, AEs, relative contraindications and indication

Drug Efficacy AES Relative contraindication

Acetaminophen (paracetamol)

++ + Liver disease

Aspirin (ASA) ++ + Kidney disease, ulcer disease, PUD, gastritis, AGE<15yr

Barbital, caffeine and analgesics

++ +++ Use of other sedative; history of medication overuse

Caffeine adjuvant ++ + Sensitivity to caffeineIsometheptens ++ + Uncontrolled HTN, CAD, PVDOpioids +++ ++++ Drug or substance abusedNSIADs ++ + Kidney disease, PUD, gastritisDihydroergotamineInjectionIntranasal

+++++++

+++

Uncontrolled HTN, CAD, PVD

ErgotamineTabletSuppositories

+++++

+++++

Prominent nausea and vomiting Uncontrolled HTN, CAD, PVD

Acute medications: efficacy, AEs, relative contraindications and indication

Drug Efficacy AES Relative contraindication

TriptanAlmotriptanTablets

+++ +/- Uncontrolled HTN, CAD, PVD

EltriptanTablets

+++ ++ Uncontrolled HTN, CAD, PVD

FrovatriptanTablets

++ +/- Uncontrolled HTN, CAD, PVD

NaratriptanTablets

++ +/- Uncontrolled HTN, CAD, PVD

RizatriptanTablets

+++ + Uncontrolled HTN, CAD, PVD

ZolmatriptanTabletsIntranasal

+++ + Uncontrolled HTN, CAD, PVD

Acute medications: efficacy, AEs, relative contraindications and indication

Drug Efficacy AES Relative contraindication

SumatriptanSubcutaneous injection

++++ + Uncontrolled HTN, CAD, PVD

Intranasal +++ + Uncontrolled HTN, CAD, PVDTablets +++ + Uncontrolled HTN, CAD, PVD

§ Rating are on a scale form + (lowed) to ++++ (highest) based on response rates and consistency of response in double-blind-controlled trials and the authors’ clinical experienceAE: Adverse events, CAD: Coronary artery disease, HIN: Hypertension, NSAIDs: Nonsteroidal and-inflammatory drugs, PUD: Peptic ulcer disease PVD: Peripheral vascular disease, SC: Subcutaneous, TIA: Transient ischemic attack

Limitation of acute treatment• Side effects and intolerance • Contraindication• Habituation• Drug-induced headache • Interaction with prophylactic therapy• Non-responders

Potential habituation-drug induced headache cycle

Dose of acute medication

Decrease in central pain threshold

Suppress of endogenouspain system

Wears off

The vicious cycle

Acute medication overuseAt least on of the following for at leastone month

1) Simple analgesics use (>1000mg ASA/ Acetaminophen) > 5days/week

2) Combination analgesics (caffeine, barbiturate- containing medication) > 3tablets/day, >3days/week

3) Opioids (>1tablet/day) > 2days/ week4) Ergotamine use (1mg PO or 0.5mg PR)

>2days/week

Prevention medication• Lessen the frequency, duration and

severity of attack• Alter natural history of disease; prevent or

delay progression from episodic to chronic form of migraine

Indications for prevention medication

• Presence of recurrent headache, despite acute treatments that interferes significantly with daily activity as reported by the patient

• Ineffective or contraindication to acute treatment

• Analgesics overuse

• Frequent attacks which increase risk of developing rebound headache

• Present of risk of permanent neurologic deficit

• Patient preference

Goal of preventive medication

• Reduce frequency and severity of attacks• Prevent or delay worsening of migraine

overtime• Improve effectiveness of acute treatment• Not cure the disease• Response of drugs varies from patient to

patient• Two-three months at full medication dose

is needed to judge effectiveness

Interventions used in migraine prevention

Class Representative agentsBeta-blockers Propranolol, Nadalol, Atenolol,

Timolol, Metopolol

Antidepressants Tricyclic antidepressant (Amitriptyline, Nortriptyline)

Calcium channel blockers Verapamil, Flunaruzine

Interventions used in migraine prevention

Class Representative agentsAntiepileptic drugs Valproate (Divalproex,

Valproic acid), Gabapentin, Topiramate

Others NSAIDs, Herbs (feverfew), Magnesium, Riboflavin, Botulinum toxin A, Behavioural modification, Lifestyle changes

Choice of preventive treatment in migraine: influence of comrbid condition

Drug Efficacy AEs Relative contraindicationsBeta blockers ++++ ++ Asthma, depression,

CHF, Raynaud’s disease, diabetes

Anti-serotonin

Pizotifen +++ ++ Obesity

Methylsergide ++++ ++++ Angina, PVD

Choice of preventive treatment in migraine: influence of comrbid condition

Drug Efficacy AEs Relative contraindicationsCalcium channel blockers

Verapamil ++ + Constipation, hypotension

Flunarizine ++++ + Parkinsonism

Choice of preventive treatment in migraine: influence of comrbid condition

Drug Efficacy AEs Relative contraindicationsAntidepressant

TCAs ++++ ++ Mania, urinary retention, heart block

SSRIs ++ + Mania

MAOIs ++++ ++++ Unreliable patient

Choice of preventive treatment in migraine: influence of comrbid condition

Drug Efficacy AEs Relative contraindications

Antiepileptic drugs

DivalproexValproate

++++ ++ Liver disease,

Bleeding tendency

Gabapentin

++ ++ Liver disease,

Bleeding tendency

Topiramate ++++ ++ Kidney stones

Choice of preventive treatment in migraine: influence of comrbid condition

Drug Efficacy AEs Relative contraindications

NSIADs

Naproxen ++++ ++ Ulcer disease, gastritis

§ Ratings are on a scale from + (lowest) to ++++ (highest)AE: Adverse events, CHF: Congestive heart failure, HTN:Hypertension, MAOls: Monoamine oxidase inhibitors, NSAIDs: Nonsteroidal anti-inflammatory drug, OCD: Obsessive compulsive disorders, PVD: Peripheral vascular disease, SSRI: Serotonin-specific reuptake inhibitor,

TCA: Tricyclic antidepressants

Effect of comorbid or coexisting conditions upon drugs selection for

migraine preventionConcurrent Disorder Medications to

ConsiderMedications to Avoid

Epilepsy Neuronal stabilizer TCAs

Insomnia TCAs Neuronal stabilizer

-

Depression TCAs Beta-blockers, Flunarizine

Bipolar Disorder Neuronal stabilizer TCAs

Hypertension Beta-blockersCalcium channel blockers

-

Vertigo Flunarizine -

Effect of comorbid or coexisting conditions upon drugs selection for

migraine preventionConcurrent Disorder Medications to Consider Medications to Avoid

Angina Calcium channel blockers Beta-blockers

-

Obesity Topiramate Valproate, TCAs, Beta-blockers, GabapentinFlunarizine

Anxiety disorders Beta-blockersTCAs

-

Raynaud syndrome Calcium channel blockers Beta-blockers

Tremor TopiramateBeta-blockers

Valproate

Practical dosing recommendations for migraine preventive agents

Drug RecommendationsPropranolol Start at 40 mg/d in divided doses

3 to 4 times a day for short-acting formulation,

twice a day for long-acting formulation

• Increase to 120 mg/d or 160 mg/d

• Assess for lightheadedness

and/or exercise intolerance

Practical dosing recommendations for migraine preventive agents

Drug RecommendationsTCAs

Amitriptyline

Nortriptyline

• Start at 10 mg/d

• Increase dose on a weekly

basis to 100 mg/d or 150

mg/d to achieve efficacy

• Side effects usually preclude

doses above 200 mg/d

Practical dosing recommendations for migraine preventive agents

Drug RecommendationsVerapamil • Start at 40 mg/d (half the 80-mg tablet) for 4

to 7 days • Increase to 40 mg BID• A typical standard dose is 80 mg in the morning, 80 mg at noon and 160 mg at bed time• Patients may be prescribed 160mg (two 80-mg tablets) TID• Some patients may benefit from 80mg in the morning, 80 mg at noon, and 240mg at bedtime of pulse-release formulation

Practical dosing recommendations for migraine preventive agents

Drug Recommendations

Flunarizine • Patient < 65 years 2 cap (5mg/cap once at bedtimes)

• Patient > 65 years 1 cap (5mg/cap once at bedtimes)

Practical dosing recommendations for migraine preventive agents

Drug RecommendationsValproate

divalproex

• Start at 250 mg at bedtime

• After 1 week or 10 days,

increase to 250 mg BID

• Titrate in 250-mg increments each week until target dose of 1000 mg is reached

Practical dosing recommendations for migraine preventive agents

Drug RecommendationsTopiramate • Start low and titrate slowly

• Begin with 15 mg or 25 mg at bedtime

• After about 4 to 7 days, begin to increase the daily dose by 25 mg. Continue each 25-mg increment for 1 week until the target dose of 100 mg is reached

• Dose may be increased above 100 mg if needed

Mechanisms of antiepileptic drug in migraine

• Gamma aminobutyric acid type A (GABAA) receptors

• Glutamate receptors• Voltage dependent sodium channels• Voltage dependent low-threshold (T-type)

calcium channels

Mechanisms of antiepileptic drug in migraine prophylaxis

Decreased Glutamate Release

Neurostabilizers Sodium channel blockage

Calcium channel blockage

Glutamate receptor

antagonist

GABA potential

Carbonic anhydrase inhibitors

Valproate x x x

Topiramate x x x x x

Gabapentin x x

Felbamate x x x x

Lamotrigin x x

Tiagabine x

Oxcarbazepine x x

Zonisamide x x x

Phenytoin x

Carbamazepine x

Modified from White HS. Pediatric Epilepsy: Diagnosis and Therapy. 2001:301-316.

Antiepileptic drug as a first drug• Migraine coexisting with:

– Epilepsy– Manic-depressive disorder– Essential tremor

• Contraindication or side effect due to– Beta-blockers– Calcium channel blockers– Antidepressants

Topiramate in Migraine prevention

• Potentiation of GABA-ergic neuro-inhibition• State-dependent blockade of voltage-dependent

Na+ channels• Modulation of high voltage-activated Ca2+

channels• Glutamate receptor antagonism at non-NMDA

(kainate/AMPA) receptors• Carbonic anhydrase: type II and IV

Topiramate

• Significant clearance by hemodialysis• In moderate to severe liver

impairment: not clinically significant affecting on plasma concentration and clearance

Significant drug interaction• Liver cytochrome P-450 iso-enzyme

CYP2C19 inhibition :20 %• Induction metabolism of oral contraceptive

pill (estrogen), digoxin• However, at < 200 mg/d not effect on

estrogen-containing pill• Overall, no significant effect on level of

other AEDs including phenytoin, carbamazepine and valproate

• Hepatic enzyme inducers such as carbamazepine, phenobarbital, phenytoin lower level of TPM

Other potential migraine prophylactic drugs

• Angiotensin converting enzyme (ACE) inhibitors

• Lisinopril

• Angiotensin II (A II) receptor antagonist • Cadesartan

• Quetiapine• Alpha2 - adrenergic presynaptic agonist

• Tizanidine

Other potential migraine prophylactic drugs

• Botulinum toxin A• Petasites• Feverfew• Riboflavin (vitamin B2)• Magnesium• Co-enzyme Q10• Acupuncture

Non-pharmacological management

• Trigger avoidance• Behavioural intervention

– Relaxation– Biofeedback– Stress management training or cognitive

behavioural therapy

Silberstein et al.

P =0.08

P =0.042

TOTAL INTENSITY SCORE

P = 0.033

Baseline 4 wk 8 wk 12 wk

- 25.2

- 11.9

- 15.2- 16.5

- 10.9

- 5.8

- 11.0

- 22.1

- 26.1

*

Treatments of TTHPharmacological treatments

»Analgesic»NSAIDS»Muscle relaxant»SSRI»Tricyclic antidepressant» ? Triptan

New Review• Patients with CTTH treated with an SSRI had a

significantly higher analgesic intake of 5 more doses per month when compared to patients treated with a tricyclic antidepressant (WMD 4.98; 95% CI 1.12 to 8.84).

• TCA also significantly reduced headache duration by 1.26 hours per day (WMD 1.26; 95% CI 0.06 to 2.45) and marginally reduced headache indexes (SMD 0.42; 95% CI 0.00 to 0.85) when compared to SSRIs in patients with CTTH.

PL Moja, C Cusi, RR Sterzi, C CanepariCochrane review published online: 20 July 2005 in Issue 3, 2005

Date of Most Recent Substantive Amendment: 4 March 2005

New Review• There were no significant differences between

SSRIs and placebo for withdrawals due to adverse events (Peto OR 1.02; 95% CI 0.31 to 3.34).

• For minor adverse events, SSRIs were generally more tolerable than tricyclics (OR 0.34; 95% CI 0.13 to 0.92).

• However, there were no differences in the number of patients withdrawing due to any reason in the SSRI and tricyclic groups (OR 1.01; 95% CI 0.56 to 1.80).

PL Moja, C Cusi, RR Sterzi, C CanepariCochrane review published online: 20 July 2005 in Issue 3, 2005

Date of Most Recent Substantive Amendment: 4 March 2005

• Overall, the existing evidence supports the value of acupuncture for the treatment of idiopathic headaches. However, the quality and amount of evidence are not fully convincing.

• For episodic tension-type headache, there is evidence that adding spinal manipulation to massage is not effective.

New Review

PL Moja, C Cusi, RR Sterzi, C CanepariCochrane review published online: 20 July 2005 in Issue 3, 2005

Date of Most Recent Substantive Amendment: 4 March 2005

New RCT trails

• Botulinum toxin (Botox®) in CTTH: not significant

• Botulinum toxin (Dysport®) in CTTH : not significant

•Padberg M.et al Cephalalgia. 2004 Aug;24(8):675-80.

•Schulte-Mattler WJ . Pain. 2004 May;109(1-2):110-4 .