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 .