Headaches:

Migraines, Tensions, and

Clusters! Oh My!
Mikael Jones, PharmD,
BCPS
 Headaches
 Mostcommon complaint
encountered by health care
professionals
– ~18 million outpatient visits annually
 International Headache Society
classification system
– Numerous types and causes of
headache
– Primary Headache Disorders
– Secondary Headache Disorders
 Headaches
 Primary headache
disorders
– Migraine
– Cluster
– Tension
Migraines:Clinical Presentation
 Prodromal Symptoms
– Photophobia/phonophobia
 Aura
– Visual or sensory/motor symptoms
 Headache
– Gradual onset with variable length
– Unilateral , throbbing in frontotemporal
region
– Nausea/vomiting
 Migraine Headaches
Pathophysiology
 Vascular Theory
– Intracerebral arterial vasoconstriction
– Followed by reactive extracranial
vasodilation
 Neurovascular Dysfunction Theory
– Trigeminovascular system
 Auras

– Vascular vs neuronal dysfunction

Neurovascular Dysfunction Theory
 Vasodilation of intracranial
extracerebral blood vessels
 Activation of perivascular trigeminal
nerves
– Release of neuropeptides Neurogenic
inflammation
 Pain signal Transmission
– Migraine pain
– Associated symptoms
Neurovascular Dysfunction Theory
 Pharmacologic Sites of Action
 Regulation of
trigeminovascular
system
– Noradrenergic
– Serotonergic
– Neuropeptide
 Pharmacology of Serotonin
 Serotonin (5-hydroxytryptamine or 5-
HT)
– Multiple MOA in the body
– Seven 5-HT receptors described
– Effects on many organ systems
 Nervous System
 Airway

 Cardiovascular

 Gastrointestinal
 Pharmacology of Serotonin
 Synthesized from L-tryptophan
 Metabolized by monoamine oxidase
 Serotonergic neurons regulate
– Mood
– Sleep
– Appetite
– Perception of pain
– Vomiting
– Temperature/Blood pressure regulation
Pharmacology of Serotonin
 Pharmacologic Targets for
Migraines
 Agonistic action on 5-HT1b receptors
– Vasoconstriction of meningeal blood
vessels
 Agonistic action on 5-HT1d receptors
– Inhibits release of neuropeptides
– Interrupt pain signal transmission
 Suppression of underlying neuronal
dysfunction
 Pharmacologic Agents for
Treatment of Migraines
 Abortive therapies  Prophylactic
– Ergot alkaloids therapies
– Serotonin agonists – Beta blockers
– NSAIDS – Antidepressants
– Combination – NSAIDS
analgesics – Valproic Acid
– Butorphanol – Methysergide
– Metoclopramide – Calcium Channel
blockers
 Ergot alkaloids
 Derived from a fungus that infects
grain
– Ergotism/ St. Anthony’s fire
– LSD
 “Dirty” receptor binding
– Binds to 5-HT, - and -adrenergic, and
dopamine receptors
– Agonist, Partial agonist, and antagonist
effects
 Ergotamine/DHE
 Ergotamine tartrate
– PO, SL, PR routes
– Products contain caffeine to increase
absorption
 Dihydroergotamine (DHE)
– IM, SQ, Nasal Spray
 Ergotamine/DHE
 5-HT receptor agonists
1
 Side effects
– Nausea/vomiting
– Chest tightness
 Separate from triptans by >24 hours
 Contraindications
– Renal and/or hepatic failure
– Coronary, cerebral, peripheral vascular
disease
 Serotonin Receptor Agonists
 Selective agonists of 5-HT1b/5-HT1d
– Vasoconstriction of pain producing
intracranial blood vessels
– Inhibition of vasoactive peptides release
– Interruption of pain signal transmission
 7 agents currently available

– Various dosage forms

– Different pharmacokinetics
– Repeat dosing/Max dose
 Serotonin Receptor Agonists
 Sumatriptan (Imitrex®)
– Tablets, SC injection, Nasal Spray
 Zolmitriptan (Zomig®)
– Tablets, Orally disintegrating, nasal
spray
 Rizatriptan (Maxalt®)
– Tablets, Orally disintegrating
 Serotonin Receptor Agonists
 Naratriptan (Amerge®)
– Tablets
 Almotriptan (Axert®)
– Tablets
 Frovatriptan (Frova®)
– Tablets
 Eletriptan (Relpax®)
– Tablets
Serotonin Receptor Agonists
Drug t1/2 (h) Elimination

Sumatriptan 2 MAO-A/Renal

Zolmitriptan 2.5-3 MAO-A/CYP

Rizatriptan 2 MAO-A/Renal

Almotriptan 3 CYP/MAO-A/
Renal
Serotonin Receptor Agonists
Drug t1/2 (h) Elimination

Naratriptan ~6 CYP/Renal

Eletriptan 3.6-5.5 CYP

Frovatriptan 26 Cyp/Renal
 Serotonin Receptor Agonists
 Adverse effects
– Fatigue
– Dizziness
– Flushing/warm sensation
– Chest symptoms
– Cardiac events
– Stroke
– Increased blood pressure
 Serotonin Receptor Agonists
 Contraindications
– Ischemic heart disease
– Uncontrolled hypertension
– Cerebrovascular disease
– Peripheral Vascular disease
 NSAIDs & Analgesics
 Prevent
neurogenically-mediated
inflammation
– Inhibition of prostaglandin synthesis
– Short-acting>Long-acting
 Combination products
– Butalbital
– Narcotics
 Midrin

– Acetaminophen/Isometheptene/Dichlor-
alphenazone
 NSAIDS & Analgesics
 Aspirin  APAP/ASA/Caffeine
 Acetaminophen – Excedrin®
 Ibuprofen  ASA/butalbital/
 Naproxen caffeine
– Fiorinal®
 Diclofenac

 Midrin
 APAP/Butalbital/
caffeine
– Fioricet®
 NSAIDs & Analgesics
 Adverse Effects
– Dyspepsia
– Nausea/vomiting
– Drowsiness (butalbital/midrin®)
– Addiction (butalbital/midrin®)
 Precautions

– Ulcer disease
– Renal disease
– ASA hypersensitivity
 Opiates
 “Rescue” narcotics
– Meperidine
– Butorphanol (Nasal Spray)
– Oxycodone
 Adverse Effects
– Addiction
– Rebound Headache
– N/V
– Constipation
 Antiemetics
 Adjunctive therapy
– Prevent/treatment migraine-induced n/v
 Common Agents
– Metoclopramide
– Chlorpromazine
 Adverse Effects
– Extrapyramidal side effects
– Drowsiness
 Prophylaxis Therapy
 Prevent Migraine occurrence
– Reduce frequency/severity/duration
 Consider for the following patients
– Significant disability
– Attacks >2/week
– Acute therapy
ineffective/contraindicated
 Beta-Blockers
 Antagonist of β-adrenergic receptors
 Raise migraine threshold

– Modulate serotonergic neurotransmission

 Adverse Effects
– Fatigue
– Sleep Disturbances
– Bradycardia
– Hypotension
– Impotence
 Beta-Blockers
 Precautions  Propranolol
– CHF – Lipophilic
– Peripheral vascular  Atenolol
disease – Hydrophilic
– Asthma  Nadolol
– Depression
– hydrophilic
– Diabetes
 Metoprolol
– β1-selective
 Antidepressants
 Tricyclic antidepressants (TCAs)
– Antagonism of 5-HT2 receptors on
cerebral vessels
– Suppression of serotonergic neuronal
activity in brain stem
 Selective Serotonin Reuptake
Inhibitors (SSRIs)
– Less effective than TCAs
 Antidepressants
 Side effects (TCAs)
– Anticholinergic
– Weight gain
– Orthostatic hypotension
– Cardiac toxicity
 Precautions
– Benign prostatic hyperplasia
– Glaucoma
– Suicide risk
 Antidepressants
 TCAs

– Amitriptyline
– Doxepine
– Imipramine
 SSRI

– Fluoxetine
 Valproic acid
 Inhibition of serotonergic neurons
– Facilitate GABA neurotransmission
 Depakote (divalproex)
– ER vs DR
 Adverse Effects
– N/V
– Tremor
– Weight gain
– Blood dyscrasias
– Hepatotoxicity
 Other anticonvulsants
 Topiramate

 Gabapentin
 Methysergide
 Ergot alkaloid
– 5-HT2 receptor antagonist
– Stabilize serotonergic neurotransmission
 Block neurogenic inflammation
 Adverse Effects
– Retroperitoneal, endocardial, pulmonary
fibrosis
 Long-term use; rare
– GI intolerance
 Methysergide
 Adverse Effects
– Insomnia
– Hallucinations
– Claudication
– Muscle cramps
 Contraindications
– Renal and/or hepatic failure
– Coronary, cerebral, peripheral vascular
disease
 Calcium Channel Blockers
 Verapamil

– Inhibition of 5-HT release

 Adverse effects
– Constipation
– Hypotension
– Bradycardia
– AV block
 NSAIDs
 Prevent
neurogenically-mediated
inflammation
– Inhibition of prostaglandin synthesis
 Menstrual migraine
 Cluster Headache
 Activation of trigeminovascular
system
– Neurogenic inflammation in cavernous
sinus
 Hypothalmic dysfunction
– Modulated by serotonergic neurons
 Abortive/Prophylactic therapy
 Cluster Headache
 Attacks occur in clusters
– 2weeks to 3 months
– Pain free intervals from months to years
 Excruciating/penetrating pain
– Unilateral in orbital, supraorbital,
temporal locations
 Conjunctivialinjection/lacrimation
 Nasal congestions/rhinorrhea
 Facial tenderness or edema
 Oxygen
 Cerebralvasconstriction
 100% O2 at 7-10L/min for 10-15 min

 No adverse effects
 Ergots/Triptans
 DHE/Ergotamine

– Injection route preferred

– Ergotamine has been used as
prophylaxis
 Sumatriptan

– SC/intranasal dosage forms

 Contraindication

 Monitoring parameters
 Lithium
 MOA: Unknown for headaches
 Adverse Effects
– Tremor
– Lethargy
– N/D
– Abdominal discomfort
– May cause non-cluster headaches
 Precautions
– Renal/Cardiovascular disease
– Dehydration
– Diuretic use
 Other agents
 Verapamil

 Methysergide

 Corticosteroids

– Prednisone 40-60mg/day tapered over 3

weeks
– Not for long-term use
 Tension Headaches
 Headache pain
– Muscular/myofacial in origin
– Increased muscle hardness
 Mild to moderate pain
– Tightness, pressure, dull ache
– Band extending bilateral back from
forehead to occiput
– Radiate to neck muscles
 Treatment
 NSAIDs/Acetaminophen

– Reduce pain related to headache

– Can use combination products
 Amitriptyline

– Prophylactic agent
 Rebound Headaches
 Self-sustaining headache-medication
cycle
– Daily headache superimposed on
original headache
 Analgesics, triptans, ergots, opioids
 Must discontinue agent and allow

headache cycle return to normal

 Limit abortive agents ~2 per week