Pharmacological Treatment of Headaches Flashcards
What are causes of Secondary HA’s?
- Often Intracranial (deep, aching, dull, not throbbing)
- Brian injury
- Tumor or infection
- Hangover
- Kidney of liver disease
- Dental problems
- Caffeine withdrawal
- HYPERTENSION
What is a Sinus HA?
Pain behind browbone and/or cheekbones.
What is a Cluster HA?
Pain is in and around one eye.
What is a tension HA?
Pain is like a band squeezing the head.
What is a migraine HA?
Pain, nausea and visual changes are typical of classic form.
What is a primary HA?
- Not caused by underlying condition.
- 90% of all HA.
- Females 3X more likely
What are symptoms of migraine?
- Recurrent, paroxysmal attacks of throbbing, pulsating pain, usually unilateral, combined w/ autonomic disturbances.
What is the HIT-6?
- Headache Impact Test.
What is characteristic of episodic migraines?
- 0-14 HA days/mo
- 2.5% progress to chronic
- Contributing factors:
- Obesity
- Smoking
- High caffeine
- Sleep disorder
- Opioid use #1 cause of conversion.
What are the 5 phases of complete migraine attack?
- Prodrome
- Aura
- HA
- Resolution
- Recovery
What is the diagnostic criteria of migraine w/o aura?
- Recurrent HA
- Untreated or unsuccessfully treated HA duration of 4-72 hr AND
- at least 2 of following:
- Unilateral
- Pulsating
- Moderate or severe intensity
- Aggravation by routine physical activity. - Associated with one of the following:
- Nausea/vomiting
- Photophobia or phonophobia.
What is diagnostic criteria for migraine w/ aura?
- Aura less than 60 min before pain.
- Visual disturbances are the most common element of migraine aura.
- blurred cloudy vision
- Scotoma
- Scintillating zigzag lines
- Flashes of light - Sensory, speech and/or language, motor, brainstem.
What is characteristic of chronic migraine?
- Tension-like or migraine-like HA occurring more than 15 days/mo for greater than 3 months w/ migraine features more than 15 days/mo
Consecutive stages in migraine attack?
- Cortical spreading depression
- Extracranial & Intracranial arterial constriction (during aura)
- Extracrania & Intracranial arterial dilation & decreased electrical activity (during attack)
What is Cortical Spreading Depression?
- Self propagating.
- Brief neuronal excitation w/ glutamate and ATP flux and large efflux of K from IC to EC.
- Long-lasting inhibition spreads across brain 2-3mm/min.
Where is cortical spreading depression seen?
Brain regions where greatest neuron to glia ratio.
-Perhaps insufficient glia to take up released K+
What are the overall effects of cortical spreading depression?
- Changes in Extracranial blood flow.
- dilation of middle meningeal artery due to leakage of blood borne factors.
- Opening of BBB
- Leakage of plasma proteins.
What is the vascular theory of Migraines?
- 5-HT release preceding pain phase
- acts on 5HT2 post-synaptic receptors on blood vessels cause vasoconstriction. - 5-HT deficiency during pain phase
- extracranial arterial dilation, associated with decrease of 5-HT release from platelets.
What does extracranial arterial constriction do?
- Decrease regional blood flow
2. May increase prostaglandin production and release.
What is the neurogenic theory of migraines?
- Changes in activity in locus coeruleus.
- Excitation of efferent neurons in trigeminal nuclei
- Release of vasoactive substances
- Vasodilation or arteries of dura mater & plasma protein extravasation (edema)
- Pain & Inflammation
- Sometimes excessive contraction of posterior neck muscles.
What do meningeal nociceptors mediate?
Throbbing pain of migraine.
What do central trigeminovascular neurons mediate?
Cutaneous allodynia
What happens with Triptan overuse?
Increase frequency of migraines, by neural adaptation, producing sensitization, perhaps explaining medication overuse headache.
What is the 3 step approach to migraine treatment?
- Non-specific Tx for mild migraine.
- Specific Tx for moderate-severe pain associated w/ some impairment of function.
- Prophylaxis in a migrainer
What is Non-specific treatment of Migraines?
- Mild Analgesics
- ASA, APAP, NSAIDs - Combination products
- Fiorinal, Fioricet, Excedrin - Isometheptine (alpha, beta agonists vasoconstrictor)
- dichloralphenazone
What are opioid non-specific treatment of acute migraine attacks?
- Butorphanol nasal spray (Stadol)
- abuse, dependence, increased risk of transformed migraine
- ONLY as last resort.
What is Metoclopramide (Reglan)?
- Anti-emetic/gastro (pro-) kinetic agent.
- Pro-kinetic to enhance gastric emptying, enhance absorption of oral agents.
- Reduce N&V
What is the MOA of Pro-kinetic agents?
- 5-HT3 receptor antagonist and 5-HT4 receptor agonist to facilitate ACh release from enteric neurons.
- Peripheral DA2 antagonist on cholinergic enteric neurons.
How does Metoclopramide act as an anti-emetic?
- Central DA2 antagonist
- Inhibits chemoreceptor trigger zone (CTZ) in area postrema.
What is Ondansetron? MOA?
- Anti-emetic, modest prokinetic
2. Inhibit 5-HT3 receptors in GI tract and in CTZ.
What are Neuroleptics?
- AKA “antipsychotic”
- Phenothiazines (Promethazine)
- DA2 antagonists.
What are other non-specific Tx of Acute Migraine Attack?
- Lidocaine
- Sedation
- Heat to relax tense muscles. Cold to constrict blood vessels.
- Hyperbaric oxygen
What is used for specific treatment for moderate-severe pain of migraines?
- To directly arrest the process:
- Ergots
- Triptans
What are the proposed MOAs of ergotamine and Triptans?
- Agonists at presynaptic 5-HT1D & 5-HT1B receptors that decrease release of pro-inflammatory NT and neuropeptides. (CGRP & Substance P)
- 5-HT1B activation to constrict cerebral and coronary arteries.
What is the ADME of Ergotamine?
- Poor oral bioavailability (F less than 1% due to extensive first pass metabolism)
- Sublingual also poor F.
- Rectal suppositories w/ caffeine.
What does the addition of caffeine to Ergotamine do?
Increase solubility to increase rate and extent of ergotamine absorption.
What are the side effects of Ergotamine?
- N&V (probably due to DA activity)
- Peripheral and probably cardiac vasoconstriction.
- Increased frequency of medication overuse migraines.
What are some complications of Ergots and related compounds?
- Severe HA due to rebound or withdrawal
- Retropentoneal fibrosis
- Gangrene
Characteristics of Dihydroergotamine (D.H.E. 45)
- Injectable (IV,IM,SC)
- Agonists at multiple 5-HT, DA, NE receptors.
- Oral F = 0.001-0.015
- Quite effective esp. IV,IM,SC
- Migranal (nasal spray)
- ALSO USED FOR MIGRAINE PROPHLYAXIS.
What are the contraindications of Ergots?
- Pregnancy category X.
- Peripheral vascular disorders.
- Severe HTN
- Coronary ischemic heart disease.
- Impaired hepatic or renal function.
- Sepsis.
Characteristics of Triptans?
- Structurally similar to 5-HT
- Highly selective 5-HT1 agonists, esp. 5-HT1D and 5-HT1B.
- Receptors located pre-juntionally on the peripheral and central ends of sensory trigeminal neurons and have NO vasoconstrictor action.
- Hyperpolarize nerve terminals, Inhibit trigeminal impulse.
What is the site of action for Triptans?
- Trigeminal nerve, outside the brain.
2. Early use helps block development of central sensitization symptoms.
Characteristics of Sumatriptan (Imitrex) PO?
- F=.14-.17 due to 1st pass of 80%
- 50-100mg onset of action 30-60 min, peak plasma 1-2 hr , 50-60% efficacy.
half life 1.7hr Duration 2hr.
Characteristics of Sumatriptan (Imitrex) SC?
- F= 0.97
- 6mg onset of action 10 min, peak plasma 12 min, 70% efficacy.
- Needle free injection (Sumavel) onset of action 10 min.
Characteristics of Sumatriptan (Imitrex) patch?
Single use, battery powered
5-20 mg
Onset of action 15 min.
What is Treximet?
85mg sumatriptan, 500 mg Naproxen
10 mg sumatriptan, 60 mg Naproxen.
What are the side effects of Sumatriptan?
- Subcutaneous injection site reactions.
2. Tightness in chest, throat tightening, coronary vasoconstriction. 5-HT1B agonist effect.
Which 2nd gen. Triptans have superior relief at 2 hours compared to Sumatriptan?
- Rizatriptan
2. Eletriptan
Which 2nd gen. Triptans have superior sustained freedom from pain?
- Rizatriptan
- Eletriptan
- Almotriptan
Which 2nd gen. Triptans have superior consistency of effect compared to sumatriptan?
- Risatriptan (++)
2. Almotriptan
What 2nd gen. Triptans have increased tolerability compared to sumatriptan?
- Naratriptan (++)
2. Almotriptan (++)
Characteristics of Zolmitiptan?
- Nasal spray
- 2.5 (up to5) mg at onset
- Equal F compared to oral tablet
- May repeat after 2hr. Not to exceed 10mg/24hr.
What are drug interactions of Triptans?
- Avoid concurrent use w/ other triptans & ergots.
- SSRIs cause serotonin syndrome
- MAOIs (within 2wks D/C) causes HTN
- All but Naratriptan.
What are cautions of Triptans?
- Should not be used in prego.
- Can cause strokes and MI in ppl w/ arteriosclerotic vascular diseases, high bp, coronary artery disease, and poorly controlled diabetes.
What are contraindications of Triptans?
- Ischemic coronary artery disease, stroke, TIAs.
- Cerebral & peripheral vascular disease.
- Uncontrolled HTN.
- Others w/ specific drugs.
What Beta Blockers are used for migraine prophylaxis?
- Propranolol (80-240 mg/d) and Timolol (20mg and up)
2. 50% of patients experience 50% efficacy = 25% therapeutic gain.
What is the MOA of Beta Blockers for Migraine prophylaxis?
- Unknown.
2. Does not correlate with beta blockade or intrinsic sympathetic activity.
What Antidepressants are used for Migraine Prophylaxis?
- Tricyclic Antidepressants.
- Amitryptyline (10-150mg/day –Only antidepressants conssistantly effective.
What is the MOA of antidepressants for Migraine Prophylaxis?
- Block NE & 5-HT re-uptake.
2. Migraine: Perhaps via interaction w/ 5-HT receptors.
What antiepileptic drugs are used for migraine prophylaxis?
Aberrant physiological state of abnormal neuronal heyperexcitability.
- Phenytoin (200-300mg/d)
- Valproic acid(250-1000mg/d)
- Topiramate (FDA approved)
- Gabapentinoids and Pregabalin
- All at anti-convulsant doses
What is done for Menstrual Migraine Prophylaxis?
- Naproxen (275 mg tid, start 3-7 days before and through menses)
- Hormonal manipulation w/ lowest dose estrogen oral contraceptives taken continuously
- Regular sleep, avoid migraine triggers, use relaxation techniques.
- PG migrainers (propranolol, verapamil, topiramate)
- NOT Valproate or Ergots.
Why are post-synaptic 5-HT2a receptor antagonists used for migraine prophylaxis?
- Block 5-HT induced temporal arterial vasoconstriction seen in early stage of migraine.
- 2a receptors mainly in temporal arteries.
Characteristics of Cyproheptadine (Periactin)?
- 5-HT2a antagonists and 5-HT1b agonist.
2. Latter may mediate its effects to constrict dilated blood vessels to reduce symptoms.
Characteristics of Methysergide (Sansert)?
- An ergot alkaloid, generally avoided due to side effects.
What are side effects of Methysergide?
- GI: reduce by gradual increase in dose.
- LSD like psychic disturbances
- Vasoconstriction
- Inflammatory fibrosis (w/ chronic Tx)
How is Botox for Migraine Prophylaxis used?
- FDA approved in pts. w/ adult chronic migraine who suffer HA on 15 or more d/mo, each lasting more than 4 hrs.
- 155 U, 31 injections into 7 muscle groups. q12wks
- NMJ blocker (10% therapeutic gain)
MOA of Memantine for Migraine Prophylaxis?
- A moderate affinity uncompetitive NMDA receptor antagonist, believed to work by competing w/ Mg in the synapse.
MOA of Ketamine for Migraine Prophylaxis?
- NMDA receptor antagonist.
2. Effective in 1/2 of patients to reduce disruptive aura.
How is Riboflavin used for Migraine prophylaxis?
- 400mg/d RDA 1.3f and 1.7m
2. Based on hypothesis that there is a mitochondrial energy deficit.
How is Magnesium used for migraine prophylaxis?
- 200-600 mg/d RDA 280f and 350m
2. Affects 5-HT receptors, NMDA receptors, NO synthesis and release.
How does Feverfew work?
- Decreases 5-HT release from platelets.
How does Butterbur work?
- An extract (Petasin) has anti-inflammatory & Vasodilatory properties.
- MOA could be Ca channel blockade and inhibition of lipoxygenase pathway.
What is the usual onset of a Cluster HA?
20-30 y/o. Peak 40-60.
When do cluster HA attacks occur?
- Occur nightly during early REM sleep.
- Brief 15-180 min
- Severe, Sharp, stabbing pain, unilateral, near/behind eye.
What is the treatment of cluster headaches?
- Mostly like migraines
- Inhaled 100% O2
- IV DHE45
- Sumatriptan
- Warfarin to an INR 1.5-1.9
What is the prophylaxis treatment of cluster HA?
- Avoid triggers like alcohol
- Valproate
- Topiramate
