Pharmacotherapy of migraine

Pharmacotherapy of Migraine

Dr ManukumarPost graduate

Dept of PharmacologyVMMC & Safdarjung hospital

• Outline• Migraine • Pathophysiology

TheoriesVascular theoryNeurogenic theoryNeurovascular theory

• Acute treatment of migraine Non-specific treatmentSpecific treatment

• Preventive treatment of migraine• Newer targets and drugs

• Second most common type of primary headache• Migraine is chronic neurological disorder

characterized by episodic attacks of headache and associated symptoms.

• Migraine prevalence is approximately 18% in females and 6% in males.

• The brain of the migraineur is particularly sensitive to environmental and sensory stimuli.

First description of migraine with visual aura.

Migraine headache

• A recent economic model estimated that losses due to decreased productivity are roughly $1.9 million for a company with 10,000 employees

Pathophysiology of migraine

• Vascular theory-attributes the phenomenon of vasodilatation.

• Neurogenic theory- neuronal events, cortical spreading depression.

• Third theory - accommodate vascular modifications with neuronal dysfunction.

Vascular theory

• Harold G Wolff first one to explain• Vasoconstriction and ischemia accounts for

symptoms of migraine aura,• Reactive vasodilatation activate primary

sensory neurons.• Therapies provides evidence for this theory.

Cortical spreading depression• NMDA receptors involved in the genesis and propagation of

CSD. CSD was blocked by NMDA receptors antagonists in various experimental models

Long lasting depression of neuronal activity.

Cortical spreading depression

perivascular trigeminal and parasympathetic nerve activation, release of vasodilator mediators, CGRP, neurokinen A, substance P

(pain signal)trigeminal ganglion trigeminal nucleus caudalis trigeminocervical complex

General diagnostic criteria of migraine.

Pharmacological treatment of migraine includes

Acute (abortive) treatmentPreventive (prophylaxis) treatment

Goals for acute treatment

1. Treat attacks rapidly and consistently without recurrence.

2. Restore the patient’s ability to function. 3. Minimize the use of back-up and rescue

medications. 4. Be cost-effective for overall management.5. Have minimal or no adverse events.

Non-specific Rx of migraine“NSAIDs”

• PGE2 and PGI2 reduce the threshold to stimulation of nociceptors, causing peripheral sensitization

• CGRP release from the terminals of the trigeminal sensory neurons is modulated by PGE2

• Blockade cyclooxygenase (COX) and hence reduced synthesis of PG

Forest plot of comparison: Ibuprofen 400 mg versus placebo

• Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD008039

26% 12%

• Postgrad Med J 2004;80:720–723.

Anti-emetics/caffeine – combination with NSAIDs

• Metoclopramide effective for nausea and vomiting associated with certain types of headaches.

• D2 antagonistic action might be responsible for relieve of migraine

• Caffeine, Block the adenosine receptor, Vasoconstricting action.

Efficacy and Safety of Acetaminophen, Aspirin, and Caffeine in Alleviating Migraine Headache Pain: Double-blind,

Randomized, Placebo-Controlled Trials

• Arch Neurol. 1998;55(2):210-217

Specific acute treatment

• Triptan-Sumatriptan, naratriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan & frovatriptan

• Selective activity on 5-HT1B/1D agonist.• Mechanisms of action

Cranial vasoconstrictionModulating neurotransmitter release from

neuronal terminals.

• The triptans -preventing the peripheral release of vasoactive peptides (CGRP), reduce PPE.

• Also inhibit the abnormal activation of peripheral nociceptors.

• The 5-HT1D receptor-selective agonist PNU-142633 showed greater potency than sumatriptan in blocking electrically induced PPE, and had little to no detectable vascular activity in carotid, meningeal arteries

Adverse Effects and Contraindications

• coronary artery vasospasm, transient myocardial ischemia, atrial and ventricular arrhythmias, MI

• Irritation at the site of injection. The most common side effect of sumatriptan nasal spray is a bitter taste.

• Contraindicated- coronary artery disease , history of stroke or transient ischemic attacks, cerebrovascular or peripheral vascular disease,

• J Manag Care Pharm. 2005;11(5):394-402

Ergot alkaloids

• The pharmacological effects of the ergot alkaloids are varied and complex; partial agonists or antagonists at serotonergic, dopaminergic, and adrenergic receptors

• Ergot alkaloids at 5-HT1B/1D receptors likely mediate their acute anti-migraine effects

Selection of patients – ergot

• Which patients?Patients requiring migraine-specific therapyPatients established on ergotamine

• Special cases Patients with very long attacks Patients with frequent headache recurrence

Adverse Effects and Contraindications of Ergot Alkaloids

• Nausea and vomiting, due to a direct effect on CNS emetic center.

• contraindicated in pregnant, peripheral vascular disease, coronary artery disease, hypertension, impaired hepatic or renal function

• In contrast to triptans, the contractile effect of ergotamine in the human isolated coronary artery is long- lasting and persists even after repeated washings

• Comparison of vasoconstriction action of ergotamine and triptan

• MaassenVanDenBrink et al., 1998

Preventive treatment of

migraine

Indications

1. Two or more attacks per month that significantly interfere with the patient’s daily routine activity

2. An unsatisfactory response to acute therapy3. contraindication to acute treatments and

adverse effects (AEs) related to them.4. Uncommon migraine conditions, including

hemiplegic migraine, migraine with prolonged aura or migrainous infarction.

The potential mechanisms of migraine preventive medications

• Raising the threshold to migraine activation by stabilizing a more reactive nervous system

• Enhancing antinociception• Inhibiting CSD• Inhibiting peripheral and/or central

sensitization• Blocking neurogenic inflammation

Preventive medication

Antidepressants

• Amitriptyline alters the 5-HT synthetic rate at the dorsal raphe nucleus.

• Enhancement of the pain threshold produced by AMT seems to be mediated by sodium channels, L-type calcium channels inhibition.

• Chronic daily administration of AMT suppresses CSD, whereas acute treatment is ineffective.

50% reduction in migraine headaches TCA Vs placebo

Jackson, JE., et al. (2010). Tricyclic antidepressants and headaches: systematic review and meta-analysis. Bmj, 341(oct20 1)

• SSRI- In a recent review, SSRIs resulted as efficacious as placebo for preventing migraine and less effective than TCA.

• In a randomized controlled study fluoxetine, venlafaxine, duloxetine versus placebo, reduced frequency of migraine attacks, but not significant.

Beta blocker

• Clinical findings support the efficacy of propranolol, timolol, atenolol, nadolol and metoprolol in migraine preventive treatment.

• Exhibit high affinity for 5-HT receptor( 1a, 1b/d,2a)

• propranolol blocked CSD in rats, without altering regional cerebral blood flow and systemic arterial blood pressure

Cont…

• 53 studies including meta-analysis involving 2403 patients who are treated with either propranolol and/or placebo , propranolol yielded 44% reduction in migraine attack.

• Two clinical trials valproic acid compared with propranolol, in both trials efficacy is identical.

Anti-epileptics

• An unbalanced activity b/w excitatory glutamatergic transmission and GABAnergic inhibition, abnormal activation of voltage-operated ionic channels; Na , Ca channels , has been postulated in these two pathological condition.

• “Valproate, topiramate”, gabapentin, lamotrigine are best for prophylaxis.

Cont..• VPA, TPM, Effect on voltage gated Na channels

modify the neuronal excitability(CSD), role of Na channels are proved in FHM.

• VPA reduces the neurogenic inflammation, plasma extravasation (Cutrer et al., 1997), possibly through a GABA-mediated mechanism

Calcium channel blockers

• In an experimental model of neurogenic inflammation, blockade of L-type channels attenuates dural vasodilatation.

• flunarizine could exert its antimigraine effect by reducing neural NO synthase (NOS) activity

• In a double- blind study, flunarizine 5 mg/day was as effective as propranolol 160 mg/day in reducing the attack frequency.

Newer targets and drugs

• Non-triptan 5-HT1 agonist, 5-HT1D agonists (PNU-109291 and PNU- 142633)

are potent inhibitors of dural plasma protein extravasation (PPE)

LY334370, which is a selective 5-HT1F agonist, inhibits single cell firing in the trigeminal nucleus caudalis (TNC)

CGRP antagonist-BIBN4096BS(olcegapant)

• CGRP mediates dilation of cerebral vasculature and increases in cerebral blood flow.

• CGRP-induced vasodilation can activate nociceptors on cerebral vessels.

• In humans, intravenous human CGRP administration induces migraine-like headache in susceptible migraineurs

CGRP Antagonist BIBN 4096 BS(olcegapant) Vs placebo

• N Engl J Med. 2004 Mar 11;350(11):1104-10

Nitric oxide synthase inhibitor

• An intravenous infusion of nitroglycerin (NTG) releases NO, causes migraine in more than 60% of migraineurs , and activates trigeminal neurons in experimental animals.

• In a small RCT, 546C88, a non-selective NOS inhibitor, was administered intravenoulsy to migraineurs during an acute attack (Lassen et al., 1998). The 2-hr headache response rate was 67% (10/15) on 546C88 versus 14% (2/14) on placebo

compound Treatment class Clinical phase

Telcagepant [MK0974)-

CGRP receptor antagonist Phase 111

Olcegepant [BIBN4096BS)- CGRP receptor antagonist phase II

B144370- CGRP receptor antagonist phase II

Lasmiditan 5-HT 1F receptor agonist Phase 111

Tezampanel (LY-293558) AMPA and kainate receptor antagonist phase 111