Migraine: Drug Classification, Triptans, Prophylaxis & Pharmacotherapy

CLASSIFICATION OF DRUGS USED IN MIGRAINE

A. Acute / Abortive Treatment

1. Non-specific (Symptomatic) Agents

• Aspirin, Ibuprofen, Naproxen, Ketorolac, Indomethacin
• Acetaminophen (paracetamol)
• Used for mild-to-moderate attacks; first-step on the "stepped care" model

• Metoclopramide, Prochlorperazine, Chlorpromazine, Domperidone

• Codeine, Tramadol (last resort)

• Aspirin + Paracetamol + Caffeine (e.g., Excedrin)

2. Migraine-Specific Agents

• Ergotamine tartrate (oral, sublingual, suppository)
• Dihydroergotamine - DHE (IV, IM, intranasal)
• Act on 5-HT1, alpha-adrenergic, and dopamine receptors

• Lasmiditan (Reyvow) - oral; no vasoconstriction; Schedule V controlled substance

• Ubrogepant (Ubrelvy) - oral
• Rimegepant (Nurtec) - oral (also used for prevention)

B. Prophylactic (Preventive) Treatment

RATIONALE OF USING TRIPTANS IN MIGRAINE [5M]

1. Pathophysiological Basis

• Trigeminal activation: Pain signals from the intracranial vasculature travel via the trigeminal nerve (CN V). Activation of trigeminal nerve endings leads to release of vasoactive neuropeptides - substance P, neurokinin A, and calcitonin gene-related peptide (CGRP) - causing neurogenic inflammation and vasodilation of meningeal vessels.
• Trigeminovascular reflex: This creates a self-reinforcing cycle of pain transmission.
• Serotonin (5-HT) deficiency: During acute migraine attacks, 5-HT levels in the brain are reduced and urinary levels of its metabolite 5-HIAA rise, suggesting a serotonin "storm" at the onset. 5-HT1 receptor agonism is anti-nociceptive at multiple levels.

2. Mechanism of Action of Triptans

• 5-HT1B receptors are located on intracranial blood vessel smooth muscle (especially meningeal vessels).
• Triptans cause selective constriction of these dilated intracranial vessels, reducing the vasodilatory component of headache pain.
• Unlike ergotamines, they do not significantly constrict peripheral or coronary vessels at therapeutic doses.

• 5-HT1D receptors are located presynaptically on trigeminal nerve terminals.
• Triptan agonism inhibits the release of CGRP, substance P, and neurokinin A from these terminals.
• This blocks neurogenic inflammation in the dura mater - a key driver of migraine pain.

• Triptans penetrate the CNS and act on second-order neurons in the trigeminal nucleus caudalis (in the brainstem), inhibiting central pain transmission.
• This explains their effectiveness even during established migraine when peripheral sensitization is already occurring.

3. Summary of Triptan Actions

Meningeal vasodilation → Triptan (5-HT1B) → Vasoconstriction ✓
Neuropeptide release  → Triptan (5-HT1D) → Inhibited ✓
Central pain relay    → Triptan (CNS)     → Suppressed ✓

4. Clinical Pharmacology

• Sumatriptan is the prototype; 70% of patients get relief within 2 hours
• All triptans improve not just headache but also nausea, photophobia, phonophobia - confirming a central neurogenic mechanism
• Oral bioavailability is reduced during migraine attacks (due to gastric stasis); SC route is fastest and most reliable
• Dose-response: If one triptan fails, a different one may work (intra-class variation exists)
• Combined with an NSAID (e.g., sumatriptan + naproxen), efficacy is superior to either alone

5. Adverse Effects

• Tingling, flushing, heaviness or pressure sensation in head/neck/chest ("triptan sensations")
• Mild, transient rise in blood pressure
• Serotonin syndrome risk if combined with SSRIs/SNRIs or MAOIs
• Do not use within 24 hours of ergot alkaloids (risk of coronary ischemia)

6. Contraindications

• Ischemic heart disease, prior MI, coronary vasospasm (Prinzmetal angina)
• Uncontrolled hypertension
• Peripheral vascular disease
• History of stroke or TIA
• Hemiplegic or basilar-type migraine (risk of vasoconstriction in posterior circulation)
• Pregnancy

(1.1) PROPHYLAXIS OF MIGRAINE [3M]

Indications for Prophylaxis

1. Attacks occur 2 or more times per month (weekly or several times/month)
2. Attacks are prolonged (>48 hours), severely debilitating, or complicated by neurologic signs
3. Abortive therapy fails, is contraindicated, or causes medication-overuse headache
4. Patient preference

Drugs Used in Prophylaxis

• Propranolol (80-240 mg/day) and Metoprolol are most evidence-based
• Mechanism: uncertain; possibly central serotonin modulation, reduced neuronal excitability
• Contraindicated in asthma, depression, severe bradycardia, diabetes on insulin
• Note: Only beta-blockers without intrinsic sympathomimetic activity (ISA) are effective - propranolol, metoprolol, timolol, nadolol, atenolol. Pindolol (has ISA) is ineffective.

• Topiramate (25-100 mg/day) and Divalproex/Valproate (500-1500 mg/day) - first-line by all major guidelines (AAN/AHS)
• Topiramate: reduces CGRP, reduces cortical spreading depression
• Divalproex: enhances GABA, modulates sodium channels
• Valproate is teratogenic - avoid in women of childbearing age

• Amitriptyline 10-150 mg at night (also nortriptyline, imipramine)
• Benefit is independent of antidepressant effect (lower doses effective for migraine)
• Useful when comorbid depression or insomnia present

• Verapamil (80-160 mg TID) - useful especially in migraine with aura
• Flunarizine (not available in USA but used widely elsewhere)

• Venlafaxine - when comorbid anxiety/depression present

• Monoclonal antibodies against CGRP or its receptor (given monthly or quarterly SC/IV):
  • Erenumab (targets CGRP receptor)
  • Galcanezumab, Fremanezumab, Eptinezumab (target CGRP ligand)
• Reduce migraine frequency by ~50% in ~50% of patients; well tolerated; expensive
• Oral CGRP antagonists: Rimegepant (twice weekly), Atogepant (daily)

• Approved specifically for chronic migraine (>=15 headache days/month)
• 155-195 units IM to head and neck muscles every 12 weeks
• Inhibits trigeminal neuropeptide release from peripheral nerve terminals

Principles of Prophylactic Therapy

• Titrate slowly to minimum effective or maximum tolerated dose
• Adequate trial: maintain for at least 3 months; full benefit may take 6 months
• Reassess at 6-12 months of adequate control - consider gradual tapering
• Avoid medications with high teratogenic potential (valproate) in women of childbearing age
• Lifestyle measures alongside drugs: regular sleep, avoidance of known triggers (certain foods, alcohol, stress, hormonal changes), regular meals

(1.2) / (1.3) PHARMACOTHERAPY OF MIGRAINE [5M]

Overall Strategy: Stratified Care

I. Acute Attack Management

Step 1 - Mild-to-Moderate Attacks

• NSAIDs: Ibuprofen (400-800 mg), Naproxen sodium (500-1000 mg), Aspirin (900-1000 mg), Ketorolac (IM)
• Acetaminophen (1000 mg) - if NSAIDs contraindicated
• Combination OTC: Aspirin + acetaminophen + caffeine

Step 2 - Moderate-to-Severe Attacks (Migraine-Specific)

• Sumatriptan 50-100 mg oral (or 6 mg SC for rapid/severe attacks; intranasal 5-20 mg)
• If nausea/vomiting prominent: use SC, intranasal, or ODT formulations
• Combine with naproxen for superior efficacy

• Ergotamine tartrate 2 mg sublingual/oral at onset; repeat in 1 hour if needed (max 6 mg/attack, 10 mg/week)
• Dihydroergotamine (DHE): IV/IM/SC or intranasal - especially for severe attacks and status migrainosus
• Not used within 24 hours of triptans

• Lasmiditan 50-200 mg oral - for patients with cardiovascular contraindications to triptans; no vasoconstriction

• Ubrogepant 50-100 mg or Rimegepant 75 mg - for triptan-intolerant/contraindicated patients

Step 3 - Antiemetics (Adjunctive)

• Metoclopramide 10 mg oral/IV: relieves nausea and improves gastric motility (enhancing drug absorption)
• Prochlorperazine (10 mg oral, 25 mg rectal, IV) - also directly abortive for acute migraine
• Chlorpromazine 25-100 mg IM/IV - for refractory attacks in ED
• Domperidone - used in some countries; does not cross BBB (less CNS effects)

Parenteral / Emergency Management

• IV DHE + antiemetic
• IV prochlorperazine or chlorpromazine
• IV corticosteroids (dexamethasone 4-8 mg) - reduces recurrence
• IV valproate sodium
• Opioids (as last resort - opioid-sparing strategy preferred)

II. Preventive Therapy (see prophylaxis section above)

Summary Diagram

MIGRAINE ATTACK
      │
      ├─ MILD/MODERATE ──→ NSAIDs / Acetaminophen ± Antiemetic
      │
      └─ MODERATE/SEVERE ─→ TRIPTAN (1st line)
                              │
                         ─────┼───── + NSAID (combo)
                              │
                         If CI ──→ Lasmiditan / Gepants
                              │
                         ERGOTS (DHE) for severe/refractory
                              │
                         IV therapy for status migrainosus

PROPHYLAXIS (≥2 attacks/month):
  1st line: Propranolol / Topiramate / Amitriptyline
  Newer: CGRP mAbs (Erenumab) / OnabotulinumtoxinA