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Tuesday, August 19, 2025

Antimigraine agents


Introduction

Migraine is a complex neurological disorder characterized by recurrent attacks of moderate-to-severe headache, often accompanied by nausea, vomiting, and heightened sensitivity to light (photophobia) or sound (phonophobia). It is a major cause of disability worldwide, impacting quality of life and productivity. Migraines are classified into different subtypes, including migraine without aura, migraine with aura, chronic migraine, and other less common variants such as hemiplegic migraine or vestibular migraine.

The treatment of migraine has advanced significantly over the past decades. Historically, therapy was limited to non-specific analgesics and ergot alkaloids. Today, treatment encompasses a broad range of targeted antimigraine agents, including serotonin receptor agonists (triptans), CGRP (calcitonin gene-related peptide) antagonists, gepants, ditans, and preventive agents such as beta-blockers, antiepileptics, and monoclonal antibodies.


Pathophysiology of Migraine

Migraine pathophysiology involves multiple interconnected mechanisms:

  • Neurovascular hypothesis: Activation of the trigeminovascular system leads to the release of vasoactive peptides (e.g., CGRP, substance P, neurokinin A), causing vasodilation and neurogenic inflammation in cerebral blood vessels.

  • Serotonergic involvement: Fluctuations in serotonin (5-HT) levels modulate pain pathways and vascular tone.

  • Cortical spreading depression: A wave of neuronal and glial depolarization propagates across the cortex, associated with aura phenomena.

  • Central sensitization: Repeated attacks lead to sensitization of central pain pathways, making patients more prone to chronic migraine.

Because of these diverse mechanisms, antimigraine therapy involves both acute treatments (to abort attacks) and preventive treatments (to reduce frequency and severity).

Classification of Antimigraine Agents

Antimigraine drugs are classified into two major categories:

  1. Abortive (Acute) Therapies – used to stop a migraine attack once it has begun.

  2. Preventive (Prophylactic) Therapies – used regularly to reduce attack frequency, severity, and disability.

1. Abortive (Acute) Antimigraine Agents

A. Non-Specific Analgesics

These remain first-line therapy for mild to moderate migraine attacks.

  • NSAIDs (Nonsteroidal Anti-Inflammatory Drugs):

    • Generic names: ibuprofen, naproxen, diclofenac, ketorolac, indomethacin.

    • Mechanism: Inhibit cyclooxygenase (COX), blocking prostaglandin synthesis and reducing inflammation and pain.

    • Adverse effects: Gastrointestinal irritation, ulceration, renal impairment, cardiovascular risks.

    • Drug interactions: Anticoagulants (increased bleeding risk), corticosteroids (increased ulcer risk).

  • Acetaminophen (Paracetamol):

    • Used for mild attacks or in combination with other drugs.

  • Combination Analgesics:

    • Aspirin + acetaminophen + caffeine (synergistic effect).

    • Risks: overuse can cause medication-overuse headache (MOH).

B. Triptans (Selective 5-HT1B/1D Agonists)

These are the cornerstone of migraine-specific acute therapy.

  • Generic names: sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, eletriptan.

  • Mechanism of action:

    • 5-HT1B receptor agonism → vasoconstriction of dilated cranial blood vessels.

    • 5-HT1D receptor agonism → inhibition of CGRP release from trigeminal neurons.

  • Administration: Oral, subcutaneous, intranasal formulations.

  • Adverse effects: Chest tightness, paresthesia, flushing, dizziness, fatigue.

  • Contraindications: Coronary artery disease, uncontrolled hypertension, cerebrovascular disease (due to vasoconstrictive effects).

  • Drug interactions: SSRIs, SNRIs, MAO inhibitors (risk of serotonin syndrome).

C. Ergot Alkaloids

Older antimigraine drugs, now less favored due to safety concerns.

  • Generic names: ergotamine, dihydroergotamine.

  • Mechanism: Non-selective serotonin receptor agonists (5-HT1), alpha-adrenergic agonists, and dopaminergic agonists. Cause vasoconstriction and inhibit trigeminal neuropeptide release.

  • Adverse effects: Nausea, vomiting, ergotism (vasospasm, ischemia, gangrene).

  • Contraindications: Pregnancy, peripheral vascular disease, coronary artery disease.

D. CGRP Receptor Antagonists (Gepants)

A new class of orally administered acute antimigraine drugs.

  • Generic names: ubrogepant, rimegepant, atogepant (also approved for prevention).

  • Mechanism: Block CGRP receptors, preventing vasodilation and neurogenic inflammation.

  • Advantages: No vasoconstriction → safer for patients with cardiovascular disease.

  • Adverse effects: Nausea, somnolence, mild hepatic enzyme elevation.

E. Ditans (5-HT1F Agonists)

Latest addition to acute antimigraine therapy.

  • Generic name: lasmiditan.

  • Mechanism: Selective 5-HT1F agonist → inhibits trigeminal nociceptive transmission without vasoconstriction.

  • Adverse effects: Dizziness, sedation, driving impairment (patients advised not to drive for 8 hours post-dose).

2. Preventive (Prophylactic) Antimigraine Agents

Preventive therapy is recommended for patients with ≥4 migraine days per month, severe attacks despite acute therapy, contraindications to acute drugs, or risk of medication-overuse headache.

A. Beta-Adrenergic Blockers

Most widely used prophylactic agents.

  • Generic names: propranolol, metoprolol, timolol, atenolol, nadolol.

  • Mechanism: Modulate adrenergic tone, stabilize vascular reactivity, and reduce cortical hyperexcitability.

  • Adverse effects: Bradycardia, hypotension, fatigue, depression, sexual dysfunction.

  • Contraindications: Asthma, COPD, bradyarrhythmias.

B. Antiepileptic Drugs (AEDs)

Effective for migraine prevention by stabilizing neuronal excitability.

  • Generic names: valproate (valproic acid, divalproex sodium), topiramate.

  • Mechanisms:

    • Valproate: enhances GABA activity, blocks sodium/calcium channels.

    • Topiramate: blocks sodium channels, enhances GABA activity, antagonizes AMPA/kainate receptors.

  • Adverse effects:

    • Valproate: hepatotoxicity, teratogenicity, weight gain.

    • Topiramate: cognitive impairment, weight loss, paresthesia, kidney stones.

C. Antidepressants

Certain classes provide dual benefit in migraine and comorbid depression/anxiety.

  • Tricyclic Antidepressants (TCAs):

    • Generic name: amitriptyline, nortriptyline.

    • Mechanism: serotonin and norepinephrine reuptake inhibition, central pain modulation.

  • SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):

    • Generic name: venlafaxine, duloxetine.

D. Calcium Channel Blockers

Particularly useful in migraine with aura.

  • Generic name: verapamil, flunarizine (not available in all countries).

  • Mechanism: Prevent calcium influx, reducing neuronal excitability and vascular reactivity.

E. CGRP Monoclonal Antibodies

Revolutionary preventive therapy targeting CGRP pathway.

  • Generic names: erenumab (CGRP receptor antibody), fremanezumab, galcanezumab, eptinezumab (target CGRP ligand).

  • Mechanism: Block CGRP or its receptor, preventing vasodilation and neurogenic inflammation.

  • Administration: Monthly subcutaneous injection (erenumab, fremanezumab, galcanezumab) or quarterly intravenous infusion (eptinezumab).

  • Advantages: High efficacy, good tolerability, no major cardiovascular risk.

  • Adverse effects: Constipation (erenumab), injection site reactions.

F. OnabotulinumtoxinA (Botox)

Approved for chronic migraine (≥15 headache days/month).

  • Mechanism: Inhibits release of neurotransmitters and neuropeptides involved in pain signaling.

  • Administration: Multiple intramuscular injections every 12 weeks.

3. Non-Pharmacological Measures

While drug therapy is central, lifestyle modifications play a supportive role:

  • Adequate sleep, regular meals, hydration.

  • Avoidance of triggers (stress, alcohol, certain foods).

  • Cognitive-behavioral therapy, biofeedback, relaxation techniques.

Adverse Effects and Precautions

  • Medication Overuse Headache (MOH): Overuse of acute antimigraine medications (triptans, NSAIDs, ergot derivatives) paradoxically increases headache frequency.

  • Pregnancy considerations:

    • NSAIDs avoided in third trimester.

    • Triptans may be used with caution (sumatriptan preferred).

    • Valproate and topiramate contraindicated due to teratogenicity.

Drug Interactions (Selected)

  • Triptans + SSRIs/SNRIs → serotonin syndrome risk.

  • Ergot alkaloids + macrolides/protease inhibitors → severe vasospasm due to CYP3A4 inhibition.

  • Beta-blockers + verapamil/diltiazem → risk of bradycardia and heart block.

  • Valproate + lamotrigine → increased lamotrigine toxicity.

Future Directions in Antimigraine Therapy

  • Small-molecule CGRP antagonists (second-generation gepants) with longer half-lives.

  • Neuromodulation devices (transcranial magnetic stimulation, vagus nerve stimulation).

  • Precision medicine approaches targeting genetic and biomarker-driven subtypes of migraine.




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