Pharmacotherapeutics of Migraine
1.
Definition
- Migraine is a recurrent neurological
disorder characterized by attacks of moderate-to-severe headache,
commonly associated with nausea, vomiting, and sensitivity to light and
sound.
- The headache is usually pulsating, often unilateral, and
aggravated by routine physical activity.
- Migraine attacks may occur with or without aura.
2. Classification of Migraine
A.
Migraine without aura
- Most common form.
- Headache occurs without preceding focal neurological symptoms.
- Usually lasts 4–72 hours if untreated or unsuccessfully
treated.
B.
Migraine with aura
- Neurological symptoms occur before or sometimes during the headache.
- Aura commonly consists of:
- Visual disturbances.
- Sensory symptoms.
- Speech disturbances.
- Visual aura is the most common.
C.
Chronic migraine
- Headache occurring on ≥15 days/month for >3 months, with
migraine features on at least 8 days/month.
3. Pathophysiology
The exact mechanism is complex, but the trigeminovascular
system plays a central role.
Sequence
Trigger
⬇️
Activation of trigeminal sensory pathways
⬇️
Release of neuropeptides, especially CGRP (calcitonin
gene-related peptide)
⬇️
Neurogenic inflammation and vasodilation
⬇️
Activation/sensitization of pain pathways
⬇️
Migraine headache
Important
mechanisms
- Activation of the trigeminal nerve.
- Release of CGRP and other neuropeptides.
- Sensitization of peripheral and central pain pathways.
- Changes in brainstem and cortical neuronal activity.
- Cortical spreading depression is strongly
associated with migraine aura.
Important
correction
Migraine is not simply a disorder of cerebral
vasodilation. Vascular changes are part of a more complex neuronal and
trigeminovascular process.
4. Common Migraine Triggers
- Stress and anxiety.
- Lack of sleep.
- Excessive sleep.
- Fasting or skipping meals.
- Dehydration.
- Bright or flashing lights.
- Strong smells.
- Hormonal changes, especially menstruation.
- Alcohol.
- Excessive caffeine or sudden caffeine withdrawal.
- Certain foods in susceptible individuals.
Memory
trick
“STRESS”
- S – Sleep disturbance
- T – Tension/stress
- R – Reduced food/fasting
- E – Environment/light/smell
- S – Substances such as alcohol/caffeine
- S – Sex/hormonal changes
5. Clinical Features
Migraine
headache
- Moderate-to-severe intensity.
- Usually unilateral but can be bilateral.
- Pulsating/throbbing character.
- Aggravated by routine physical activity.
- Duration commonly 4–72 hours.
Associated
symptoms
- Nausea.
- Vomiting.
- Photophobia.
- Phonophobia.
- Sometimes osmophobia.
- Fatigue.
- Difficulty concentrating.
6. Stages of a Migraine Attack
A migraine attack may have four phases.
1.
Prodrome
May occur hours to days before headache.
Symptoms:
- Mood changes.
- Fatigue.
- Yawning.
- Food cravings.
- Neck stiffness.
- Difficulty concentrating.
2.
Aura
Occurs in some patients.
Symptoms may include:
- Flashing lights.
- Zig-zag lines.
- Blind spots.
- Tingling or numbness.
- Speech difficulty.
3.
Headache
- Severe headache.
- Pulsating pain.
- Nausea/vomiting.
- Photophobia.
- Phonophobia.
4.
Postdrome
After the headache:
- Fatigue.
- Weakness.
- Difficulty concentrating.
- Mood changes.
Easy
sequence
Prodrome → Aura → Headache → Postdrome
7. Diagnosis
Migraine is primarily a clinical diagnosis.
Diagnosis is based on:
- Headache history.
- Duration.
- Frequency.
- Character and location of pain.
- Associated symptoms.
- Presence or absence of aura.
- Identification of triggers.
- Neurological examination.
Investigations
- Routine imaging is not required for typical migraine with a
normal neurological examination.
- MRI/CT may be considered when there are atypical features or
suspicion of another neurological disorder.
8. Goals of Pharmacotherapy
The major goals are:
- Rapidly relieve the acute headache.
- Relieve nausea and vomiting.
- Restore normal functioning.
- Prevent recurrence during the attack.
- Reduce frequency and severity of future attacks.
- Improve quality of life.
- Minimize adverse effects.
- Avoid medication-overuse headache.
9. Pharmacological Treatment
Migraine treatment has two major components:
A.
Acute/abortive treatment
Used during an attack.
Examples:
- NSAIDs.
- Paracetamol.
- Triptans.
- Gepants.
- Dihydroergotamine in selected situations.
- Antiemetics.
B.
Preventive treatment
Used regularly to reduce the frequency and severity of
attacks.
Examples:
- Beta blockers.
- Topiramate.
- Valproate.
- Amitriptyline.
- Candesartan.
- CGRP-targeting therapies.
- OnabotulinumtoxinA for chronic migraine.
10. Acute Treatment of Migraine
A.
NSAIDs
Examples:
- Ibuprofen.
- Naproxen.
- Diclofenac.
- Aspirin.
Mechanism
- Inhibit cyclooxygenase (COX).
- Reduce prostaglandin synthesis.
- Decrease pain and inflammation.
Uses
- Mild-to-moderate migraine.
- Can also be used in moderate attacks.
Adverse
effects
- Gastric irritation.
- Dyspepsia.
- GI ulceration/bleeding.
- Renal impairment.
- Fluid retention.
11. Paracetamol
Mechanism
- Produces analgesic and antipyretic effects through central
mechanisms.
Uses
- Mild-to-moderate migraine.
- Particularly useful when NSAIDs are unsuitable.
Adverse
effects
- Usually well tolerated at therapeutic doses.
- Hepatotoxicity with excessive doses.
12. Triptans
Examples
- Sumatriptan
- Rizatriptan.
- Zolmitriptan.
- Eletriptan.
- Naratriptan.
Mechanism
Triptans are selective 5-HT₁B/5-HT₁D receptor agonists.
They:
- Constrict certain cranial blood vessels.
- Inhibit trigeminal nerve activation.
- Decrease release of CGRP and other neuropeptides.
- Reduce neurogenic inflammation and pain transmission.
Important
memory trick
TRIPTANS → 5-HT₁B/₁D
Uses
- Moderate-to-severe acute migraine.
- Particularly useful when simple analgesics are ineffective.
Adverse
effects
- Tingling.
- Dizziness.
- Flushing.
- Chest/neck pressure or tightness.
- Paresthesia.
Contraindications/cautions
Because of vasoconstrictive effects, triptans should
generally be avoided in patients with:
- Ischemic heart disease.
- Previous myocardial infarction.
- Significant cerebrovascular disease.
- Certain peripheral vascular disorders.
- Uncontrolled hypertension.
13. Ergot Alkaloids
Example
- Ergotamine
- Dihydroergotamine.
Mechanism
- Act on multiple serotonin, adrenergic, and dopaminergic receptors.
- Produce cranial vasoconstriction and inhibit trigeminal neurogenic
inflammation.
Uses
- Acute migraine in selected patients.
Limitations
- More adverse effects and contraindications than triptans.
- Generally less preferred than modern therapies.
Adverse
effects
- Nausea.
- Vomiting.
- Paresthesia.
- Peripheral ischemia.
- Excessive vasoconstriction.
14. Antiemetics
Migraine commonly causes nausea and vomiting.
Examples:
- Metoclopramide
- Prochlorperazine.
- Domperidone in appropriate settings.
Metoclopramide
- Dopamine D₂ receptor antagonist.
- Reduces nausea and vomiting.
- Can also improve gastric emptying and enhance absorption of oral
migraine medicines.
Adverse
effects
- Drowsiness.
- Restlessness.
- Extrapyramidal reactions, particularly with higher exposure or
susceptible patients.
15. Newer Acute Migraine Drugs
A.
CGRP receptor antagonists — Gepants
Examples:
- Ubrogepant.
- Rimegepant.
- Zavegepant.
Mechanism
- Block CGRP receptors.
- Reduce CGRP-mediated migraine signaling.
Advantages
- Do not produce the vasoconstriction associated with triptans.
- Useful in selected patients who cannot take triptans.
B.
Lasmiditan
Mechanism
- Selective 5-HT₁F receptor agonist.
- Reduces trigeminal pain signaling without significant
vasoconstriction.
Important
adverse effect
- Dizziness.
- Sedation.
Important
counseling
- Patients should follow restrictions on driving/operating machinery
after taking it according to prescribing instructions.
16. Preventive Treatment of Migraine
Preventive therapy is considered when:
- Attacks are frequent.
- Attacks are disabling.
- Acute treatment is ineffective or poorly tolerated.
- Acute medicines are contraindicated.
- Medication-overuse headache is present.
- Patient preference favors prevention.
17. Beta Blockers
Important examples:
- Propranolol
- Metoprolol.
- Timolol.
Mechanism
The precise mechanism in migraine prevention is not
completely understood.
They may:
- Modulate adrenergic activity.
- Reduce neuronal excitability.
- Alter central pain pathways.
Uses
- Migraine prophylaxis.
Adverse
effects
- Bradycardia.
- Hypotension.
- Fatigue.
- Sleep disturbances.
- Bronchospasm.
Precaution
- Use cautiously or avoid nonselective beta blockers in patients with
asthma/bronchospastic disease.
18. Topiramate
Mechanism
Topiramate has multiple actions, including:
- Blockade of voltage-gated sodium channels.
- Enhancement of GABA-mediated inhibition.
- Reduction of excitatory glutamate activity.
- Inhibition of certain carbonic anhydrase isoenzymes.
Uses
- Migraine prevention.
- Also used as an antiepileptic drug.
Adverse
effects
- Paresthesia.
- Cognitive slowing.
- Weight loss.
- Fatigue.
- Kidney stones.
- Metabolic acidosis.
Important
pregnancy point
- Topiramate carries important fetal risks and should be avoided for
migraine prevention during pregnancy unless specifically directed under
specialist guidance.
19. Valproate
Mechanism
- Enhances GABA-mediated inhibition and reduces neuronal excitability
through multiple mechanisms.
Uses
- Migraine prophylaxis in selected patients.
Adverse
effects
- Weight gain.
- Tremor.
- Gastrointestinal effects.
- Hepatotoxicity.
- Thrombocytopenia.
- Pancreatitis.
Major
precaution
Valproate is highly teratogenic
and should generally be avoided for migraine prevention in pregnancy and in
people who could become pregnant unless there is no suitable alternative and
strict specialist precautions are followed.
20. Amitriptyline
Drug
class
- Tricyclic antidepressant.
Mechanism
- Inhibits reuptake of serotonin and norepinephrine.
- Modulates central pain pathways.
Uses
- Migraine prevention.
- Particularly useful when migraine is associated with insomnia or
depression.
Adverse
effects
- Sedation.
- Dry mouth.
- Constipation.
- Weight gain.
- Orthostatic hypotension.
- Anticholinergic effects.
21. Candesartan
Drug
class
- Angiotensin II receptor blocker (ARB).
Uses
- Migraine prevention in appropriate patients.
Adverse
effects
- Dizziness.
- Hypotension.
- Hyperkalemia.
Important
pregnancy point
- ARBs should be avoided during pregnancy.
22. CGRP-Targeted Preventive Therapy
Modern preventive therapies include:
Monoclonal
antibodies
- Erenumab.
- Fremanezumab.
- Galcanezumab.
- Eptinezumab.
Mechanism
They target the CGRP pathway by:
- Blocking the CGRP receptor, or
- Binding CGRP itself.
Advantages
- Specifically target an important migraine pathway.
- Useful for patients with frequent or disabling migraine.
Adverse
effects
Depending on the drug:
- Injection-site reactions.
- Constipation, particularly with erenumab.
- Hypersensitivity reactions.
23. OnabotulinumtoxinA
Use
- Mainly used for chronic migraine.
Mechanism
- Reduces release of neurotransmitters and neuropeptides involved in
peripheral pain signaling.
Administration
- Given by multiple injections at specific sites according to a
standardized regimen.
Adverse
effects
- Injection-site pain.
- Neck pain.
- Muscle weakness.
- Local discomfort.
24. Medication-Overuse Headache
Frequent use of acute migraine medicines can itself
contribute to chronic headache.
Common
offending drugs
- Triptans.
- Ergotamines.
- Opioids.
- Combination analgesics.
- Frequent NSAID/analgesic use.
Management
- Educate the patient.
- Reduce/withdraw the overused medication appropriately.
- Start preventive therapy when indicated.
- Establish a safer acute-treatment strategy.
Key
point
Overuse of acute medication → more headache → more
medication → further headache.
25. Non-Pharmacological Management
Important measures include:
- Maintain regular sleep.
- Avoid skipping meals.
- Maintain adequate hydration.
- Regular physical activity.
- Stress management.
- Relaxation techniques.
- Identify individual migraine triggers.
- Limit excessive caffeine.
- Maintain a headache diary.
Headache
diary records
- Date and time of attack.
- Duration.
- Severity.
- Possible trigger.
- Medication used.
- Response to treatment.
- Menstrual relationship when relevant.
26. Treatment Flowchart
Migraine attack
⬇️
Mild–moderate
attack
→ Paracetamol/NSAID
→ Add antiemetic if required
⬇️
Moderate–severe
attack or inadequate response
→ Triptan
⬇️
If triptan unsuitable/ineffective
→ Appropriate gepant or other alternative
Frequent/disabling
attacks
→ Consider preventive therapy
⬇️
Possible options:
→ Propranolol/metoprolol
→ Topiramate
→ Amitriptyline
→ Candesartan
→ CGRP-targeted therapy
→ OnabotulinumtoxinA for chronic migraine
⬇️
Monitor frequency, severity, adverse effects, and quality
of life
27. Key Exam Points
- Main neurotransmitter/peptide: CGRP.
- Major pathway: Trigeminovascular system.
- Migraine with aura: associated with cortical
spreading depression.
- First-line acute options: NSAIDs/appropriate analgesics
for mild attacks.
- Specific acute antimigraine drugs: Triptans.
- Triptan receptor: 5-HT₁B/5-HT₁D.
- Important triptan action: inhibits trigeminal activation
and CGRP release.
- Important preventive beta blocker: Propranolol.
- Important antiepileptic for prevention: Topiramate.
- Important newer pathway: CGRP.
- CGRP monoclonal antibodies: Erenumab, fremanezumab,
galcanezumab, eptinezumab.
- Chronic migraine: OnabotulinumtoxinA is an
important preventive option.
- Major problem from excessive acute medication: Medication-overuse headache.
28. High-Yield Memory Tricks
Acute
treatment
“N-T-G-A”
- N → NSAIDs
- T → Triptans
- G → Gepants
- A → Antiemetics
Preventive
treatment
“B-T-V-A-C”
- B → Beta blockers
- T → Topiramate
- V → Valproate
- A → Amitriptyline
- C → CGRP-targeted drugs
Triptans
“TRIPTAN = 5-HT₁B/₁D”
Migraine
pathway
Trigeminovascular activation → CGRP release → pain
29. One-Minute Revision
Migraine
→ Recurrent moderate/severe headache
→ Often pulsatile + nausea + photophobia/phonophobia
→ Trigeminovascular activation
→ ↑ CGRP
Acute
attack
→ Mild/moderate → NSAID/paracetamol
→ Moderate/severe → Triptan
→ Nausea → Metoclopramide/other antiemetic
→ Triptan unsuitable → CGRP antagonist (gepant) or
appropriate alternative
Prevention
→ Propranolol
→ Topiramate
→ Amitriptyline
→ Candesartan
→ CGRP monoclonal antibodies
→ Chronic migraine → OnabotulinumtoxinA
Remember for mcq questions