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Pharmaceutical Options for Migraine Prevention

Posted on May 19 2025, By: Cerebral Torque

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Pharmaceutical Options for Migraine Prevention

A comprehensive guide to medication classes, efficacy, dosing, and considerations for personalized preventive treatment
Updated May 2025
Quick Navigation - Pharmaceutical Migraine Prevention Complete Guide
Understanding Migraine Prevention First-Line Preventive Medications Second-Line Preventive Medications Combination Therapy CGRP Antagonists in Detail Head-to-Head Comparisons Principles of Preventive Treatment Special Populations Treatment Failure & Next Steps Uncommon & Emerging Medications Investigational Treatments Monitoring Recommendations Personalizing Treatment

Understanding Migraine Prevention

Pharmaceutical preventive treatments aim to reduce the frequency, severity, and duration of migraine attacks, improve responsiveness to acute treatments, and prevent progression from episodic to chronic migraine.

Some Key Indications for Preventive Treatment

  • Frequent or long-lasting migraine attacks (typically ≥4 headache days per month)
  • Significant disability or diminished quality of life despite appropriate acute treatment
  • Contraindication to or failure of acute therapies
  • Risk of medication overuse/adaptation headache from acute medications
  • Certain migraine patterns, such as hemiplegic migraine or migraine with brainstem aura

When selecting a preventive medication, comorbid conditions, potential adverse effects, medication cost, and patient preferences should all be taken into account. Most preventive medications require 2-3 months at an optimal dose to determine effectiveness, but it depends on the medications and comorbid conditions like depression/anxiety or obesity.

First-Line Preventive Medications for Migraine

These medications have established efficacy and are commonly recommended as initial options for migraine prevention.

Drug Class Specific Medications Dosing Considerations
Beta Blockers Propranolol Metoprolol Timolol Atenolol (probable efficacy) Nadolol (probable efficacy)
  • Propranolol: 40-240 mg daily in divided doses
  • Metoprolol: 50-200 mg daily in divided doses
  • Timolol: 10-30 mg daily in divided doses
  • Atenolol: 25-100 mg once daily
  • Nadolol: 20-240 mg once daily
 Favorable: Hypertension, cardiovascular conditions Avoid in: Asthma, COPD, depression, diabetes, Raynaud's phenomenon

Propranolol is likely to cause weight gain. Metoprolol is also effective and cardioselective. Common side effects include fatigue, dizziness, sleep disturbances, and sexual dysfunction. Not recommended for smokers or adults over 60 years old.

Antidepressants Amitriptyline (TCA) Venlafaxine (SNRI)
  • Amitriptyline: Starting at 10 mg at bedtime; range 10-100 mg at bedtime
  • Venlafaxine: Starting at 37.5 mg once daily; range 75-150 mg once daily
 Favorable: Depression, anxiety, insomnia, neuropathic pain Avoid in: Cardiac conduction disorders, suicidality risk, narrow-angle glaucoma

Amitriptyline has anticholinergic effects including dry mouth, constipation, and urinary retention. Venlafaxine may cause hypertension, insomnia, and has withdrawal symptoms if discontinued abruptly.
Anticonvulsants Topiramate Valproate (contraindicated in women of childbearing potential)
  • Topiramate: Starting at 25 mg daily; titrate by 25 mg weekly to target of 100 mg daily in divided doses (range 50-200 mg daily)
  • Valproate: 500-1500 mg daily
 Favorable: Concurrent epilepsy; topiramate for patients with obesity Avoid in: Pregnancy, kidney stones, glaucoma, cognitive impairment

Topiramate side effects include paresthesias, cognitive impairment, metabolic acidosis, kidney stones, and weight loss. Valproate may cause weight gain, hair loss, and tremor. Valproate is teratogenic and contraindicated in women of childbearing potential.
CGRP Antagonists Monoclonal Antibodies:
  • Erenumab
  • Fremanezumab
  • Galcanezumab
  • Eptinezumab
Small Molecules:
  • Rimegepant
  • Atogepant
  • Erenumab: 70-140 mg SC monthly
  • Fremanezumab: 225 mg SC monthly or 675 mg SC quarterly
  • Galcanezumab: 120 mg SC monthly (after 240 mg loading dose)
  • Eptinezumab: 100-300 mg IV quarterly
  • Rimegepant: 75 mg orally every other day
  • Atogepant: 10-60 mg orally once daily
 Favorable: Patients who failed other preventives, those preferring infrequent dosing Avoid in: Cardiovascular/cerebrovascular disease, pregnancy (?), hypertension

These newer options generally have fewer side effects than traditional preventives. Common side effects include injection site reactions and constipation (monoclonal antibodies) or nausea and abdominal pain (small molecules). Hair loss has also been associated with this class. High cost may limit access.

Second-Line Preventive Medications

When first-line medications are ineffective, contraindicated, or not tolerated, the following alternatives may be considered. These medications have varying levels of evidence supporting their use in migraine prevention.

Drug Class Specific Medications Dosing Considerations
Other Tricyclic Antidepressants Nortriptyline Protriptyline Doxepin
  • Nortriptyline: Starting at 10 mg at bedtime; range 10-75 mg at bedtime
  • Protriptyline: Starting at 5 mg daily; range 5-30 mg daily in divided doses
  • Doxepin: Starting at 10 mg at bedtime; range 10-75 mg at bedtime
 Favorable: Depression, anxiety, insomnia, neuropathic pain Avoid in: Cardiac conduction disorders, suicidality risk, narrow-angle glaucoma

Nortriptyline has fewer anticholinergic side effects than amitriptyline, making it better tolerated by many patients while maintaining efficacy. May be a good option for patients who experienced dry mouth, constipation, or urinary retention with amitriptyline. Protriptyline is less sedating but more activating than other TCAs. All TCAs may cause weight gain, orthostatic hypotension, and prolonged QT interval.
Calcium Channel Blockers Verapamil Flunarizine (not available in US)
  • Verapamil: 120-480 mg daily in divided doses
  • Flunarizine: 5-10 mg daily
 Favorable: Hypertension in smokers or elderly patients, Raynaud's phenomenon Concerns: Tolerance may develop, constipation, edema

Evidence for verapamil is limited. Flunarizine is more widely studied outside the US. Be alert for development of tolerance after 8 weeks of treatment.
ACE Inhibitors/ARBs Lisinopril Candesartan
  • Lisinopril: 10-20 mg once daily
  • Candesartan: 16 mg once daily
 Favorable: Hypertension Avoid in: Pregnancy, renal artery stenosis

Limited evidence from small studies. Side effects include cough (ACE inhibitors although ARBs may also cause this), dizziness, and hypotension. Contraindicated in pregnancy.
Other Anticonvulsants Gabapentin
  • Gabapentin: 900-2400 mg daily in divided doses
 Favorable: Comorbid pain conditions, sleep disturbances Concerns: Sedation, dizziness, edema

Evidence for migraine prevention is limited. Better supported for other pain syndromes. Side effects include sedation, dizziness, and weight gain.
NSAIDs Naproxen
  • Naproxen: 500-1100 mg daily in divided doses
 Favorable: Short-term use, menstrual migraine Avoid in: GI disorders, renal disease, cardiovascular disease

Primarily used for short-term prevention or menstrual migraine. Long-term use limited by GI, renal, and cardiovascular risks.

Combination Therapy for Migraine Prevention

Combination treatments for migraine prevention present a promising approach for addressing the diverse and complex mechanisms underlying migraine pathophysiology. Recent research suggests that combining medications with different mechanisms of action may enhance efficacy in patients who don't respond adequately to monotherapy.

Key Combination Approaches

  • Dual CGRP Pathway Targeting: Combining CGRP monoclonal antibodies with gepants may enhance efficacy by targeting both the CGRP peptide and its receptor through their distinct molecular sizes and mechanisms.
  • OnabotulinumtoxinA and CGRP Treatments: This combination offers synergistic pain relief by inhibiting different components of the trigeminovascular system. OnabotulinumtoxinA primarily works on C-fibers while CGRP-targeted therapies affect Aδ-fibers.
  • Oral Non-CGRP Treatments: Combining conventional preventives (antihypertensives, anticonvulsants, antidepressants) provides an affordable option that may address comorbid conditions simultaneously.

Practical Considerations for Combination Therapy

Despite promising results, several factors should be considered when implementing combination treatments:

  • Cost Concerns: High costs of certain combinations (e.g., OnabotulinumtoxinA with CGRP monoclonal antibodies) may limit accessibility.
  • Drug-Drug Interactions: Gepants are metabolized by CYP3A4, potentially interacting with other medications sharing this pathway (e.g., topiramate).
  • Dosing Strategies: "Start low, go slow" dosing may be particularly important when combining treatments to minimize adverse effects.
  • Patient Selection: Combination therapy may be most appropriate for patients with treatment-resistant migraine or those with specific comorbidities.
While current guidelines largely overlook combination therapy, exploring the balance between potential benefits and risks is relevant for developing more effective, individualized treatment approaches for patients with difficult-to-treat migraine.

CGRP Antagonists in Detail

The development of CGRP antagonists represents a major advancement in migraine prevention. These medications target the calcitonin gene-related peptide pathway, which plays a key role in migraine pathophysiology.

CGRP Monoclonal Antibodies
Erenumab (Aimovig) CGRP Receptor Antagonist
Fremanezumab (Ajovy) CGRP Ligand Antagonist
Galcanezumab (Emgality) CGRP Ligand Antagonist
Eptinezumab (Vyepti) CGRP Ligand Antagonist
Small Molecule CGRP Antagonists
Rimegepant (Nurtec ODT) CGRP Receptor Antagonist
Atogepant (Qulipta) CGRP Receptor Antagonist

Advantages of CGRP Antagonists

  • Specifically target migraine pathophysiology
  • Generally well-tolerated with fewer side effects than traditional preventives
  • Convenient dosing schedules (monthly/quarterly injections or daily/every other day oral options)
  • Effective for patients who have failed multiple traditional preventives
  • May provide earlier and more sustained benefit than other preventive agents

Special Considerations for CGRP Antagonists

Despite their advantages, CGRP antagonists have limitations to consider:

  • Cardiovascular Safety: CGRP has theoretical cardioprotective effects. Patients with recent cardiovascular or cerebrovascular events were excluded from clinical trials.
  • Pregnancy: Limited data available; generally not recommended during pregnancy.
  • Hypertension: Cases of new or worsening hypertension have been reported, particularly with erenumab.
  • Cost: These newer agents are typically more expensive than traditional preventives and may have insurance restrictions.
  • Drug Interactions: Small molecule CGRP antagonists (rimegepant, atogepant) have significant interactions with CYP3A4 inhibitors and inducers.

Head-to-Head Comparisons of Preventive Treatments

One of the challenges in choosing a preventive medication for migraine is determining which treatment might be most effective for a particular patient. While there are numerous studies comparing preventive medications to placebo, direct head-to-head comparisons between active treatments are relatively rare. These comparative studies provide valuable information for clinicians making treatment decisions.

Based on the evidence-based guidelines developed by the Italian Society for the Study of Headache (SISC) and the International Headache Society (IHS), several important head-to-head comparisons have been evaluated:

Drug Comparison Superior Treatment Quality of Evidence Strength of Recommendation
Erenumab (70-140 mg/4 weeks) vs.
Topiramate (up to 100 mg daily)

Erenumab showed greater efficacy and better tolerability

 Low Strong
Topiramate (50 mg daily) vs.
Propranolol (80 mg daily)

Topiramate demonstrated better results

 Very low Weak
Flunarizine (10 mg daily) vs.
Metoprolol (200 mg daily)

Flunarizine outperformed metoprolol

 Low Weak
Metoprolol (200 mg daily) vs.
Acetylsalicylic acid (300 mg daily)

Metoprolol demonstrated superior efficacy

 Very low Weak

Clinical Implications of Head-to-Head Studies

  • CGRP Pathway Medications: The strong recommendation for erenumab over topiramate suggests that CGRP-targeting therapies may offer advantages over traditional preventives, particularly for patients who have not responded well to or cannot tolerate conventional options.
  • Medication Selection: When selecting between different medication classes, these comparative studies can help guide treatment decisions, though the generally low quality of evidence highlights the need for more robust head-to-head trials.
  • Personalized Approach: Despite these comparisons, treatment should be individualized based on patient comorbidities, preferences, tolerability, and access considerations.
  • Research Gaps: The limited number of high-quality comparative studies underscores the need for more direct comparisons, particularly between newer agents and established preventives.
The head-to-head comparison between erenumab and topiramate represents a significant advance in our understanding of relative efficacy between traditional and newer preventive options. This comparison provides clinicians with evidence-based guidance when choosing between medication classes.

Principles of Preventive Treatment

50%
Reduction in Migraine
Target response for successful prevention is traditionally a 50% reduction in migraine frequency. However, new guidance has been proposed as a 50% reduction can still leave patients in chronic or disabling territory
2-3
Months
Typical time needed to evaluate medication efficacy at an optimal dose
6-12
Months
Duration of successful preventive treatment before considering tapering

Successful migraine prevention requires a methodical approach. The following principles can help improve outcomes and adherence:

  • Start Low, Go Slow: Begin with low doses and titrate gradually to minimize side effects and optimize tolerability.
  • Allow Adequate Trial: Most preventive medications require 2-3 months at an optimal dose to determine effectiveness. In some cases, it may take up to 6-12 months to determine effectiveness.
  • Set Realistic Expectations: The goal is not complete elimination of migraine, but a significant reduction in frequency and severity.
  • Address Comorbidities: Choose medications that may also benefit comorbid conditions (e.g., antidepressants for concurrent depression). Furthermore, addressing comorbid conditions may also allow migraine to respond more effectively to treatment and decrease migraine progression.
  • Monitor Medication Overuse/Adaptation: Patients with medication adaptation headache have reduced efficacy of preventives.
For patients who don't respond to initial prevention therapy, consider switching to a medication from a different class rather than adding a second agent. If patients have a partial response, adding a second preventive medication from a different class may be beneficial.

Special Populations and Considerations

Women of Childbearing Potential

Medication selection requires careful consideration of teratogenic risk and contraception needs:

  • Avoid valproate: Contraindicated due to high teratogenic risk and associated with decreased IQ in exposed children.
  • Caution with topiramate: Associated with increased risk of oral clefts and low birth weight when used during pregnancy.
  • Beta blockers: Relative safety during pregnancy but may be associated with intrauterine growth restriction and neonatal bradycardia.
  • CGRP antagonists: Limited safety data during pregnancy; generally not recommended.
  • Consider non-pharmacological approaches: Behavioral interventions, biofeedback, and lifestyle modifications may be preferable during pregnancy planning.
Elderly Patients

Age-related changes affect treatment decisions:

  • Avoid beta blockers: Generally not recommended as first-line in patients over 60 years due to increased cardiovascular risk.
  • Use caution with antidepressants: Increased sensitivity to anticholinergic effects and sedation; start with lower doses.
  • Consider verapamil or ACE inhibitors/ARBs: May be preferred for those with hypertension.
  • Monitor for drug interactions: Polypharmacy is common in older adults; check for potential interactions.
Menstrual Migraine

For predictable perimenstrual migraine attacks:

  • Short-term prevention: NSAIDs or triptans started 2 days before expected onset of menstruation and continued for 5-7 days.
  • Hormonal options: Extended-cycle or continuous hormonal contraceptives to minimize hormone fluctuations.
  • Standard preventives: Traditional preventive medications may be less effective for pure menstrual migraine.

Treatment Failure and Next Steps

Despite appropriate preventive treatment, some patients continue to experience significant migraine burden. Several approaches may be considered for treatment-resistant cases:

Strategies for Treatment-Resistant Migraine

  • Switch to different class: If ineffective response after 2-3 months at optimal dose, try a medication from a different class.
  • Combination therapy: For partial responders, consider adding a second preventive from a different class.
  • CGRP antagonists: Clinical trials show efficacy in patients that have failed traditional medications.
  • Onabotulinumtoxin A (Botox): Consider for patients whose migraine has evolved to chronic migraine (≥15 headache days per month).
  • Neuromodulation devices: More on this here.
  • Referral to headache center: Complex cases benefit from specialized care at a dedicated headache center.

Common Reasons for Treatment Failure

  • Inadequate dosing or duration: Not reaching therapeutic dose or not continuing treatment long enough to see benefit.
  • Medication overuse/adaptation headache: Frequent use of acute medications (≥10-15 days/month) interfering with preventive effectiveness.
  • Misdiagnosis: The underlying headache disorder may not be migraine or may be a secondary headache.
  • Unrealistic expectations: Expecting complete elimination of headaches rather than reduction.
  • Poor adherence: Side effects or complex dosing regimens leading to inconsistent medication use.

Uncommon and Emerging Preventive Medications

Beyond the well-established preventive medications, numerous other agents have been investigated or used off-label for migraine prevention. Many of these medications have limited evidence, but may be considered in specific clinical scenarios when first-line options are ineffective, contraindicated, or poorly tolerated.

Antidepressants Beyond Amitriptyline and Venlafaxine
SNRIs: Duloxetine, Desvenlafaxine, Milnacipran Limited Evidence

While venlafaxine (SNRI) has demonstrated efficacy in migraine prevention, evidence for other serotonin-norepinephrine reuptake inhibitors is less robust. Duloxetine (60-120 mg daily) may be beneficial in patients with comorbid depression, anxiety, or pain disorders. Desvenlafaxine and milnacipran (best for comorbid fibromyalgia) have insufficient evidence for routine use but may be considered when other SNRIs are not tolerated.

SSRIs: Fluoxetine, Fluvoxamine Less Effective

Selective serotonin reuptake inhibitors generally show less efficacy than SNRIs or tricyclic antidepressants for migraine prevention. In some studies, they have shown to be similar to placebo.

Other Antidepressants: Mirtazapine (Tetracyclic), Desipramine (TCA), Doxepin (TCA) Case Reports

Mirtazapine (15-30 mg at bedtime) may help patients with comorbid depression and sleep disturbances. Tricyclics beyond amitriptyline, such as desipramine and doxepin, have less evidence but similar mechanisms of action and may be alternatives when amitriptyline is not tolerated.

MAOIs: Phenelzine Last Resort

Monoamine oxidase inhibitors such as phenelzine have shown efficacy in treatment-resistant cases but significant dietary restrictions and potential serious drug interactions limit their use to specialists in refractory cases.

Additional Anticonvulsants
Lamotrigine For Aura

Despite limited efficacy for migraine frequency reduction, lamotrigine (50-200 mg daily) may have a special role in reducing the frequency or severity of migraine aura. It is generally less effective for headache prevention.

Levetiracetam Limited Evidence

Levetiracetam (1000-3000 mg daily) has shown mixed results in open-label studies. It may be considered in patients with comorbid epilepsy, but is not a routine preventive due to neuropsychiatric side effects including irritability and mood changes.

Additional Antihypertensives
ARBs: Telmisartan Less Studied

While candesartan has the most evidence among ARBs, telmisartan (40-80 mg daily) may be an alternative in patients with hypertension who cannot tolerate candesartan. Evidence is primarily from small studies and clinical experience.

Selective Beta Blockers: Nebivolol, Bisoprolol Alternative Options

Nebivolol (5-10 mg daily) and bisoprolol (5-10 mg daily) are more cardioselective than propranolol and may be better tolerated in patients with respiratory conditions. Limited evidence suggests efficacy comparable to other beta blockers.

Calcium Channel Blockers: Flunarizine, Amlodipine Variable Evidence

Flunarizine (5-10 mg daily), unavailable in the US, has good evidence for efficacy in several European studies. Amlodipine (dihydropyridine calcium channel blocker) has minimal supportive evidence but may be considered in patients with comorbid hypertension who cannot tolerate other preventives.

Central Alpha Agonists: Clonidine Limited Efficacy

Despite earlier use, clonidine has shown poor efficacy in controlled studies and is not recommended for routine migraine prevention. Side effects include sedation, dry mouth, and rebound hypertension if stopped abruptly.

Glutamate Modulators
NMDA Antagonists: Memantine, Amantadine, Ketamine Experimental

Memantine (N-methyl-D-aspartate receptor antagonist, 5-20 mg daily) has shown promise in small studies for migraine prevention, especially in patients with comorbid cognitive concerns. Amantadine has limited evidence. Ketamine (NMDA receptor antagonist) is primarily investigated for acute treatment of refractory migraine in monitored settings rather than prevention.

Hormonal Agents
Estrogen For Menstrual Migraine

Estrogen supplementation (estradiol 1.5 mg gel or 100 μg patch) during the perimenstrual period can help prevent menstrual migraine in some women. Continuous hormonal contraception to avoid estrogen withdrawal is another strategy.

Spironolactone Limited Data

This aldosterone antagonist (50-200 mg daily) may have benefit in women whose migraine worsen with fluid retention or hormonal fluctuations, though evidence is largely anecdotal. May be more helpful in women with polycystic ovary syndrome (PCOS).

Anthistamines and Ergot Derivatives
Antihistamines: Cyproheptadine, Hydroxyzine For Pediatric/Young Adults

Cyproheptadine (4-12 mg daily) has been used particularly in pregnancy and pediatric and young adult populations, with modest efficacy. Its serotonin antagonist properties may contribute to its mechanism. Hydroxyzine may help patients with comorbid anxiety or allergic conditions.

Ergot Alkaloids: Methylergonovine Specialist Use Only

Methylergonovine is rarely used for migraine prevention due to significant cardiovascular risks and is primarily reserved for specialist use in carefully selected refractory cases.

Other Agents with Limited Evidence
Metformin For PCOS/Insulin Resistance

Metformin may help reduce migraine frequency in patients with comorbid insulin resistance or polycystic ovary syndrome (PCOS). The connection between insulin resistance and migraine remains an area of ongoing research.

Acetazolamide For Specific Syndromes

This carbonic anhydrase inhibitor may be helpful in specific migraine subtypes, particularly those with hemiplegic features or associated with episodic ataxia. Not recommended for routine prevention.

Anxiolytics: Buspirone, Clonazepam Adjunctive Use

Buspirone may help patients with comorbid anxiety that could trigger migraine attacks. Clonazepam and other benzodiazepines are generally avoided due to dependence risk but might be considered for very short-term use in select situations.

Muscle Relaxants: Baclofen For Comorbid Muscle Tension

Baclofen has limited evidence but may be helpful in patients with significant muscle tension contributing to headaches.

Local Anesthetics: Lidocaine, Bupivacaine, Mexiletine Specialized Procedures

Peripheral nerve blocks with lidocaine or bupivacaine can provide temporary relief for some patients. Oral mexiletine has very limited evidence and significant cardiac risks. This is commonly used as a bridge therapy for Botox as well during the Botox "wear-off" period.

Melatonin: Recent Research is Promising!
Melatonin Strong Clinical Evidence

Melatonin (3-5 mg at bedtime) has demonstrated significant efficacy for migraine prevention in well-designed clinical trials. A randomized, double-blind, placebo-controlled study published in the Journal of Neurology, Neurosurgery & Psychiatry compared melatonin 3 mg to amitriptyline 25 mg (a tricyclic antidepressant and first-line migraine preventive) and placebo in 196 patients with migraine.

Key findings include:

  • Superior to placebo: Melatonin significantly reduced headache frequency compared to placebo (2.7 fewer migraine days per month vs. 1.1 for placebo, p=0.009)
  • Comparable to amitriptyline: Melatonin's reduction in migraine days (2.7) was statistically similar to amitriptyline (2.2 days)
  • Better responder rate: Melatonin was superior to amitriptyline in the percentage of patients achieving greater than 50% reduction in migraine frequency
  • Favorable side effect profile: Significantly better tolerated than amitriptyline
  • Positive effect on weight: While amitriptyline was associated with weight gain, the melatonin group experienced slight weight loss

Melatonin's favorable safety profile, lack of significant drug interactions, and positive effect on sleep make it an excellent option for:

  • Patients with comorbid insomnia or disrupted sleep patterns
  • Those who cannot tolerate or have contraindications to traditional preventive medications
  • Patients concerned about weight gain associated with many preventive medications
  • As adjunctive therapy alongside other preventive treatments
Investigational Agents
Cannabinoids: CBD, THC, CBN, CBG, etc. Early Research

Research indicates that the endocannabinoid system (ECS) plays a vital role in migraine pathophysiology. Studies suggest that endocannabinoid deficiency contributes to the condition. Phytocannabinoids (THC, CBD, CBG, etc.) show promise in small studies for reducing migraine pain and medication use through their interactions with cannabinoid receptors. Some patients report benefits from CBD or CBN-melatonin combinations for sleep-related migraine triggers. However, well-designed randomized clinical trials are still needed to confirm effectiveness and safety of specific cannabinoids for migraine treatment.

Low-dose Naltrexone Investigational

Low-dose naltrexone (1.5-4.5 mg at bedtime) has theoretical anti-inflammatory properties that may benefit migraine, but clinical evidence is limited to anecdotal reports and small case series.

Psilocybin Early Research

There is emerging interest in the potential of psilocybin for cluster headache and migraine prevention. Early research shows promise, but availability is limited to clinical trials or specific jurisdictions where legal. Not recommended for routine clinical use at this time.

Antipsychotics: Haloperidol, Droperidol, Chlorpromazine Acute Treatment

These agents are occasionally used in emergency settings for acute treatment of status migrainosus but are generally not recommended for preventive therapy due to risk of extrapyramidal and metabolic side effects.

Clinical Pearls for Uncommon Preventives

  • Consider Comorbidities: Many of these agents are best used when they can simultaneously address a comorbid condition (e.g., duloxetine for migraine with depression and pain).
  • Benefit-Risk Assessment: Many uncommon preventives have significant side effect profiles or limited evidence, requiring careful benefit-risk assessment.
  • Specialist Consultation: Consider referral to headache specialists when considering these less common options, particularly for medications with significant risks.
  • Trial Periods: As with standard preventives, allow adequate trial periods (typically 2-3 months) before determining efficacy.
  • Monitor Closely: More frequent follow-up may be needed when using medications with limited evidence or higher risk profiles.
The use of uncommon preventive medications underscores the complexity and heterogeneity of migraine. While these options expand the preventive armamentarium, their use should be guided by evidence where available, attention to individual patient factors, and appropriate risk-benefit analysis.

Emerging and Investigational Treatments

Research into migraine prevention continues to evolve, with several promising approaches under investigation:

Additional Gepants
Further small-molecule CGRP antagonists are in development, building on the success of approved options like rimegepant and atogepant
Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Antagonists
Targeting another neuropeptide pathway implicated in migraine pathophysiology
Novel Neuromodulation
Advanced non-invasive and minimally invasive neuromodulation techniques
Glutamate Receptor Modulators
Compounds targeting glutamate pathways to prevent cortical spreading depression
The migraine prevention landscape continues to evolve rapidly. As our understanding of migraine pathophysiology deepens, more targeted and effective preventive treatments are being developed that may offer better efficacy with fewer side effects.

Recommended Monitoring for Preventive Medications

Regular monitoring is essential to evaluate efficacy, detect adverse effects, and ensure optimal treatment outcomes.

Medication Baseline Assessment Ongoing Monitoring
Beta Blockers
  • Vital signs (BP, HR)
  • ECG (for patients with cardiac history)
  • Baseline mood assessment
  • BP and HR at follow-up visits
  • Monitor for fatigue, depression, sleep disturbances
  • Watch for bradycardia, hypotension, bronchospasm (especially in non-selective beta blockers)
Topiramate
  • Basic metabolic panel
  • Baseline weight
  • Pregnancy test for women of childbearing potential
  • Electrolytes and bicarbonate levels
  • Weight changes
  • Monitor for cognitive effects, paresthesias
  • Eye symptoms (potential for angle closure glaucoma)
Valproate
  • Liver function tests
  • CBC with platelets
  • Pregnancy test (contraindicated in pregnancy)
  • Liver function tests periodically
  • CBC with platelets
  • Weight changes
  • Monitor for tremor, hair loss, sedation
Antidepressants
  • BP (especially for venlafaxine)
  • Baseline mood assessment
  • ECG for TCAs in patients >40 years or with cardiac history
  • BP at follow-up visits (venlafaxine)
  • Monitor for dry mouth, constipation, sedation (TCAs)
  • Monitor for suicidal ideation, especially in younger patients
CGRP Antagonists
  • BP measurement
  • Pregnancy test for women of childbearing potential
  • Assessment of cardiovascular risk factors
  • BP at follow-up visits (especially erenumab)
  • Monitor for constipation, injection site reactions
  • For oral agents: liver function in select high-risk patients

Personalizing Preventive Treatment

Successful migraine prevention requires an individualized approach that considers the patient's migraine characteristics, comorbidities, preferences, and treatment goals. While the range of available preventive medications continues to grow, the fundamental principles remain consistent:

  • Select medications based on both efficacy and tolerability profile
  • Consider comorbidities when choosing preventive agents
  • Start with low doses and titrate slowly
  • Provide adequate trial duration to evaluate effectiveness
  • Monitor for side effects and adherence regularly
  • Reassess and adjust treatment as needed based on response

The recent development of CGRP antagonists has significantly expanded the preventive treatment options, particularly for patients who have not responded to or tolerated traditional preventives. The head-to-head studies showing superiority of newer agents like erenumab over traditional options such as topiramate provide valuable evidence to guide treatment selection. As our understanding of migraine pathophysiology deepens and research continues, we can anticipate further innovations in migraine prevention that may offer even more targeted and effective approaches to reduce the burden of this common and disabling condition.

References

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  2. Ornello R, Caponnetto V, Ahmed F, et al. Evidence-based guidelines for the pharmacological treatment of migraine. Cephalalgia. 2025;45:3331024241305381.
  3. Puledda F, Sacco S, Diener HC, et al. International Headache Society Global Practice Recommendations for Preventive Pharmacological Treatment of Migraine. Cephalalgia. 2024;44:3331024241269735.
  4. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024;64:333.
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  6. Haghdoost F, Puledda F, Garcia-Azorin D, et al. Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: A systematic review and network meta-analysis of phase 3 randomised controlled trials. Cephalalgia. 2023;43:3331024231159366.
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  8. Sun W, Cheng H, Xia B, et al. Comparative Efficacy and Safety of Five Anti-calcitonin Gene-related Peptide Agents for Migraine Prevention: A Network Meta-analysis. Clin J Pain. 2023;39:560.
  9. Peterlin BL, Bond DS, Ailani J, et al. Weight loss with atogepant during the preventive treatment of migraine: A pooled analysis. Cephalalgia. 2024;44:3331024241299753.
  10. Goadsby PJ, Reuter U, Hallström Y, et al. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med. 2017;377:2123.
  11. Pellesi L, Garcia-Azorin D, Rubio-Beltrán E, et al. Combining treatments for migraine prophylaxis: the state-of-the-art. The Journal of Headache and Pain. 2024;25:214.
  12. Castro F, Baraldi C, Pellesi L, Guerzoni S. Clinical Evidence of Cannabinoids in Migraine: A Narrative Review. J Clin Med. 2022 Mar 8;11(6):1479.

This information is provided for educational purposes only and does not constitute medical advice. Always consult with your healthcare provider for diagnosis and treatment of medical conditions.

MigraineScience Blog

Mon, Jun 16, 25

Migraine with Brainstem Aura

Comprehensive guide to Migraine with Brainstem Aura (MBA) - symptoms, diagnosis, treatment options, and latest research on whether it actually affects the brainstem. Patient-friendly explanations included.

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