Migraine Pharmaceutical Treatment Pearls
Posted on April 26 2025,
Migraine Treatment Pearls
Acute Treatment Recommendations
NSAIDs
Dosage
Use lowest effective dose due to dose-dependent gastrointestinal side effects. Choose based on individual patient response and preference as no single NSAID is proven superior.
Timing
Take as soon as possible after pain onset for enhanced efficacy. Clinical practice suggests early intake significantly improves effectiveness.
Selection Strategy
There is no evidence that one NSAID is superior to another. Choice should be based on the patient's preference and individual response to specific NSAIDs, considering the most favorable efficacy/tolerability profile.
Indomethacin
Limit use to selected cases due to its potent COX inhibition and nitric oxide-mediated effects on cerebral blood flow. Exercise caution with cerebrovascular and cardiovascular risk factors and use only for short periods.
Celecoxib (Celebrex)
A selective COX-2 inhibitor with better GI tolerability but requires careful patient selection. Oral solution formulation (120 mg) has been FDA-approved for acute migraine. Like other Coxibs, exercise caution in patients with cardiovascular risk factors.
Coxibs vs Traditional NSAIDs
In subjects who tolerate NSAIDs well, use traditional NSAIDs rather than coxibs. Coxibs cause less gastrointestinal toxicity but may have greater cardiovascular risk with no substantial gain in efficacy over NSAIDs.
Triptans
Timing
Take within one hour from onset when pain is mild. Early treatment is more effective before symptoms are fully developed and central sensitization occurs. For migraine with aura, wait for aura resolution before taking.
Formulation
For patients with moderate/severe nausea or vomiting, prefer intranasal or orally disintegrating formulations. For severe nausea or early vomiting, consider nasal spray or subcutaneous sumatriptan. For rapid pain escalation or attacks fully developed upon awakening, subcutaneous formulation is recommended.
Headache Relapse
Repeat triptan at least 2 hours after previous dose if relapse occurs. For frequent relapses, consider switching to longer half-life triptans (eletriptan, naratriptan, frovatriptan) or combining with fast-acting NSAIDs (naproxen sodium, ibuprofen lysine, diclofenac potassium).
Non-Response
Try a specific triptan at least three times before declaring non-response. A responder shows benefit in at least 3 out of 4 consecutive attacks. Try at least three different triptans (including subcutaneous sumatriptan) before concluding non-response to the entire class.
Usage Limit
Limit to fewer than 10 days per month to decrease medication overuse/adaptation headache risk. Triptans can lead to medication overuse/adaptation headache sooner and at lower doses than other acute treatments, so monitoring intake frequency is essential.
Pharmacokinetics
For long attacks with high relapse rates: frovatriptan, eletriptan, naratriptan (longer half-lives). For rapid pain escalation: rizatriptan (shorter time to peak plasma level). For consistent efficacy across multiple attacks: almotriptan, naratriptan (higher oral bioavailability).
Tolerability
If a triptan is not tolerated and adverse events are mild to moderate, consider a lower dose before discontinuing. Almotriptan has a more favorable tolerability profile and should be considered if other triptans cause side effects.
Drug Interactions
Adjust rizatriptan dose (reduce from 10 mg to 5 mg) when taken with propranolol. Avoid triptans within 24h of ergotamine. Use caution with MAO inhibitors - contraindicated with sumatriptan, rizatriptan, almotriptan, and zolmitriptan within 2 weeks of MAO inhibitor treatment.
Acetaminophen (Paracetamol)
Dosage
1000 mg at onset; second dose after 6h if ineffective; maximum two 1000 mg doses in 24h. If the second dose is ineffective, switch to a different acute drug.
Efficacy
Less effective than NSAIDs/triptans but better tolerated at gastric level. Consider as first-line treatment in patients with gastric intolerance to salicylates and other NSAIDs or in patients with gastric disorders.
Combination Analgesics
Timing
Take at the beginning of an attack. All oral combinations should be taken early for maximum effectiveness. For migraine with aura, combination drugs containing triptans should be taken after aura resolution.
Selection
ASA+metoclopramide or paracetamol+domperidone for attacks with nausea. Avoid opioid combinations as first-line. Use combinations for moderate-severe headache not responding to single drug treatments.
Usage Limit
Limit to less than 10 days/month to reduce medication overuse/adaptation headache risk. Combinations containing codeine have greater potential for overuse and dependency compared to single analgesics.
Combination Benefits
Paracetamol+ASA+caffeine may be superior to components alone. Caffeine enhances absorption and has analgesic activity through adenosine receptor blockade and activation of antinociceptive pathways. Triple combination taken early is quicker and more effective than monotherapy.
Headache Relapse
For relapse after initial response, use a second dose of the same combination (at least 2h after previous dose) or switch to a rescue medication. Consider alternative routes (rectal, intramuscular, intravenous) when nausea/vomiting are prevalent.
Opioid-Containing Combinations
Use combinations with codeine or tramadol only when other options fail. Monitor for dependency risk, especially with codeine (varies based on CYP2D6 metabolizer status). Avoid in patients with poor or ultra-rapid CYP2D6 metabolism and in those with renal impairment.
Lasmiditan
Dosing
Initial dose of 100 mg. Can decrease to 50 mg for better tolerability or increase to 200 mg for improved efficacy. For elderly patients (65+ years), consider starting with 50 mg due to higher incidence of adverse events.
Special Precautions
Avoid driving or operating machinery for at least 8 hours after taking lasmiditan. Use caution with activities requiring heightened attention due to impairment after single doses of 50-200 mg.
Cardiovascular Considerations
Safe to use in patients with cardiovascular risk factors or cardiovascular disease. Unlike triptans, lasmiditan has no contraindications related to cardiovascular conditions, making it a valid option for patients who cannot take triptans.
CGRP Antagonists (Gepants)
Available Agents for Acute Treatment
Ubrogepant (Ubrelvy) - oral tablet for acute treatment, FDA-approved in 2019.
Rimegepant (Nurtec ODT) - orally disintegrating tablet for both acute and preventive treatment.
Zavegepant (Zavzpret) - intranasal spray for acute treatment, ideal for patients with severe nausea/vomiting.
Ubrogepant Dosing
Start at 50 mg; can increase to 100 mg if response unsatisfactory. Both doses show similar efficacy, with slightly higher adverse event rates at 100 mg (nausea, somnolence, dry mouth).
Treatment Timing
Can be considered during prodrome phase before pain onset. Evidence shows effectiveness when taken during prodrome, with 46% of treated events avoiding moderate/severe headache (vs. 29% with placebo).
Use with Anti-CGRP Antibodies
Can be used with anti-CGRP monoclonal antibodies for prevention. Pharmacokinetics of ubrogepant not significantly affected by co-administration with erenumab or galcanezumab, though long-term effects of dual CGRP inhibition require monitoring.
Zavegepant Considerations
Consider intranasal zavegepant for patients with severe nausea/vomiting during attacks. Nasal delivery bypasses digestive system, making it useful when gastroparesis affects oral medication absorption.
Advantages over Triptans
Unlike triptans, gepants do not cause vasoconstriction, making them suitable for patients with cardiovascular disease or risk factors. They can be a good option for patients who cannot take triptans or have inadequate response to them.
Common Side Effects
Generally well-tolerated with mild side effects including nausea, constipation, fatigue, and occasional site reactions. No significant hepatotoxicity has been observed with the newer gepants, unlike the first-generation agents.
Caution
Use with caution in patients with vascular disease, severe constipation, inflammatory bowel disease, COPD, or Raynaud's phenomenon. CGRP is a potent vasodilator in reduced perfusion and has numerous biological functions throughout the body.
Opioids
Recommendation
Very limited evidence for efficacy. Only consider after optimization of non-opioid treatments. Never use in patients with concurrent/past substance use disorders, active psychiatric disorders, or medication overuse/adaptation headache.
Monitoring
If used, initiate trial with titration and close monitoring for improvement. Discontinue if no clinically meaningful improvement in pain or function. Patient education and strict monitoring of frequency are mandatory to prevent misuse.
Treatment Strategy
First-Line Selection
Triptans preferred for efficacy and should be first-line for severe/disabling attacks (stratified approach). For mild-moderate attacks, can start with NSAIDs and use triptans as second-line if NSAIDs fail (step-care approach). Click here for head-to-head comparisons.
Approach by Attack Severity
For the same patient: use triptans for moderate-severe attacks, NSAIDs for mild attacks. This severity-based approach helps minimize triptan use while ensuring effective relief for all attack intensities.
Poor Response Management
Consider triptan+NSAID combination for triptan-resistant attacks; closely monitor for overuse/adaptation. Combinations with proven efficacy include sumatriptan+naproxen, frovatriptan+dexketoprofen, and rizatriptan+paracetamol.
Newer Options for Triptan Non-responders
For patients who do not respond to or cannot take triptans, consider gepants (Ubrelvy, Nurtec ODT, Zavzpret) or ditans (Reyvow). Both classes lack the vasoconstrictive effects of triptans and may be suitable for patients with cardiovascular contraindications.
Preventive Treatment Recommendations
Antidepressants
Amitriptyline Dosing
Start with 10 mg at bedtime; increase to 25 mg over 2 weeks. For inadequate response, can increase to 50 mg. For optimal tolerability, use gradual titration with weekly increments. Evaluate effectiveness after at least 4 weeks at target dose.
Other Antidepressant Options
Venlafaxine (75-150 mg) may be effective, particularly at the 150 mg extended-release dose. Fluoxetine shows no advantage over placebo. Higher doses (75-150 mg daily) may be appropriate for patients with comorbid depression.
Patient Selection
Consider for patients with psychiatric comorbidities (depression, anxiety) before starting migraine-specific preventives. Check for benefit on migraine outcomes in these patients before adding additional preventive treatments.
Antiseizure Medications
Topiramate Dosing
Target 100 mg daily for both episodic and chronic migraine. Use 4-week titration with 25 mg weekly increases to minimize adverse events. 200 mg daily dose may not provide additional efficacy and could be less tolerated.
Valproate Dosing
600-1500 mg daily for episodic migraine. Start at 200-250 mg daily, then increase to 200-250 mg twice daily after one week, with subsequent weekly increases to target dose. Extended-release formulation can start at 500 mg once daily.
Treatment Duration
Evaluate effectiveness after 8-12 weeks at target dose. Patients with partial response should know cumulative benefits may occur over 6-12 months. If no response after 8-12 weeks, switch to alternative preventive treatment.
Special Considerations
Absolutely avoid topiramate/valproate in women with childbearing potential due to significant teratogenic risk. Women exposed to topiramate during pregnancy have increased risk of neurodevelopmental disorders and autism in offspring.
Alternative ASMs
Consider lamotrigine (50-200 mg daily) for migraine with aura, with particular efficacy for brainstem aura and hemiplegic migraine. Use slow titration to reduce risk of cutaneous adverse events. Levetiracetam (500-1000 mg daily) may be considered after failure of other preventives.
Patient Selection
Topiramate may benefit overweight patients due to its weight loss properties. Both drugs work well for episodic and chronic migraine, including those with medication overuse/adaptation. Both are contraindicated in pregnancy and should be avoided in severe hepatic impairment.
Switching Between ASMs
Consider switching to alternative ASM if intolerance or lack of effectiveness with first ASM at therapeutic doses. Ineffectiveness or adverse effects with one ASM doesn't predict response to other ASMs due to diverse mechanisms of action.
OnabotulinumtoxinA (Botox)
Dosing
Start at 155 units following PREEMPT protocol. For patients with less than 50% response after first injection, increase to 195 units for subsequent treatments. Alternative administration schemes are not recommended due to lack of evidence.
Evaluation Timeline
Assess effectiveness after at least 6 months (two administrations). Almost half of patients respond during first treatment cycle, with additional 11.3% and 10.3% responding during second and third cycles. Patients not responding to first two cycles unlikely to respond to third.
Administration Protocol
Use PREEMPT protocol exclusively. Alternative injection schemes lack sufficient evidence, though research continues on new approaches. Available data do not support non-PREEMPT administration paradigms.
CGRP Pathway Medications for Prevention
CGRP Monoclonal Antibodies
Erenumab (Aimovig) - targets CGRP receptor; subcutaneous injection monthly.
Galcanezumab (Emgality) - targets CGRP ligand; subcutaneous injection monthly.
Fremanezumab (Ajovy) - targets CGRP ligand; subcutaneous injection monthly or quarterly.
Eptinezumab (Vyepti) - targets CGRP ligand; intravenous infusion every 3 months.
Oral Gepants for Prevention
Atogepant (Qulipta) - oral tablet specifically developed for preventive treatment of episodic and chronic migraine.
Rimegepant (Nurtec ODT) - orally disintegrating tablet approved for both acute and preventive treatment.
Efficacy
CGRP antibodies reduce monthly migraine days by at least 50% in a significant proportion of patients. About one-third of patients achieve "super-response" (≥75% reduction). Can be effective in patients who have failed multiple other preventive treatments.
Side Effects
Generally well-tolerated. Common side effects include injection site reactions, constipation (particularly with erenumab), and mild increase of infection risk (particularly with Emgality and Vyepti) although this small increase is likely only relevant to those that may be immunocompromised. Long-term safety profile continues to be monitored but appears favorable.
Patient Selection
The American Headache Society recommends that anti-CGRP(-R) monoclonal antibodies be considered a first-line treatment for migraine prevention.
Atogepant Response Predictors
Use with caution in patients with vascular disease, severe constipation, inflammatory bowel disease, COPD, or Raynaud's phenomenon due to widespread CGRP receptor distribution and vasodilatory effects.
Erenumab Response Predictors
Negative predictors include chronic migraine (OR 0.63), daily headache (OR 0.41), and 3+ preventive medication failures (OR 0.54). Positive predictors include older age (OR 1.22 per 10-year increase) and unilateral headache (OR 2.31).
Response Assessment
52.3% achieve ≥50% reduction in monthly migraine days; 39.0% as early responders, 14.2% as late responders. Consider extended assessment (16 weeks vs. 12); 30-49% reduction may be realistic goal for resistant cases.
Preventive Treatment Strategy
Comparisons Between Treatments
Most head-to-head comparisons are neutral or inconclusive. Valproate and propranolol appear equivalent for migraine prevention, as do propranolol and flunarizine, and propranolol and timolol. No definitive treatment sequence is established. Click here for more head-to-head comparisons.
Prioritization
Safety should be prioritized over efficacy when selecting preventive treatments, as efficacy is generally comparable while adverse event profiles differ between medications.
Combination Treatments
When combining preventive treatments, use minimal effective doses of each and choose drugs with different tolerability profiles (e.g., amitriptyline which causes weight gain with topiramate which causes weight loss rather than two drugs with similar side effects).
Transitioning Between Treatments
When switching treatments due to inefficacy, consider a 2-week overlap period to maintain some benefit while the new medication reaches therapeutic levels. When switching due to tolerability issues, a washout period may be necessary depending on the medications involved.
Special Populations & Considerations
Pregnancy & Lactation
Acute Treatment in Pregnancy
Acetaminophen is first-line. Triptans as second-line; if needed, prefer sumatriptan, naratriptan, or rizatriptan which show no evidence of teratogenicity in population-based studies, though there are conflicting results about increased risk of premature birth.
Avoid in Pregnancy
Avoid NSAIDs, ergotamine, and combination analgesics with caffeine or opioids. NSAIDs can cause renal injury, oligohydramnios, ductus arteriosus constriction, and other complications. Ergotamine is associated with low birthweight, preterm birth, acute fetal hypoxia, and myocardial ischemia.
Acute Treatment in Lactation
Safe options include paracetamol, ibuprofen, naproxen, diclofenac, eletriptan, and sumatriptan. Amounts in milk are much less than doses given to infants, and adverse effects in breastfed infants are rare. Most NSAIDs result in low infant exposure via breast milk.
Avoid in Lactation
Avoid combinations with codeine/tramadol and ergotamine. Maternal use of opioids during breastfeeding can cause infant drowsiness and severe CNS depression. Ergotamine may cause adverse effects in infants and decreased milk production.
Preventive Treatment in Pregnancy
Avoid valproate and topiramate due to high teratogenic risk. Women exposed to topiramate during pregnancy have risk of neurodevelopmental disorders and autism in offspring comparable to valproate exposure. Prefer preventive medications without teratogenic risks.
CGRP Antagonists in Pregnancy
Anti-CGRP monoclonal antibodies and gepants are not recommended during pregnancy due to limited safety data. CGRP has important vascular functions that may affect fetal development. Discontinue these medications before planned pregnancy or as soon as pregnancy is confirmed.
Menstrual Migraine
Acute Treatment
Rizatriptan 10 mg shows best overall evidence for pain freedom and pain relief between 2 and 24 hours compared to other treatments. Menstrual attacks are often more severe and disabling, warranting migraine-specific treatment.
Short-term Prevention
Consider starting triptans 2-3 days before expected onset of menstruation. Frovatriptan 2.5 mg daily or twice daily and zolmitriptan 2.5 mg twice or three times daily show good evidence. Naratriptan is least effective compared to frovatriptan and zolmitriptan.
CGRP Antagonists and Monoclonal Antibodies
Recent research demonstrates that while anti-CGRP monoclonal antibodies and onabotulinumtoxinA effectively reduce overall migraine and headache days, they have limited impact specifically on perimenstrual headache days. A 2025 study showed that these treatments preferentially reduce non-perimenstrual migraine with the perimenstrual window remaining a period of high headache risk despite treatment, suggesting hormonal mechanisms may predominate during this time.
Medical Conditions
Renal Impairment
In severe renal impairment (CrCl < 15), almotriptan, rizatriptan, and eletriptan are contraindicated. Zolmitriptan and frovatriptan require no dose adjustments. For mild-moderate impairment, rizatriptan needs dose adjustment (maximum 5 mg/24h) and eletriptan (maximum 20 mg/24h).
Hepatic Impairment
In severe hepatic impairment, all triptans are contraindicated except zolmitriptan (maximum 5 mg/24h). For mild-moderate impairment, frovatriptan needs no adjustment; rizatriptan (≤5 mg/24h), sumatriptan (≤25-50 mg/24h), naratriptan (1-2.5 mg/24h), zolmitriptan (1.25-5 mg/24h), and almotriptan (6.25-12.5 mg/24h) require adjustments.
Cardiovascular Disease
Consider lasmiditan or gepants instead of triptans in patients with cardiovascular risk factors or established disease. Triptans are contraindicated in patients with coronary artery disease, cerebrovascular disease, peripheral vascular disease, and uncontrolled hypertension due to vasoconstrictive effects.
CGRP Pathway Cautions
Use gepants and CGRP antibodies with caution in vascular disease, severe constipation, IBD, COPD, or Raynaud's phenomenon. CGRP is a potent vasodilator and has important functions in various body systems including intestine, bronchial endothelium, and skin.
Elderly Patients
Acute Treatment Considerations
Begin with lower doses of acute medications due to age-related changes in metabolism. Monitor closely for cardiovascular effects with triptans. Consider gepants as alternatives for patients with cardiovascular risk factors, which are more common in this population.
Preventive Treatment Considerations
Start with low doses and titrate slowly. Be aware of potential drug interactions with concurrent medications commonly used by elderly patients. Beta-blockers require careful monitoring in patients with cardiac conduction abnormalities.
Anti-CGRP Monoclonal Antibodies
Limited data in elderly populations but may be considered when conventional options are contraindicated or ineffective. Age appears to be a positive predictor for erenumab response. Monitor for potential age-related adverse effects including constipation and hypertension.
Pediatric Patients
Acute Treatment
Ibuprofen (10 mg/kg) is first-line for children; acetaminophen (15 mg/kg) is an alternative. Both are effective, but ibuprofen provides faster relief. For adolescents with moderate-severe attacks unresponsive to NSAIDs, triptans (particularly almotriptan, rizatriptan, and sumatriptan/naproxen combination) may be considered. Nasal spray formulations are preferable for children with nausea/vomiting or those unable to swallow pills.
Triptans in Children
For children ≥5 years with moderate-severe migraine unresponsive to analgesics, consider triptans. FDA-approved options include rizatriptan for ages 6-17, and almotriptan, zolmitriptan nasal spray, and sumatriptan-naproxen for ages ≥12. For younger children (ages 6-10, <50kg), start with the smallest available dose: rizatriptan 2.5 mg, almotriptan 6.25 mg, sumatriptan 5-10 mg nasal spray, or zolmitriptan 2.5 mg.
Preventive Treatment
Evidence for preventive medications in children is limited. Topiramate has the strongest evidence but requires monitoring for cognitive and behavioral effects. Propranolol and amitriptyline are alternatives with less supporting evidence. The CHAMP study showed placebo was as effective as amitriptyline or topiramate, suggesting first-line preventives should have minimal side effects.
Emergency Treatment
For severe attacks in emergency settings, consider IV fluid therapy with prochlorperazine (0.15 mg/kg, maximum 10 mg) followed by ketorolac (0.5 mg/kg, maximum 30 mg). Alternatives include subcutaneous sumatriptan, IV metoclopramide, or IV DHE for status migrainosus. Pretreatment with diphenhydramine can prevent dystonic reactions associated with prochlorperazine.
Medication Overuse/Adaptation Prevention
Limit analgesics to ≤14 days/month and triptans to ≤9 days/month to prevent medication overuse/adaptation headache. Encourage tracking headache frequency and medication use in a diary. Opioids, barbiturates, and benzodiazepines should not be used for pediatric migraine due to risk of dependency and lack of efficacy.
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