What is the risk of headache and how should it be managed when using Auvelity (dextromethorphan‑bupropion) together with Spravato (esketamine)?

Headache Risk and Management with Auvelity-Spravato Combination

Direct Answer: Expect Headache as a Common Side Effect

Headache is one of the most common adverse effects of Auvelity (dextromethorphan-bupropion), occurring frequently enough to warrant proactive management planning when combining with Spravato (esketamine). 1

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Headache Incidence with Auvelity

• Headache is explicitly listed among the most common adverse effects of dextromethorphan-bupropion, alongside dizziness, nausea, and somnolence 1
• Bupropion monotherapy is associated with headaches and migraines as documented adverse effects 2
• The combination of these two medications (Auvelity + Spravato) may theoretically increase headache burden, though no direct interaction studies exist in the provided evidence

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First-Line Treatment Algorithm for Medication-Induced Headache

Immediate Acute Management

• Start with NSAIDs as first-line therapy: ibuprofen 400-800 mg, naproxen sodium 500-825 mg, or aspirin 1000 mg at headache onset 3
• The combination of acetaminophen 1000 mg + aspirin 500-1000 mg + caffeine 130 mg achieves pain reduction to mild or none in 59.3% of patients at 2 hours 4
• Acetaminophen alone is ineffective for headache treatment and should not be used as monotherapy 3

Critical Frequency Limitation

• Limit all acute headache medications to no more than 2 days per week to prevent medication-overuse headache 4, 3
• Simple analgesics (NSAIDs, acetaminophen) must be used fewer than 15 days per month 3
• Completely avoid medications containing barbiturates, caffeine, butalbital, or opioids, as these carry the highest risk of causing medication-overuse headache 3

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When to Initiate Preventive Therapy

Indications for Prevention

• Start preventive therapy if the patient experiences two or more headache attacks per month producing disability for 3+ days per month 3
• Preventive therapy is also indicated if acute medications are being used more than twice per week 3
• Consider preventive therapy if acute treatments have failed or are contraindicated 3

First-Line Preventive Options

• Amitriptyline 30-150 mg/day has the strongest evidence for headache prevention and is particularly beneficial when psychiatric comorbidity exists (depression, anxiety) 3
• This is especially relevant given that both Auvelity and Spravato are used for depression treatment
• Beta-blockers (propranolol 80-240 mg/day, timolol 20-30 mg/day) are effective alternatives, particularly for pure migraine without tension features 3

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Escalation Strategy for Severe Headaches

If NSAIDs Fail After 2-3 Episodes

• Escalate to triptans for moderate-to-severe headaches: sumatriptan 50-100 mg, rizatriptan 10 mg, or eletriptan 40 mg 4
• The combination of sumatriptan 50-100 mg PLUS naproxen sodium 500 mg is superior to either agent alone 4
• Triptans must be limited to fewer than 10 days per month to prevent medication-overuse headache 3

Rescue Medication Strategy

• Establish a cooperative arrangement for home rescue medication (opioid or butalbital-containing compound) to avoid emergency department visits for severe headaches unresponsive to other treatments 3
• Rescue medications permit relief without complete pain elimination or return to normal function 3
• Reserve opioids only for cases where all other evidence-based treatments are contraindicated, sedation is acceptable, and abuse risk has been addressed 4

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Special Considerations for This Combination

Dopaminergic Enhancement Rationale

• Bupropion (component of Auvelity) provides dopaminergic enhancement, which may theoretically improve esketamine response durability 5
• The combination of dextromethorphan and bupropion targets glutamatergic and dopaminergic pathways, which may influence headache pathophysiology 5, 6

Monitoring Strategy

• Document headache frequency, severity, and pattern at baseline before starting combination therapy
• Reassess at 2 weeks, 4 weeks, and 8 weeks to determine if headaches are worsening, stable, or improving
• If headaches occur more than 2 days per week by week 4, initiate preventive therapy immediately rather than increasing acute medication use 3

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Critical Pitfalls to Avoid

• Do not allow patients to increase frequency of acute medication use in response to treatment failure, as this creates a vicious cycle of medication-overuse headache 4
• Never substitute opioids or butalbital compounds as first-line rescue medications due to limited efficacy, risk of dependence, and potential for rebound headaches 4, 3
• Do not delay preventive therapy while trialing multiple acute strategies, as this undermines timely control of chronic headache patterns 4
• Avoid establishing a pattern of frequent opioid use for headache management, as this can lead to medication-overuse headache, dependency, and rebound headaches 4