What is the appropriate indomethacin dosing regimen for an adult with a headache that responds to indomethacin (e.g., hemicrania continua or paroxysmal hemicrania)?

Indomethacin Dosing for Indomethacin-Responsive Headaches

For adults with indomethacin-responsive headaches (paroxysmal hemicrania or hemicrania continua), start with 25 mg three times daily (75 mg/day total) and expect complete headache resolution within 1–3 days; if side effects develop, reduce to the minimum effective dose (often 25–50 mg/day) after initial response is achieved. 1

Initial Diagnostic Dosing ("Indotest")

• Administer 50 mg indomethacin intramuscularly as a diagnostic test when you need rapid confirmation of an indomethacin-responsive headache disorder. 2
• In paroxysmal hemicrania, expect a protective refractory period beginning within 22–73 minutes after injection, with attacks completely suppressed for approximately 13 hours. 2
• In hemicrania continua, complete pain relief occurs at a mean of 73 minutes (±66 minutes) after 50 mg IM injection, lasting approximately 13 hours. 2
• This parenteral test provides a definitive diagnostic answer within hours rather than waiting days for oral titration, which is particularly valuable when differentiating from other unilateral headache disorders. 2

Standard Oral Dosing Regimen

• Begin with 25 mg three times daily (75 mg/day total) as the standard starting dose for both paroxysmal hemicrania and hemicrania continua. 1
• The mean effective dose across patients is 84 mg/day (±32 mg), so 75 mg/day captures most patients' therapeutic threshold. 1
• Expect complete headache resolution within 3 days of starting treatment at therapeutic doses—if no response occurs by day 3, the diagnosis should be reconsidered. 1, 2
• By definition, these headache disorders require absolute response to indomethacin; partial response suggests an alternative diagnosis. 3, 4

Dose Reduction Strategy After Initial Response

• After achieving sustained headache control, attempt dose reduction in all patients because 42% can maintain a pain-free state with 40–60% less indomethacin than the initial dose. 1
• Reduce by 25 mg every 2–4 weeks while monitoring for headache recurrence, aiming for the minimum effective maintenance dose. 1
• Some patients ultimately require only 25 mg/day for long-term control after initial higher-dose induction. 5, 1

Managing Indomethacin Intolerance

• Gastrointestinal side effects occur in approximately 23% of patients during long-term treatment but are usually manageable with ranitidine or proton-pump inhibitors. 1
• When gastrointestinal symptoms limit indomethacin tolerance, add pregabalin 150 mg/day, which may allow reduction of indomethacin from 75 mg/day to 25 mg/day while maintaining headache control. 5
• This combination strategy addresses the reality that continuous high-dose indomethacin can cause intolerable gastrointestinal disorders that force dose reduction or discontinuation. 5

Critical Dosing Principles

• Never accept partial headache response as confirmation of paroxysmal hemicrania or hemicrania continua—these diagnoses require complete and sustained symptom resolution with indomethacin. 4, 2
• The diagnosis has serious implications because it commits patients to potentially lifelong treatment with a drug that carries gastrointestinal and renal risks. 2
• Indomethacin works through cyclooxygenase inhibition, but its unique efficacy in these specific headache disorders (versus other NSAIDs) remains incompletely understood. 3

Long-Term Safety Profile

• No major adverse events were observed in patients followed for an average of 3.8 years on continuous indomethacin therapy for these conditions. 1
• The safety and tolerability profile of prolonged indomethacin treatment is favorable when doses are reduced to the minimum effective level after initial response. 1
• Routine monitoring for gastrointestinal symptoms and renal function is prudent during long-term therapy, though specific monitoring intervals are not established in the literature. 1

When Indomethacin Fails or Cannot Be Used

• Limited alternative options exist for patients who cannot tolerate indomethacin or wish to discontinue medication. 4
• Pregabalin represents the best-documented alternative or adjunct, allowing indomethacin dose reduction in some cases. 5
• For patients requiring indomethacin discontinuation, expect headache recurrence and consider trial of pregabalin monotherapy, though efficacy data are limited. 5, 4