What is the recommended pharmacologic management, including first‑line and alternative agents with dosing, for persistent (>48 hours) or intractable (>1 month) hiccups after reversible causes have been excluded?

Pharmacologic Management of Persistent and Intractable Hiccups

For persistent or intractable hiccups after excluding reversible causes, baclofen (5-20 mg three times daily) or gabapentin should be used as first-line therapy, with chlorpromazine (25-50 mg three to four times daily) and metoclopramide reserved for refractory cases. 1

First-Line Pharmacologic Agents

Baclofen (Preferred First-Line)

• Start with 5 mg three times daily and titrate up to 20 mg three times daily as needed 1
• Baclofen is supported by small randomized, placebo-controlled trials demonstrating efficacy 1
• Significantly less likely to cause side effects during long-term therapy compared to neuroleptic agents 1
• Single oral doses have successfully terminated intractable hiccups lasting years 2

Gabapentin (Alternative First-Line)

• Gabapentin is equally appropriate as first-line therapy based on observational data 1
• Shares the safety advantage of baclofen with lower risk of side effects compared to standard neuroleptics during prolonged use 1

Second-Line (Reserve) Agents

Chlorpromazine

• Dosing: 25-50 mg three to four times daily orally 3
• For intractable hiccups specifically, use 25-50 mg three to four times daily; if symptoms persist for 2-3 days, parenteral therapy is indicated 3
• Observational data support effectiveness 1
• Monitor for hypotension and neuromuscular reactions, particularly in elderly or debilitated patients 3
• Increase dosage gradually in elderly patients who are more susceptible to adverse effects 3

Metoclopramide

• Supported by small randomized, placebo-controlled trials 1
• Acts as both a prokinetic and dopamine antagonist 4
• Reserve for cases not responding to baclofen or gabapentin 1

Treatment Algorithm

1. Exclude and treat underlying causes first - gastroesophageal reflux disease, medications, metabolic disorders, or structural lesions 1, 5

2. Consider empirical trial of anti-reflux therapy if gastroesophageal reflux is suspected as the etiology 1

3. Initiate baclofen 5 mg three times daily as first-line pharmacotherapy 1

   • Titrate upward to 20 mg three times daily based on response 1
   • Alternative: Start gabapentin if baclofen is contraindicated 1

4. If inadequate response after appropriate titration, add or switch to chlorpromazine 25-50 mg three to four times daily 3, 1

5. Metoclopramide may be used as an alternative second-line agent 1, 4

Critical Safety Considerations

• Chlorpromazine requires gradual dose escalation and close monitoring for hypotension and extrapyramidal symptoms 3
• Elderly patients need lower starting doses and slower titration with all agents 3
• Neuroleptic agents (chlorpromazine, metoclopramide) carry higher risk of long-term side effects, justifying their reserve status 1

Evidence Quality Context

No adequately powered, well-designed trials exist for hiccup treatment 1. The recommendation for baclofen and gabapentin as first-line agents is based on their combination of limited efficacy data from small controlled trials (baclofen, metoclopramide) or observational studies (gabapentin, chlorpromazine) plus superior safety profiles during the prolonged therapy often required for intractable hiccups 1.