What is the role of Gabapentin (anticonvulsant) in treating refractory hiccups?

Gabapentin as Second-Line Therapy for Refractory Hiccups

Gabapentin should be considered as an effective second-line agent for refractory hiccups at doses of 300-1200 mg daily in divided doses, particularly when first-line agents like chlorpromazine or baclofen have failed or are contraindicated due to side effects. 1

Evidence Supporting Gabapentin Use

Efficacy Profile

• Gabapentin demonstrates consistent therapeutic success across multiple case series, with positive outcomes reported in all 17 case reports and 2 case series evaluating its use for persistent or intractable hiccups 1
• The medication typically shows rapid onset of action, with complete resolution of hiccups within 24 hours in documented cases 2
• Therapeutic response is maintained even at low doses (100 mg twice daily), making it particularly suitable for patients at risk of medication side effects 2

Recommended Dosing Strategy

• Start with gabapentin 100-300 mg twice daily and titrate upward based on clinical response 2, 1
• Maximum effective doses range from 1200-3600 mg daily in divided doses, though lower doses are often sufficient for hiccup control 3, 1
• Duration of therapy typically ranges from 3 weeks to several months, with successful discontinuation after symptom resolution 2

Clinical Context and Patient Selection

Ideal Candidates for Gabapentin Therapy

• Patients in stroke rehabilitation or palliative care settings where chlorpromazine's sedating and extrapyramidal side effects are particularly undesirable 1
• Transplant recipients requiring hiccup control without drug-drug interactions with immunosuppressants, as gabapentin lacks significant interactions with transplant medications 2
• Patients who have failed or cannot tolerate baclofen, which commonly causes severe CNS side effects at therapeutic doses 2
• Patients with aripiprazole-induced hiccups, where low-dose gabapentin (300 mg twice daily) has shown complete regression 4

Mechanism of Action

• Gabapentin likely works by reducing nerve impulse transmission and modulating diaphragmatic activity through its effects on voltage-gated calcium channels 4
• The medication binds to the α2-δ subunit of voltage-gated calcium channels and inhibits release of excitatory neurotransmitters (glutamate, norepinephrine, substance P), which may interrupt the hiccup reflex arc 3

Safety and Tolerability Profile

Advantages Over Alternative Agents

• Gabapentin is very well tolerated with only minor adverse effects reported (dizziness, somnolence), unlike chlorpromazine which causes significant sedation and extrapyramidal symptoms 1
• No serious drug-drug interactions with immunosuppressants or other transplant medications, making it safer than many alternatives in complex patients 2
• Minimal cardiovascular effects, unlike some first-line agents that can cause hypotension 3

Common Side Effects to Monitor

• Dizziness and somnolence are the most frequently reported adverse effects, though these are typically mild at the doses used for hiccups 3, 1
• Dry mouth and constipation may occur but are less common than with other agents 3

Treatment Algorithm for Refractory Hiccups

First-Line Approach

• Address reversible causes first: GERD, gastric distension, CNS lesions, metabolic abnormalities, and medication-induced hiccups 4
• Consider chlorpromazine or baclofen as initial pharmacotherapy if no contraindications exist 1

Second-Line Escalation to Gabapentin

• Initiate gabapentin 300 mg twice daily when first-line agents fail or cause intolerable side effects 4, 1
• Assess response within 24-48 hours, as therapeutic effect typically occurs rapidly 2
• Titrate upward by 300 mg every 3 days if needed, to a maximum of 1200-1800 mg daily in divided doses 3, 1

Combination Strategies

• Gabapentin may be combined with interventional approaches such as phrenic nerve pulsed radiofrequency when monotherapy is insufficient 5
• Consider adding gabapentin after interventional procedures if symptoms persist, as this combination has shown complete resolution in refractory cases 5

Critical Pitfalls to Avoid

• Do not use gabapentin as first-line therapy without attempting standard agents like chlorpromazine or baclofen first, as the evidence base for gabapentin consists primarily of case reports rather than controlled trials 1
• Avoid premature discontinuation before 3 weeks of therapy, as some patients require sustained treatment for durable symptom control 2
• Do not overlook underlying causes such as CNS lesions, GERD, or medication effects (particularly aripiprazole) that may require specific interventions 4
• Recognize that gabapentin does not accelerate gastric emptying, so it should not be used as primary therapy for gastroparesis-related hiccups without addressing the underlying motility disorder 3

Duration of Therapy and Discontinuation

• Plan for 3-4 weeks of therapy after complete symptom resolution before attempting discontinuation 2
• Taper gabapentin gradually over 1-2 weeks rather than abrupt cessation to avoid symptom recurrence 6
• Monitor for hiccup recurrence after discontinuation, as some patients may require longer-term maintenance therapy 6