Hiccups in Adults: A Comprehensive Clinical Review

Dr Neeraj Manikath , claude.ai

Abstract

Hiccups, or singultus, represent involuntary spasmodic contractions of the diaphragm and intercostal muscles, followed by sudden glottic closure. While typically benign and self-limiting, persistent and intractable hiccups can significantly impact quality of life and may herald serious underlying pathology. This review examines the pathophysiology, differential diagnosis, diagnostic approach, and evidence-based management of hiccups in adults, with practical insights for internists.

Introduction

Hiccups affect virtually all humans at some point, with episodes typically lasting minutes to hours. However, when hiccups persist beyond 48 hours (persistent hiccups) or extend beyond one month (intractable hiccups), they warrant thorough investigation and management. The prevalence of persistent hiccups is estimated at 1 in 100,000, with males affected four times more frequently than females. Understanding the complex reflex arc and diverse etiologies is essential for effective clinical management.

Pathophysiology: The Hiccup Reflex Arc

The hiccup reflex involves a complex neural pathway with three components:

Afferent limb: Vagus nerve (75%), phrenic nerve (25%), and sympathetic fibers (T6-T12). Any irritation along these pathways can trigger hiccups.

Central processing: The "hiccup center" is not anatomically discrete but involves the medulla oblongata, reticular formation, hypothalamus, and cervical spine segments C3-C5. This explains why diverse central nervous system pathologies can manifest with hiccups.

Efferent limb: Primarily the phrenic nerve innervating the diaphragm, with contributions from accessory respiratory muscles.

Pearl: The characteristic "hic" sound results from glottic closure occurring approximately 35 milliseconds after diaphragmatic contraction, creating sudden negative intrathoracic pressure against a closed glottis.

Classification and Etiology

Acute Hiccups (<48 hours)

Common benign triggers include:

Gastric distension (overeating, carbonated beverages, aerophagia)
Sudden temperature changes (hot liquids, cold beverages)
Alcohol consumption
Smoking
Excitement or emotional stress

Persistent Hiccups (>48 hours) and Intractable Hiccups (>1 month)

A systematic approach categorizes etiologies anatomically:

Gastrointestinal (most common in clinical practice):

Gastroesophageal reflux disease (GERD) accounts for up to 80% of persistent cases in some series
Gastric distension, gastroparesis
Peptic ulcer disease
Pancreatitis, pancreatic malignancy
Hepatobiliary disease, hepatomegaly
Bowel obstruction, inflammatory bowel disease

Thoracic:

Mediastinal masses (lymphoma, thymoma)
Myocardial infarction (particularly inferior wall)
Pericarditis, pericardial effusion
Esophageal lesions (tumors, strictures, candidiasis)
Diaphragmatic irritation (subphrenic abscess, pneumonia)

Neurological:

Stroke (particularly brainstem)
Tumors (posterior fossa, brainstem)
Multiple sclerosis
Meningitis, encephalitis
Head trauma
Neuromyelitis optica

Oyster: Intractable hiccups may be the presenting feature of brainstem stroke, particularly lateral medullary syndrome (Wallenberg syndrome), sometimes preceding other neurological symptoms by hours to days.

Metabolic/Toxic:

Uremia (chronic kidney disease)
Hyponatremia, hypocalcemia
Hypocapnia (hyperventilation)
Diabetes mellitus complications
Alcohol intoxication or withdrawal
General anesthesia (postoperative hiccups occur in 0.5-2% of procedures)

Infectious/Inflammatory:

COVID-19 (emerging recognition as presenting symptom)
Herpes zoster
Tuberculosis
Malaria
Neurosyphilis

Iatrogenic:

Medications: dexamethasone, benzodiazepines, barbiturates, alpha-methyldopa, chemotherapeutic agents
Post-procedural: endoscopy, bronchoscopy, central line placement
Post-surgical: abdominal, thoracic, or neurosurgical procedures

Psychogenic:

Conversion disorder
Malingering (rare)

Hack: Remember the mnemonic "HICCUPS" for life-threatening causes requiring urgent evaluation:

Heart (myocardial infarction, pericarditis)
Infection (meningitis, encephalitis)
CNS lesions (stroke, tumor)
Chemical/metabolic (uremia, hypocalcemia)
Uremia
Pharyngeal/laryngeal irritation
Stomach/esophagus pathology (perforation, obstruction)

Diagnostic Approach

History and Physical Examination

A thorough history should explore:

Onset, duration, frequency, and pattern
Associated symptoms (dysphagia, chest pain, neurological symptoms, weight loss, fever)
Medication review (including recent additions or changes)
Recent procedures or surgery
Past medical history (malignancy, neurological disease, immunosuppression)
Social history (alcohol, smoking)

Physical examination should include:

Complete neurological examination (cranial nerves, cerebellar function, sensory/motor assessment)
Cardiovascular and respiratory examination
Abdominal examination (hepatosplenomegaly, masses, peritoneal signs)
Ear, nose, throat examination (pharyngeal irritation, foreign bodies)

Investigations

The extent of investigation depends on duration and clinical context.

First-tier investigations for persistent hiccups:

Complete blood count, comprehensive metabolic panel
Chest radiograph
Electrocardiogram
Upper gastrointestinal endoscopy (if gastroesophageal symptoms present)

Second-tier investigations (intractable cases or red flags):

CT chest/abdomen/pelvis with contrast
MRI brain and cervical spine (if neurological symptoms or signs)
Echocardiography (if cardiac symptoms)
pH monitoring or esophageal manometry (if GERD suspected)
Bronchoscopy (if pulmonary symptoms)
Specialized investigations based on clinical suspicion

Pearl: In immunocompromised patients with intractable hiccups, consider opportunistic infections including CNS toxoplasmosis, cryptococcal meningitis, or cytomegalovirus disease.

Management Strategies

Non-pharmacological Interventions

While evidence is largely anecdotal, numerous physical maneuvers may terminate acute hiccups by interrupting the reflex arc:

Vagal stimulation techniques:

Valsalva maneuver
Carotid sinus massage (contraindicated in elderly or those with carotid disease)
Drinking ice-cold water rapidly
Swallowing granulated sugar (one teaspoon)
Nasopharyngeal stimulation (catheter insertion)

Respiratory maneuvers:

Breath-holding
Rebreathing into paper bag (increases PCO2)
Hyperventilation followed by breath-holding

Hack: The "digital rectal massage" technique, while unconventional, has case report evidence and involves gentle circular digital stimulation for 30-60 seconds. This stimulates pelvic nerves, interrupting the reflex arc. Though awkward to suggest, it may be effective when other measures fail.

Pharmacological Management

No medication is FDA-approved specifically for hiccups in the United States, making treatment largely empirical and off-label.

First-line agents:

Baclofen (GABA-B agonist): Most evidence-based option for persistent/intractable hiccups. Start 5 mg three times daily, titrate to 20 mg three times daily. Response rate approximately 60-80%. Mechanism involves central inhibition of the reflex arc. Taper gradually when discontinuing to avoid withdrawal.

Chlorpromazine: Historically considered "gold standard." Dose 25-50 mg orally or intramuscularly three to four times daily. Concerns about extrapyramidal side effects and sedation limit use, particularly in elderly patients. Consider as alternative when baclofen ineffective.

Metoclopramide: Particularly useful when GERD-related. Dose 10 mg three to four times daily. Prokinetic and antiemetic properties address underlying gastric pathology. Risk of tardive dyskinesia with prolonged use.

Second-line and adjunctive agents:

Gabapentin: Starting dose 300 mg daily, increasing to 900-1800 mg daily in divided doses. Growing evidence base, particularly for neuropathic etiologies. Generally well-tolerated.

Haloperidol: 2-5 mg orally or intramuscularly. Effective but significant side effect profile.

Midazolam: For intractable cases, continuous infusion in hospital setting may be necessary. Requires monitoring.

Nifedipine: 10-20 mg three times daily. Limited evidence but may help in selected cases.

Hack: For GERD-related hiccups, consider the "triple therapy" approach: proton pump inhibitor (omeprazole 40 mg daily) plus baclofen (15-30 mg daily) plus gabapentin (900-1800 mg daily). This addresses the underlying pathology while inhibiting the reflex centrally through multiple mechanisms.

Interventional Procedures

Reserved for refractory cases:

Phrenic nerve blockade or crush: Temporary or permanent interruption. Success rates 80-90% but risk of hemidiaphragm paralysis.

Vagal nerve stimulation: Emerging therapy with case series showing efficacy.

Acupuncture: Multiple randomized trials show benefit, particularly at acupoint P6 (Neiguan). Consider in patients preferring non-pharmacological approaches.

Hypnosis and behavioral therapy: May benefit psychogenic cases or provide adjunctive support.

Special Populations

Postoperative patients: Hiccups occur in approximately 1-2% of surgical patients, particularly after abdominal or thoracic procedures. Early mobilization, addressing gastric distension, and judicious use of baclofen or metoclopramide are reasonable approaches.

Cancer patients: Hiccups affect up to 30% of terminal cancer patients. Consider structural causes (mediastinal masses, hepatomegaly), metabolic derangements, or medication effects (dexamethasone, chemotherapy). Palliative approach emphasizes symptom control with baclofen or chlorpromazine.

Chronic kidney disease: Uremic hiccups affect 30-50% of dialysis patients. Optimize dialysis adequacy, correct metabolic abnormalities, and consider baclofen (dose-adjust for renal function) or gabapentin.

Oyster: In patients with persistent hiccups and negative initial workup, consider temporal arteritis in those over 50 with concurrent headache or jaw claudication. The association is rare but well-documented.

Complications and Quality of Life Impact

Intractable hiccups significantly impair quality of life through:

Sleep deprivation and fatigue
Difficulty eating and weight loss
Interference with speech and social functioning
Wound dehiscence in postoperative patients
Aspiration risk
Depression and anxiety

Recognizing these impacts underscores the importance of aggressive investigation and treatment rather than dismissing hiccups as benign nuisance.

Conclusion

Hiccups represent a diagnostic and therapeutic challenge in internal medicine. While acute episodes are typically benign, persistent and intractable hiccups demand systematic evaluation for underlying pathology. A structured approach examining gastrointestinal, thoracic, neurological, and metabolic causes, combined with targeted investigations, identifies treatable etiologies in the majority of cases. Baclofen remains the most evidence-based pharmacological therapy, though individualized treatment selection based on suspected etiology optimizes outcomes. Recognition of life-threatening causes and aggressive management of refractory cases are essential competencies for internists.

Final Pearl: Always document hiccup frequency and characteristics at baseline and during treatment. This objective measure guides therapeutic decisions and helps distinguish true improvement from placebo effects or natural resolution.

Selected References

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Cymet TC. Retrospective analysis of hiccups in patients at a community hospital from 1995-2000. J Natl Med Assoc. 2002;94(6):480-483.
Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. Am J Gastroenterol. 1992;87(12):1789-1791.
Kohse EK, Hollmann MW, Bardenheuer HJ, Kessler J. Chronic hiccups: an underestimated problem. Anesth Analg. 2017;125(4):1169-1183.
Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil. 2012;18(2):123-130.
Petroianu G, Hein G, Stegmeier-Petroianu A, Bergler W, Rüfer R. Gabapentin "add-on therapy" for idiopathic chronic hiccup. J Clin Gastroenterol. 2000;30(3):321-324.
Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol. 2009;7(4):122-127.
Smith HS, Busracamwongs A. Management of hiccups in the palliative care population. Am J Hosp Palliat Care. 2003;20(2):149-154.

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