Diagnosis and Management of Hiccups in the Patient - Oncology ...

Manuscript submitted July 14, 2008; accepted May 26, 2009. 

Correspondence to: Mark A. Marinella, MD, FACP, Dayton 

Physicians, LLC, 1382 east Stroop road, Dayton, OH 

45429; telephone: 937-293-4383; fax: 937-293-4365; e-mail: 

Mmarinella@pol.net 

J Support Oncol 2009;7:122–127, 130 © 2009 Elsevier Inc. All rights reserved. 

review 

Diagnosis and Management of Hiccups 

in the Patient with Advanced Cancer 

Mark A. Marinella, MD, FACP 

C 

ancer patients experience a variety of 

disease- and treatment-related respiratory 

complications that can significantly 

impair quality of life. Some of 

the most common of these complications encountered 

in clinical practice include cough, 

hemoptysis, dyspnea, airway obstruction, aspiration 

syndromes, thromboembolic disease, infection, 

and hiccups. 1 

Severe hiccups are responsible for approximately 

4,000 annual hospitalizations in the United 

States. 2 However, the incidence of prolonged 

hiccups in the oncology population is unclear, 

and may be underreported due to the presence 

of other pressing comorbid complications that 

commonly occur in the palliative and hospice 

settings. The typical cancer patient has many 

and often simultaneous risk factors for developing 

hiccups, so clinicians providing adjuvant 

or palliative care should be familiar with the 

pathophysiology, etiologies, and management of 

this potentially debilitating complication. 

Definition 

Hiccups occur when an abrupt, involuntary 

spasm of the diaphragm and intercostal muscles 

is followed by sudden closure of the glottis, generating 

the characteristic onomatopoeic “hic” 

sound. 3–6 The medical term for hiccups, singultus, 

is of Latin origin and means to gasp or sigh. 7 

Hiccups were first attributed to phrenic nerve 

irritation by Shortt in 1833. 8 Clinically, most 

hiccup episodes are benign, of acute onset, and 

self-limited, typically ceasing within minutes. 6 

However, persistent and intractable hiccups are 

defined as lasting for more than 48 hours or 1 

month, respectively. 6,9 

Abstract Benign, self-limited hiccups are more of a nuisance, but persistent 

and intractable hiccups lasting more than 48 hours and 1 month, 

respectively, are a source of significant morbidity in the patient with advanced 

malignancy. The hiccup reflex is complex, but stimulation of vagal 

afferents followed by activation of efferent phrenic and intercostal nerve 

pathways results in contraction of the diaphragm and intercostal muscles, 

respectively. The etiology of hiccups in the cancer and palliative care population 

may include chemotherapy, electrolyte derangements, esophagitis, 

and neoplastic involvement of the central nervous system (CNS), thorax, 

and abdominal cavity. Prolonged hiccups can result in depression, fatigue, 

impaired sleep, dehydration, weight loss, malnutrition, and aspiration syndromes. 

Evaluation should be symptom-directed, focusing mainly upon 

the CNS and thoracoabdominal cavities as well as assessment of medications 

and serum chemistries. Most patients with ongoing hiccups require 

pharmacotherapy, with chlorpromazine being the only US Food and Drug 

Administration-approved agent. However, numerous other medications 

have been reported to be efficacious for treating intractable hiccups. 

Gabapentin has recently been shown to terminate hiccups effecitvely in 

cancer patients and may emerge as a therapy of choice in the palliative 

setting due to favorable tolerability, pain-modulating effects, minimal adverse 

events, and lack of drug interactions. 

Pathophysiology 

The pathogenesis of hiccups is complex and not 

fully understood but is generally mediated from a 

variety of etiologies with similar neurophysiologic 

mechanisms resulting in diaphragmatic contraction 

and spasm. 1,2 interestingly, hiccup episodes 

involve unilateral contraction of the left hemidiaphragm 

in approximately 80% of cases. 9,10 The 

frequency of hiccups ranges from 4–60/minute, 

with little intraindividual variability. 10,11 There is 

no clear physiologic purpose of hiccups, although 

this remains debated. 

The hiccup-reflex arc is composed of afferent 

and efferent limbs and a central hiccup center. 6,12–14 

The afferent pathway consists of the vagus nerve 

(cranial nerve X), the phrenic nerve (derived 

from cervical segments C2–C4), and the sympathetic 

chain (derived from thoracic segments T6– 

T12). 14 The sympathetic nervous system may play 

Dr. Marinella is a 

practicing medical 

oncologist, Hematology- 

Oncology of Dayton, 

and Assistant Clinical 

Professor, Department 

of internal Medicine, 

wright State University 

School of Medicine, 

Dayton, Ohio. 

122 www.SupportiveOncology.net Th e Jo u r n a l o f Su p p o rT i v e on c o l o g y

some role in the generation and/or propogation of hiccups, as 

they cease after administration of the beta-receptor antagonist 

carvedilol. 15 The vagus nerve, in particular, can be activated in 

various anatomic areas (thoracic and abdominal viscera as well 

as within head and neck structures). For instance, irritation 

of the auricular branch of the vagus nerve (Arnold’s nerve), 

which innervates the auditory canal, by cerumen, foreign bodies, 

bugs, and even hair, has resulted in hiccups. 16 

CNS areas such as the brainstem respiratory center, the 

reticular activating system (rAS) in the medulla oblongata, 

the hypothalamus, and temporal lobes are also involved in the 

pathogenesis of hiccups, although their precise contributions 

remain to be elucidated. 6,17 release of 5-hydroxytryptamine 

from gut enterochromaffin cells and enteric vagal afferents 

following administration of various chemotherapeutic agents 

(especially cisplatinum) may lead to hiccups. 18 

An additional mechanism of stimulating the hiccup arc is 

via stimulation of the chin integument. Stimulation of the chin 

via shaving produced transient hiccups in two patients. 16 The 

authors postulated that sensory afferents to the spinal tract of 

the trigeminal nerve project to the rAS, which subsequently 

recruits activation of the phrenic nerve nucleus leading to 

stimulation of the efferent hiccup arc. 16 in these patients, the 

hiccups disappeared after anesthetizing the mental nerve, suggesting 

that the trigeminal nerve plays a role in the hiccup 

mechanism. 

The efferent pathway of the hiccup arc primarily consists 

of the phrenic nerve, the primary motor input to the 

diaphragm. 6,13,14 Additionally, the external intercostal (derived 

from segments T1–T11) and the scalenus anticus nerves 

stimulate contraction of the intercostal and scalene muscles, 

respectively. 1–6 Shortly after activation of the hiccup arc, the 

recurrent laryngeal nerve stimulates closure of the glottis, resulting 

in the characteristic “hic” sound. 2 

Significant acute negative intrathoracic pressure may occur, 

resulting as hypotension, bradycardia, pneumomediastinum, 

and subcutaneous emphysema. 6,19 Mathew 20 studied the effects 

of neonatal hiccups on systemic arterial pressure and noted 

acute, transient declines in systolic pressures that were attributed 

to decreased stroke volume and vascular resistance. This 

decline in vascular resistance appears to result from increased 

dilation and volume of the thoracic aorta induced by decreases 

in hiccup-associated intrathoracic pressure. 20 whether hiccupassociated 

systolic hypotension is deleterious to cardiovascular 

function in adults is unclear, but it remains a plausible etiology 

of pathologic hemodynamic changes in those patients with underlying 

heart disease. 

Hiccups often follow acute gastric distention in such situations 

as endoscopy, rapid ingestion of food or carbonated beverages, 

gastric outlet obstruction, or small bowel obstruction— 

all of which are believed to stimulate gastric vagal afferent 

activity. 2,3,6 Gluck and Pop 21 reproducibly demonstrated the 

induction of acid-induced hiccups via esophageal acid perfusion 

in a patient with chronic hiccups. Additionally, esophageal 

distention has been implicated to cause hiccups via stimulation 

of mechanoreceptors and is the presumed pathogenic 

Table 1 

Etiologies of Hiccups in the Patient with Cancer 

Malignancy 

Esophagogastric cancer 

Colon cancer 

Hepatoma 

Leukemia 

Lung cancer 

Lymphoma 

Pancreatic cancer 

Renal cancer 

Liver metastasis 

Metabolic Derangements 

Hyponatremia, hypokalemia, hypocalcemia 

Renal failure 

Uremia 

Uncontrolled diabetes mellitus 

Hypoadrenalism 

CNS Pathology 

Brain tumors (eg, gliomas, metastatic tumors) 

Stroke 

Hematoma/cerebral hemorrhage 

Encephalitis/meningitis 

Brain abscess/toxoplasmosis 

Cardiovascular Disorders 

Myocardial ischemia/infarction 

Pericardial effusion/pericarditis 

Thoracic/Pulmonary Disorders 

Pneumonia 

Pleural effusion/pleuritis 

Thoracic herpes zoster 

Mechanical ventilation 

Gastrointestinal Disorders 

Erosive esophagitis 

Infectious esophagitis (eg, herpes simplex, Candida species) 

Peptic ulcer disease 

Gastric distention from food, liquid, air, endoscopy 

Gastric outlet or small bowel obstruction 

Pancreatitis 

Ascites 

Cholecystitis 

Subdiaphragmatic abscess 

Surgical Procedures/General Anesthesia 

Epidural Injections with Local Anesthetics 

Psychogenic 

vo l u m e 7, nu m b e r 4 ■ Ju ly/au g u S T 2009 www.SupportiveOncology.net 

Marinella 

cause of hiccups associated with achalasia, esophageal tumors, 

strictures, and food impaction. 2–6,21 indeed, Fass et al 22 induced 

acute, transient hiccups in 40% of healthy subjects with inflation 

of proximal esophageal balloons. interestingly, all of the 

patients in this study who developed hiccups were men. 22 This 

finding is in keeping with recent studies revealing a significant 

male predominance of hiccups in patients receiving cytotoxic 

chemotherapy. 18,23 The mechanisms for male predominance of 

hiccups in these studies are not explained. Because a variety 

of processes can result in hiccups, it remains most likely that 

123

Advanced Cancer: Diagnosis and Management of Hiccups 

Table 2 

Causes of Drug-induced Hiccups 

Utilized in Cancer Care 

Antibiotics 

Benzodiazepines 

Corticosteroids (especially dexamethasone) 

Anabolic steroids 

Perphenazine 

General inhalational anesthesia 

Opioids 

Chemotherapeutic agents (significant male predominance) 

Cisplatinum 

Carboplatin 

Cyclophosphamide 

Docetaxel 

Etoposide 

Gemcitabine 

Irinotecan 

Paclitaxel 

Vindesine 

Vinorelbine 

stimulation of the vagus or phrenic nerves, diaphragm, head 

and neck structures, or CNS areas by anatomic lesions; metabolic 

derangements; or drugs induce hiccups through complex 

neural mechanisms that continue to be elucidated. 

Etiologies of Hiccups in Patients with Cancer 

Perhaps more than any patient population in medicine, 

those with malignancy represent some of the most medically 

complex situations due not only to cancer and metastasis but 

also to unrelated comorbidities; supportive pharmacologic 

treatments; infectious complications; and anticancer therapies 

such as chemotherapy, radiotherapy, and surgery. As such, 

many potential mechanisms for induction of the hiccup reflex 

exist, with many patients possessing several factors, often making 

it difficult to pinpoint the exact etiology. 

Tables 1 and 2 display some of the most commonly reported 

causes of hiccups in the cancer population. Overall, pathology 

of the gastrointestinal tract, thoracic viscera, and CNS is 

among the most common etiologies of persistent and intractable 

hiccups. 2,5,6 For instance, erosive or infectious esophagitis 

is common in the cancer and palliative care setting, as is gastric 

distention resulting from malignant gastric outlet and small 

bowel obstruction. 24–26 in addition, pneumonia, malignant 

pleural effusion, empyema, and chest wall zoster may invoke 

the afferent hiccup arc and lead to singultus. 1,6,8,27 

Stimulation of various CNS centers involved with the 

physiology of hiccups by primary or metastatic brain tumors, 

stroke, cerebral hemorrhage, abscess, meningoencephalitis, 

or malignant hydrocephalus may also be etiologic. 28–33 various 

metabolic derangements, most commonly hyponatremia, may 

induce the hiccup reflex. 34,35 Hypoadrenalism has been reported 

to result in hiccups. 36 Myocardial infarction is a well-described 

precipitant of hiccups and likely results from ischemic 

activation of vagal pathways. 37 Thoracic, abdominal, or pelvic 

tumors invading the diaphragm or vagus nerve may stimulate 

hiccups .2–6,38,39 

Drug-induced causes are protean, with benzodiazepines, 

corticosteroids, antibiotics, opioids, and cytotoxic agents 

among the most common in patients with cancer. A more extensive 

listing can be found in Table 2. 40–49 A study by Takiguchi 

et al 23 showed a significant male predominance of hiccups 

following cytotoxic chemotherapy. 

Patient Evaluation 

Acute, self-limited hiccups of less than 48 hours’ duration 

typically do not require exhaustive evaluation. Persistent and 

intractable hiccups without obvious explanation, such as those 

precipitated by a drug, usually require a diagnostic evaluation to 

exclude potentially treatable or life-threatening precipitants. 

A meticulous physical examination with attention to head 

and neck structures, heart, lungs, chest wall, skin, abdomen, 

and CNS should be performed. The external auditory canals 

should be examined to exclude inflammation, foreign bodies, 

hairs, or impacted cerumen. 16,50 Careful neurologic examination 

with attention to dysfunction of each of the hiccupproducing 

areas (eg, afferent limb, CNS structures, and efferent 

limb) should be performed. 2 if cancer is suspected, a search 

for lymphadenopathy or mass lesions is essential. 

Site-directed imaging studies such as chest radiography, 

abdominal radiography, CT, or Mri should be obtained if any 

element of the history or physical examination suggests an etiology 

affecting a particular organ system. examples could include 

pneumonia, ileus or bowel obstruction, brain metastasis, 

or intra-abdominal malignancy. in patients with odynophagia 

or dysphagia, upper endoscopy should be performed to detect 

erosive or infectious esophagitis, stricture, or malignancy. 26 

electrocardiography should be obtained to exclude myocardial 

ischemia. 4,6,37 

Basic laboratory studies including serum electrolytes and 

creatinine levels should be routine, because hyponatremia 

is a common etiology of hiccups in acutely ill patients, although 

hypocalcemia, hypokalemia, or renal failure may be 

discovered. 6,34,35 Other invasive studies such as lumbar puncture 

to exclude CNS infection or bronchoscopy to exclude 

infection or a neoplasm should be performed only on a caseby-case 

basis. 

Complications of Persistent and 

Intractable Hiccups 

Table 3 displays some of the most common complications 

of ongoing hiccups that may be encountered in the patient 

with cancer. General complications of intractable hiccups include 

anxiety and exacerbation of depressive symptoms, both 

of which are common in patients with advanced or terminal 

cancer. 1,5,6 Sleep impairment due to nocturnal hiccups minimizes 

necessary restorative sleep and leads to daytime somnolence 

and fatigue, which may worsen anxiety, depression, 

appetite, and cognitive function. 51 

Chronic hiccups increase energy expenditure through con- 


traction of skeletal muscles; this result increases caloric requirements, 

which are often difficult to meet in patients who 

are receiving chemotherapy or radiation therapy. Hiccups 

may interfere with the intake of fluids and food, leading to 

poor caloric intake, which can result in malnutrition, weight 

loss, and dehydration. volume depletion and dehydration may 

result in decreased renal blood flow and impaired elimination 

of neurotoxic opioid metabolites. if a hiccup paroxysm occurs 

during food ingestion, aspiration may lead to life-threatening 

acute airway obstruction or aspiration pneumonitis and respiratory 

failure. 

Negative intrathoracic pressures generated during severe 

hiccup paroxysms may result in pneumomediastinum. 6,17,20 Hypotension 

may result from mechanisms mentioned previously 

and may be more likely to occur in the setting of hypotension 

or underlying cardiovascular dysfunction. 20 Dehiscence of sternal 

and other surgical incisions has been described. 6,19 Some 

authors have reported death as a complication of intractable 

hiccups, although multiple comorbidities in the cancer population 

make this distinction difficult. 3–6 

Nonpharmacologic Options 

Benign, self-limited hiccups do not require pharmacologic 

or invasive maneuvers for termination. However, some patients 

may attempt folk remedies and other nonpharmacologic 

approaches, which may be acceptable if clinically appropriate. 

Some folk remedies that anecdotally have been reported 

to terminate hiccups include stimulation of the palate or 

pharynx with a cotton applicator or catheter; traction on the 

tongue; pressure over the eyebrow area; lifting the uvula with 

a spoon; performing a valsalva maneuver; gargling or drinking 

ice water; eating a spoonful of granulated sugar or peanut 

butter; drinking water from the opposite side of a cup; biting a 

lemon; black pepper–induced sneezing; sudden fright; breathholding; 

and breathing into a paper bag. increased pCO2 and 

cerebral vasoconstriction may be the physiologic explanation 

for hiccup cessation following breath-holding or paper bag 

breathing. 6,16,52–54 Digital rectal massage has been reported to 

be effective at terminating intractable hiccups in small case 

series55,56 ; however, this measure is uncomfortable and should 

not be attempted in the setting of neutropenia or severe perianal 

dermatitis. Of course, not all these approaches are appropriate 

for a given patient, but they may be worth trying if they 

would not be detrimental for an individual patient. 

Pharmacologic Treatment 

Patients with persistent or intractable hiccups usually require 

pharmacologic intervention, especially if quality of life is 

impaired or medical complications are apparent. 52,57 The only 

medication approved by the US Food and Drug Administration 

(FDA) for hiccups is the antipsychotic phenothiazine 

chlorpromazine, which may not be optimal for all patients due 

to adverse effects such as hypotension, urinary retention, glaucoma, 

or delirium (Table 4). 4,6,57 

Treatments dating to the 1970s and 1980s include the anticonvulsants 

phenytoin, valproic acid, and carbamazepine. 6,52,58 

Table 3 

Complications of Hiccups 

Anxiety 

Arrhythmia 

Aspiration syndromes 

Bradycardia/heart block 

Carotid dissection 

Dehydration 

Depression 

Dyspnea/hypoxia 

Fatigue 

Malnutrition 

Pneumomediastinum 

Sleep deprivation 

Speech impairment 

Subcutaneous emphysema 

Vomiting 

Weight loss 

Wound dehiscence 



These drugs may inhibit hiccups at the central level through 

blockade of neural sodium channels but possess a narrow therapeutic 

index and the tendency for multiple drug interactions, 

making them less than optimal in patients with advanced 

cancer who typically receive numerous medications. Amitriptyline, 

an older tricyclic antidepressant, may terminate hiccups 

but is associated with significant adverse effects, mainly of an 

anticholinergic nature. 6 Metoclopramide has been utililzed for 

at least 20 years and is often effective for termination of hiccup, 

most likely through central dopaminergic blockade. 57,59 

Haloperidol, a dopamine antagonist, may be useful in patients 

with concurrent agitated delirium, but monitoring for extrapyramidal 

symptoms is important. 34,52,57 The antispasmodic 

GABA (gamma aminobutyric acid) antagonist baclofen has 

some efficacy for the treatment of intractable hiccups but may 

not be well tolerated by elderly patients due to the frequent 

occurrence of ataxia, delirium, dizziness, and sedation. 36,57 

The calcium channel blocker nifedipine has been reported 

to terminate persistent hiccups but has a propensity for inducing 

hypotension, which may be especially severe in volumecontracted 

patients or those receiving opioids. 60,61 Nimodipine 

is a newer calcium channel blocker that has been reported to 

be effective in a few case reports. 62 The mechanism of hiccup 

termination with nifedipine and nimodipine is likely secondary 

to blockade of neuromuscular calcium channels. 60–62 

Bolus intravenous infusion of the sodium channel–blocking 

anesthetic lidocaine has terminated hiccups in postoperative 

patients, but the risk for cardiovascular and neurologic toxicities 

should be considered in the frail patient with advanced 

malignancy. 63 Nebulized lidocaine may be effective via a local 

anesthetic effect upon irritant sensory afferents and has a 

much greater safety profile than does the intravenous route. 64 

Similarly, nebulized saline solution has been reported by some 

authors to terminate hiccups in the palliative care settting. 65 

Although benzodiazepines, especially valium, are wellknown 

precipitants of hiccups, the intravenous agent mida- 

125


zolam has been successfully utilized in patients with terminal 

hiccups. 66 Midazolam infusion may be especially useful if intractable 

hiccups occur in the setting of refractory terminal 

delirium or agitation. 

The neurostimulant methylphenidate may terminate hiccups 

through inhibition of dopamine and norepinephrine uptake. 

Patients with concurrent depression or opioid-induced 

sedation may be good candidates for methylphenidate treatment 

of hiccups. 67,68 

Nefopam, an intravenous nonopioid analgesic structurally 

related to antiparkinsonian and antihistaminic medications, 

has been reported to abruptly terminate hiccups in 

three patients with refractory hiccups, one of whom had acute 

leukemia. 69,70 

Carvedilol suppressed a 2-year bout of hiccups in a patient 

with tardive dyskinesia. 15 Although the mechanism is unclear, 

antagonism of the sympathetic component of the afferent hiccup 

arc may be responsible. whether beta-adrenergic antagonists 

as a class are useful for treating hiccups is unclear, as data 

are insufficient. 

Dexamethasone, although a recognized cause of hiccups, 71,72 

has terminated persistent hiccups in patients with acquired immunodeficiency 

syndrome (AiDS) with progressive multifocal 

leukoencephalopathy. 73 

Because patients with advanced or terminal malignancy 

are often receiving numerous medications and have multiple 

comorbidities and organ dysfunction, a pharmacologic agent 

with minimal adverse effects and drug interactions would be 

of benefit. recently, case series of the effectiveness of gabapentin 

on the termination of intractable hiccups have been 

reported. 45,75 Gabapentin, a newer antiepileptic drug commonly 

utilized in cancer and palliative medicine as an adjuvant 

pain medication, produces blockade of neural calcium 

channels and increases release of GABA, which may modulate 

diaphragmatic excitability. 74,76 Gabapentin is not hepatically 

metabolized and possesses no known significant drug 

interactions, making it a potentially useful agent in the advanced 

cancer setting. Low binding to plasma proteins makes 

gabapentin attractive in cancer patients, who often manifest 

hypoproteinemia due to malnutrition or liver dysfunction. 

Porzio et al 74 reported effective hiccup cessation with gabapentin 

in three patients with advanced malignancy, with no 

obvious adverse effect. Gabapentin may be especially useful 

for hiccup therapy in patients requiring adjuvant analgesia 

related to neuropathic cancer pain. whether gabapentin will 

emerge as front-line treatment for persistent and intractable 

hiccups in the palliative care and hospice settings remains to 

be seen. 

Other Therapeutic Approaches 

Acupuncture may provide relief from intractable hiccups. 

However, it may be difficult to perform in severely ill patients 

and to find a practitioner with expertise. 77,78 

Phrenic nerve block with a local anesthetic has been utilized 

to treat intractable hiccups in several patients with advanced 

malignancies, including pancreatic, gastric, and lung carci- 

Table 4 

Reported Therapies for Persistent/Intractable Hiccups 

Pharmacologic therapy 

Baclofen 

Carvedilol 

Chlorpromazine 

Gabapentin 

Haloperidol 

Ketamine 

Lidocaine infusion 

Methylphenidate 

Metoclopramide 

Nebulized saline or lidocaine 

Nefopam 

Nifedipine/nimodipine 

Olanzapine 

Phenytoin 

Valproic acid 

Irritation of the pharynx with a rubber catheter 

Digital rectal stimulation 

Phrenic nerve block with local anesthesia 

Acupuncture 

Folk remedies 

nomas. Calvo et al 79 administered a 1% lidocaine solution via 

ultrasonographic guidance to the area of the phrenic nerve to 

five cancer patients with intractable hiccups. Hiccups ceased 

in all five patients within 5 minutes. Hiccups did not recur 

in three patients, and there were no adverse effects. 79 Phrenic 

nerve injection may be a reasonable option for drug-refractory 

hiccups if an experienced practitioner is available. 

Conclusion 

Prolonged hiccups can lead to many detrimental effects in 

the cancer and palliative care patient, including depression, 

poor sleep, exhaustion, malnutrition, weight loss, and aspiration 

syndromes. Pharmacologic treatment of benign, selflimited 

hiccups is generally unwarranted, but a variety of noninvasive 

folk remedies may be attempted in select patients. 

Chlorpromazine is the only FDA-approved drug for hiccup 

treatment. However, despite the lack of adequately powered 

and randomized trials involving hiccup treatment, the literature 

supports the utility of a variety of agents, including metoclopramide, 

haloperidol, baclofen, midazolam, and calcium 

channel antagonists. in a small case series, gabapentin has recently 

been demonstrated to be effective for the termination 

of hiccups in patients with advanced malignancy. As gabapentin 

is well tolerated, with few adverse events and drug interactions, 

it may be an ideal drug for treating persistent and 

intractable hiccups in the palliative and advanced cancer setting. 

Other benefits of gabapentin include pain-modulating 

and antiseizure effects. Further trials are necessary to define 

the role of gabapentin in the palliative setting. 

Conflicts of interest: None to disclose. 


References PubMed ID in brackets 

1. Ripamonti C, Fusco F. Respiratory problems in 

advanced cancer. Support Care Cancer 2002;10:204– 

216.[11904785] 

2. Schuchmann JA, Browne BA. Persistent hiccups 

during rehabilitation hospitalization: three case 

reports and review of the literature. Am J Phys Med 

Rehabil 2007;86:1013–1018.[18090442] 

3. Hansen BJ, Rosenberg J. Persistent postoperative 

hiccups: a review. Acta Anaesthesiol Scand 

1993;37:643–646.[8249552] 

4. Lewis JH. Hiccups: causes and cures. J Clin 

Gastroenterol 1985;7:539–552.[2868032] 

5. Fodstad H, Nilsson S. Intractable singultus: a 

diagnostic and therapeutic challenge. Br J Neurosurg 

1993;7:255–260.[8338646] 

6. Rousseau P. Hiccups. South Med J 1995;88:175– 

181.[7839159] 

7. Alderfer BS, Arciniegas DB. Treatment of intractable 

hiccups with olanzapine following recent 

severe traumatic brain injury. J Neuropsychiatry Clin 

Neurosci 2006;18:551–552.[17135383] 

8. Reddy BV, Sethi G, Aggarwal A. Persistent hiccups: 

a rare prodromal manifestation of herpes zoster. 

Indian J Dermatol Venereol Leprol 2007;73:352–353. 

[17921622] 

9. Tegeler ML, Baumrucker SJ. Gabpentin for 

intractable hiccups in palliative care. Am J Hosp Palliat 

Care Med 2008;25:52–54.[18292481] 

10. Samuels L. Hiccup: a ten-year review of 

anatomy, etiology, and treatment. Can Med Assoc J 

1952;67:315–322.[13009550] 

11. Souadjian JV, Cain JC. Intractable hiccup: etiologic 

factors in 220 cases. Postgrad Med 1968;43:72– 

77.[5638775] 

12. Na SJ, Lee SI, Chung TS, Choi YC, Lee KY. 

Pneumomediastinum due to intractable hiccups as 

the presenting symptom of multiple sclerosis. Yonsei 

Med J 2005;46:292–295.[15861505] 

13. Krakauer EL, Zhu AX, Bounds BC, Sahani 

D, McDonald KR, Brachtel EF. Case records of 

the Massachusetts General Hospital. Weekly 

Clinicopathological exercises. Case 6-2005: a 58year-old 

man with esophageal cancer and nausea, 

vomiting, and intractable hiccups. N Engl J Med 

2005;352:817–825.[15728815] 

14. Kahrilas PJ, Shi G. Why do we hiccup? Gut 

1997;41:712–713.[9414986] 

15. Stueber D, Swartz CM. Carvedilol suppresses 

intractable hiccups. J Am Board Fam Med 

2006;19:418–421.[16809659] 

16. Todisco T, Todisco C, Bruni L, Donato R. Chin 

stimulation: a trigger point for provoking acute hiccups. 

Respiration 2004;71:104.[14872123] 

17. McAllister RK, McDavid AJ, Meyer TA, 

Bittenbinder TM. Recurrent persistent hiccups 

after epidural steroid injection and analgesia with 

bupivacaine. Anesth Analg 2005;100:1834–1836. 

[15920222] 

18. Liaw CC, Wang CH, Chang HK, et al. Gender 

discrepancy observed between chemotherapyinduced 

emesis and hiccups. Support Care Cancer 

2001;9:435–441.[11585270] 

19. Santos G, Cook WA, Frater RW. Reclosure of 

sternotomy disruption produced by hiccups. Chest 

1974;66:189–190.[4854044] 

20. Mathew OP. Effects of transient intrathoracic 

pressure changes (hiccups) on systemic arterial pressure. 

J Appl Physiol 1997;83:371–375.[9262429] 

21. Gluck M, Pop CE 2nd. Chronic hiccups and 

gastroesophageal reflux disease: the acid perfusion 

test as a provocative maneuver. Ann Intern Med 

1986;105:219–220.[3729205] 

22. Fass R, Higa L, Kodner A, Mayer EA. Stimulus 

and site specific induction of hiccups in the oesophagus 

of normal subjects. Gut 1997;41:590–593. 

[9414962] 

23. Takiguchi Y, Watanabe R, Nagao K, Kuriyama 

T. Hiccups as an adverse reaction to cancer chemotherapy. 

J Natl Cancer Inst 2002;94:772.[12011230] 

24. Pollack MJ. Intractable hiccups: a serious sign 

of underlying systemic disease. J Clin Gastroenterol 

2003;37:272–273.[12960732] 

25. Cain JS, Amend W. Herpetic esophagitis causing 

intractable hiccups. Ann Intern Med 1993;119:249. 

[8323098] 

26. Pooran N, Lee D, Sideridis K. Protacted hiccups 

due to severe esophagitis: a case series. J Clin 

Gastroenterol 2006;40:183–185.[16633116] 

27. Burdette SD, Marinella MA. Pneumonia 

presenting as singultus. South Med J 2004;97:915. 

[15455988] 

28. Stotka VL, Barcay SJ, Bell HS, Clare FB. 

Intractable hiccough as the primary manifestation 

of brain stem tumor. Am J Med 1962;32:312–315. 

[13917547] 

29. al Deeb SM, Sharif H, al Moutaery K, Biary N. 

Intractable hiccup induced by brainstem lesion. J 

Neurol Sci 1991;103:144–150.[1880531] 

30. Park MH, Kim BJ, Koh SB, Park MK, Park KW, Lee 

DH. Lesional location of lateral medullary infarction 

presenting hiccups (singultus). J Neurol Neurosurg 

Psychiatry 2005;76:95–98.[15608002] 

31. Chang YY, Chen WH, Liu JS, Shih PY, Chen 

SS. Intractable hiccup caused by medulla oblongata 

lesions. J Formos Med Assoc 1993;92:926–928. 

[7908580] 

32. Jansen PH, Joosten EM, Vingerhoets HM. 

Persistent periodic hiccups following brain abscess: 

a case report. J Neurol Neurosurg Psychiatry 

1990;53:83–84.[2303837] 

33. Badawi RA, Birns J, Ramsey DJ, Kalra L. Hiccups 

and bilateral carotid artery dissection. J R Soc Med 

2004;97:331–332.[15229260] 

34. George J, Thomas K, Jeyaseelan L, Peter JV, 

Cherian AM. Hyponatremia and hiccups. Natl Med J 

India 1996;9:107–109.[8664818] 

35. Lazarevic V, Hägg E, Wahlin A. Hiccups and 

severe hyponatremia associated with high-dose 

cyclophosphamide in conditioning regimen for 

allogeneic stem cell transplantation. Am J Hematol 

2007;82:88.[16917917] 

36. Hardo PG. Intractable hiccups—an early 

feature of Addison’s disease. Postgrad Med J 

1989;65:918–919.[2616432] 

37. Ikram H, Orchard RT, Read SE. Intractable 

hiccuping in acute myocardial infarction. Br Med J 

1971;2:504.[5579495] 

38. Chand EM, Nasir A, Pascal RR. Pathologic 

quiz case: refractory hiccups in a man after liver 

transplantation for hepatitis C. Arch Pathol Lab Med 

2003;127:248–250.[12562249] 

39. Bloom VR. Hypernephroma presenting 

with intractable hiccup. Lancet 1959;1:915–916. 

[13655629] 

40. Ruan X, Couch JP, Shah R, Wang F, Liu HN. 

Persistent hiccup associated with intrathecal morphine 

infusion pump therapy. Am J Phys Med Rehabil 

2007;86:1019–1022.[18090443] 

41. Wilcox SK. Persistent hiccups after slow-release 

morphine. Palliat Med 2005;19:568–569.[16295294] 



42. Cersosimo RJ, Brophy MT. Hiccups with high 

dose dexamethasone administration: a case report. 

Cancer 1998;82:412–414.[9445200] 

43. Bonioli E, Bellini C, Toma P. Pseudolithiasis and 

intractable hiccups in a boy receiving ceftriaxone. N 

Engl J Med 1994;331:1532.[7969321] 

44. Jover F, Cuadrado JM, Merino J. Possible 

azithromycin-associated hiccups. J Clin Pharm Ther 

2005;30:413–416.[15985056] 

45. Miyaoka H, Kamijima K. Perphenazineinduced 

hiccups. Pharmacopsychiatry 1999;32:81. 

[10333169] 

46. Gold M, Spruyt O, Toner GC. Chronic hiccups 

following chemotherapy. J Pain Symptom Manage 

1999;18:387–388.[10641462] 

47. Liaw CC, Wang CH, Chang HK, et al. Cisplatinrelated 

hiccups: male predominance, induction by 

dexamethasone, and protection against nausea and 

vomiting. J Pain Symptom Manage 2005;30:359–366. 

[16256900] 

48. Ifran A, Kaptan K, Beyan C. Intractable hiccups 

may develop with cyclophosphamide infusion. Am J 

Hematol 2004;77:319–320.[15495237] 

49. Errante D, Bernardi D, Bianco A, Zanatta N, 

Salvagno L. Recurrence of exhausting hiccup in a patient 

treated with chemotherapy for metastatic colon 

cancer. Gut 2005;54:1503–1504.[16162960] 

50. Wagner MS, Stapczynski JS. Persistent hiccups. 

Ann Emerg Med 1982;11:24–26.[7055350] 

51. Arnulf I, Boisteanu D, Whiltelaw WA, Cabane 

J, Garma L, Derenne JP. Chronic hiccups and sleep. 

Sleep 1996;19:227–231.[8723381] 

52. Williamson BW, MacIntyre IM. Management 

of intractable hiccup. Br Med J 1977;2:501–503. 

[890370] 

53. Bellingham-Smith E. The significance and 

treatment of obstinate hiccough. Practitioner 

1938;140:166–171. 

54. Hiccup remedies. N Engl J Med 1972;286:323. 

[5007237] 

55. Odeh M, Oliven A. Hiccups and digital rectal 

massage. Arch Otolaryngol Head Neck Surg 

1993;119:1383.[17431994] 

56. Odeh M, Bassan H, Oliven A. Termination of 

intractable hiccups with digital rectal massage. J 

Intern Med 1990;227:145–146.[2299306] 

57. Friedman NL. Hiccups: a treatment review. 

Pharmacotherapy 1996;16:986–995.[8947969] 

58. Petroski D, Patel AN. Letter: diphenylhydantoin 

for intractable hiccups. Lancet 1974;1:739. 

[4132462] 

59. Madanagopolan N. Metoclopramide in hiccup. 

Curr Med Res Opin 1975;3:371–374.[1183218] 

60. Mukhopadhyay P, Osman MR, Wajima T, 

Wallace TI. Nifedipine for intractable hiccups. N Engl 

J Med 1986;314:1256.[3010106] 

61. Lipps DC, Jabbari B, Mitchell MH, Daigh JD 

Jr. Nifedipine for intractable hiccups. Neurology 

1990;40:531–532.[2314596] 

62. Hernández JL, Fernández-Miera MF, Sampedro 

I, Sanroma P. Nimodipine treatment for intractable 

hiccups. Am J Med 1999;106:600.[10335738] 

63. Cohen SP, Lubin E, Stojanovic M. Intravenous 

lidocaine in the treatment of hiccup. South Med J 

2001;94:1124–1125.[11780683] 

64. Neeno TA, Rosenow EC 3rd. Intractable hiccups: 

consider nebulized lidocaine. Chest 1996;110:1129– 

1130.[8874292] 

65. De Ruysscher D, Spaas P, Specenier P. Treatment 

of intractable hiccup in a terminal cancer patient 

continued on page 130 

127


Review continued from page 127 

1. with nebulized saline. Palliat Med 1996;10:166– 

167.[8800827] 

2. Wilcock A, Twycross R. Midazolam for intractable 

hiccup. J Pain Symptom Manage 1996;12:59–61. 

[8718918] 

3. Maréchal R, Berghmans T, Sculier P. Successful 

treatment of intractable hiccup with methylphenidate 

in a lung cancer patient. Support Care Cancer 

2003;11:126–128.[12560943] 

4. Macris SG, Gregory GA, Way WL. 

Methylphenidate for hiccups. Anesthesiology 

1971;34:200–201.[5545709] 

5. Worz R. Control of cancer pain with analgesics 

acting in the central nervous system. Recent Results 

Cancer Res 1984;89:100–106.[6141626] 

6. Bilotta F, Rosa G. Nefopam for severe hiccups. N 

Engl J Med 2000;343:1973–1974.[11186682] 

7. Ross J, Eledrisi M, Casner P. Persistent hiccups 

induced by dexamethasone. West J Med 1999;170:51– 

52.[9926738] 

8. Vazquez JJ. Persistent hiccup as a side-effect 

of dexamethasone treatment. Hum Exp Toxicol 

1993;12:52. 

9. McKeogh M. Dexamethasone for intractable 

hiccoughs in a patient with AIDS and PML. Palliat Med 

1994;8:337–338.[7812485] 

10. Porzio G, Aielli F, Narducci F, et al. Hiccup in 

patients with advanced cancer successfully treated 

with gabapentin: report of three cases. N Z Med J 

2003;116:U605.[14581957] 

11. Alonso-Navarro H, Rubio L, Jiménez-Jiménez 

FJ. Refractory hiccup: successful treatment with 

gabapentin. Clin Neuropharmacol 2007;30:186–187. 

[17545753] 

12. Tegeler ML, Baumrucker SJ. Gabapentin for 

intractable hiccups in palliative care. Am J Hosp Palliat 

Care 2008;25:52–54.[18292481] 

13. Liu FC, Chen CA, Yang SS, Lin SH. Acupuncture 

therapy rapidly terminates intractable hiccups complicating 

acute myocardial infarction. South Med J 

2005;98:385–387.[15813167] 

14. Schiff E, River Y, Oliven A, Odeh M. Acupuncture 

therapy for persistent hiccups. Am J Med Sci 

2002;323:166–168.[11908864] 

15. Calvo E, Fernández-La Torre F, Brugarolas A. 

Cervical phrenic nerve block for intractable hiccups in 

cancer patients. J Natl Cancer Inst 2002;94:1175–1176. 

[12165648]

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