C Diagnosis and Management of Hiccups in the Patient with Advanced Cancer

r e v i e w
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.
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.
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
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
122
© 2009 Elsevier Inc. All rights reserved.
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
www.SupportiveOncology.net
Dr. Marinella is a
practicing medical
oncologist, HematologyOncology of Dayton,
and Assistant Clinical
Professor, Department
of Internal Medicine,
Wright State University
School of Medicine,
Dayton, Ohio.
The Journal of Supportive Oncology
Marinella
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 Mathew20 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 Pop21 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
cause of hiccups associated with achalasia, esophageal tumors,
strictures, and food impaction.2–6,21 Indeed, Fass et al22 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
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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
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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
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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 al23 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 conThe Journal of Supportive Oncology
Marinella
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
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
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
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-
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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
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Advanced Cancer: Diagnosis and Management of Hiccups
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 al74 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-
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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 al79 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.
The Journal of Supportive Oncology
Marinella
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