Curr Treat Options Gastro

DOI 10.1007/s11938-020-00273-3

Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

Chronic Hiccups
Zachary Wilmer Reichenbach, MD, PhD1,2
Gregory M. Piech, MD, MPH1
Zubair Malik, MD1,*
Address
*,1
Department of Gastroenterology, Lewis Katz School of Medicine at Temple
University Hospital, 3401 N. Broad St., 8th floor Parkinson Pavilion, Philadelphia,
PA, 19140, USA
Email: zubair.malik@tuhs.temple.edu
2
Center for Substance Abuse Research (CSAR), Lewis Katz School of Medicine,
Temple University, Philadelphia, PA, USA

* Springer Science+Business Media, LLC, part of Springer Nature 2020

Zachary Wilmer Reichenbach and Gregory M. Piech contributed equally to this work.
This article is part of the Topical Collection on Neurogastroenterology and GI Motiliy

Keywords Hiccups I Singultus I Hiccough

Abstract
Purpose of review Nearly 4000 patients will be admitted to hospital in the US this year for
hiccups. Hiccups are controlled by a complex reflex arc between peripheral receptors and the
brainstem. Any disruption along this pathway may produce hiccups. Typically, hiccups
resolve spontaneously but in certain pathologies symptoms may persist. Persistent hiccups
may be considered a sign of underlying pathology. The most common cause involves GERD.
Recent findings Based on etiologies, studies have shown that first-line therapy
should use a proton pump inhibitor (PPI) and involve appropriate gastrointestinal
consultation. If symptoms persist, other etiologies such as central causes need to
be explored.
Summary We review the pathophysiology of hiccups including multiple causes and
the appropriate work up for each. We review several studies examining new
treatments, both pharmacological and interventional, that may help patients.
Initial therapy should still involve a PPI but several new therapies may be
beneficial.

Introduction
Hiccups, or singultus, can be bothersome but typically intercostal muscle myoclonus followed by laryngeal clo-
resolve quickly. Hiccups consist of eratic diaphragmatic sure [1]. The abrupt rush of air entry creates the
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

characteristic “hic” sound [1]. Singultus derives from the
Latin term singult, which means “the act of catching
one’s breath while sobbing” [1]. While described in
ancient texts, the term hiccup was first reported by
Lupton in 1627 [2, 3]. Hiccups repeat at cycles of 4–60
events per minute [4, 5••, 6]. Typically, hiccups involve
left unilateral diaphragmatic contractions but can in-
volve bilateral diaphragm and intercostal muscles [4,
7]. Prolonged hiccups lead to a decrease in quality of
life through exhaustion, malnutrition, weight loss, de-
hydration, and even death [1, 5••].
Temporary (transient) singultus lasts less than 48 h
while persistent singultus lasts from 2 days to 1 month
[4, 5••, 8, 9•, 10•, 11•]. Intractable hiccups last longer
than 1 month [4, 5••, 8, 9•, 10•, 11•]. Recurrent hic-
cups last longer than transient and occur with frequent
repetition [11]. The longest case of hiccups persisted
from 1922 to 1990, 69 years and 9 months, in a farmer
from Iowa from a small intracranial bleed after the
farmer fell lifting a pig [12, 13].

Incidence
Recent analysis suggests approximately 4000 admissions yearly in the USA for
hiccups [4, 10•, 12]. The prevalence in hospitalized patients is 54 per
100,000 patients (0.054%) [8]. Overall, patients with temporary
singultus composed 44.1% of patients, persistent hiccups 36.9%, and
intractable 19% [5••]. A retrospective study found that male patients
comprised 67.5% of the patients with temporary singultus and 89.4% of
persistent singultus [5••]. Intractable hiccups are more common in men
with a reported incidence as high as 91% and the risk increases with
greater height and weight [4, 6, 10•, 12].
Women are more likely to have psychogenic hiccups precipitated by
factors such as anxiety, conversion reactions, emotional stress, and ex-
citement [10•]. In a study of 220 patients, a psychogenic factor was
found to be causative in 92% of females while 93% of men had an
organic cause [14]. Due to the high incidence of psychogenic hiccups, an
underlying psychiatric evaluation may be necessary [10•, 14]. However,
practitioners should refrain from the diagnosis of psychogenic hiccups
without an appropriate work up [10•].
Patients with cancer have a higher than expected incidence of hiccups
with a reported prevalence of from 3.9 to 4.5% [8]. Additionally, pa-
tients with disorders of the central nervous system (CNS) such as
Parkinson’s disease more frequently report hiccups as well [4, 6]. Pa-
tients with gastroesophageal reflux disease (GERD) report hiccups as
frequently as 8–10% of the time [4, 6].

Hiccup reflex arc

Hiccups arise from a tightly controlled and complex reflex arc composed of
three general components: the afferent limb, processing in the CNS, and the
efferent pathway. The afferent limb includes the vagal, phrenic, and sympathetic
nerves from T6-T12 that relay somatic and visceral sensory information to the
central midbrain [1, 8, 12, 15].
The second aspect of the reflex arc involves the processing in the CNS
between the brainstem and the cervical spine [7, 16]. Central processing
 Chronic Hiccups Reichenbach et al.

Table 1. Causes of hiccups

Category Notes
Central causes Typically any disruption to the central processing
in the CNS. Either by mass affect or physiological
change in signaling.
CVA
APS Secondary to SLE, resulted in CVA
Aneurysms
Vasogenic edema In the setting of aseptic meningitis
Type 1 Arnold-Chiari malformations
Tumors Brainstem—astrocytomas, cavernomas
Trauma
Parkinson disease Including dopamine replacement therapy
Neurosyphilis
Psychogenic Increased with anxiety, stress, excitement
Peripheral causes Typically irritation of the afferent and less frequently
efferent limb. GI pathology common.
GERD
Helicobacter pylori infection
Belching
Hiatal hernias
Esophagitis
Eosinophilic esophagitis (EoE)
Bowel obstruction
Gastric volvulus
Hepatitis
Gallbladder disease
Pancreatitis
Gastric distention May follow large meals, carbonated beverages, aerophagia
Post-operative gastric distention May be due to gastroparesis
Esophageal tumors Including stenting for palliation
Foods Hot/Cold foods, spicy foods
Alcohol
Smoking Tobacco or cannabinoids
Pulmonary causes Asthma, bronchitis, pleuritis, PE, bronchoscopy
Lymphadenopathy Including mediastinal sarcoidosis
MI/cardiac ischemia
Infections HZV, HSV, influenza, malaria, tuberculosis
Iatrogenic Placement of central lines and trans-venous pacing
Stimulation of the chin Reported after shaving
Global causes Typically metabolic derrangements that affect signaling
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

Table 1. (Continued)
Category Notes
Hypocapnia
Hypocalcemia
Hypokalemia
Hyponatremia
Uremia
Medication induced Typically affects signaling potential in the
central or efferent/afferent limbs
Chemotherapuetics Particularly cisplatin, carboplatin, etoposide
Steroids Conflicting data. Seems to increase the risk
of chemotherapeutics.
Antibiotics
Benzodiazepines Biphasic effect--induces hiccups at low doses,
therapuetic for treatment at high doses
Opioids
Methohexital
Antipsychotics
Dopamine agents

CVA—central venous accident; APS—antiphospholipid syndrome; SLE—systemic lupus erythematosus; GERD—gastrointestinal reflux syndrome;
PE—pulmonary embolism; MI—myocardial ischemia; HZV—herpes zoster virus; HSV—herpes simplex virus

requires interaction between the midbrain and the brainstem including the
medulla oblongata, reticular formation, hypothalamus, and cervical spinal cord
segments C3-C6 [1, 2, 4, 17]. The central processing also includes the inspira-
tory dorsal group of the nucleus tractus solitarii, the ventral group of the nucleus
ambiguous, the subthalamic nuclei, and phrenic nerve nuclei [2, 10•, 12].
Chemoreceptors in the periaqueductal gray and glossopharyngeal nuclei also
provide input [1, 4, 10•, 12, 17]. Hiccups can become persistent due to
excessive activity of the solitary nucleus of the medulla [4]. While the central
component is in the medulla, it is separate from pathways that regulate
rhythmic breathing [10•, 18]. Central processing of the hiccup reflex
seems to be mediated by γ-aminobutyric acid (GABA), dopamine, and
serotonin [1, 4, 16, 17].
The third portion, the efferent limb, contains the phrenic nerve (C3-C5)
innervating the diaphragm, anterior scalene muscle innervation (C5-C7), recur-
rent laryngeal nerve, and accessory nerves leading to the intercostal muscles (T1-
T11) [6–8, 11, 16]. Peripheral signaling relies on epinephrine, norepinephrine,
acetylcholine, and histamine [10•].
During inspiration, the hiccup exists as a sudden contraction of the dia-
phragm and intercostal muscles which is then followed by laryngeal closure
[16]. The recurrent laryngeal nerve ensures closure of the glottis [4]. Elevations
in pCO2, vagal maneuvers, GABA-ergic agents, and dopamine antagonists
inhibit the hiccup reflex [4]. Injury or pathology affecting the cervical
spinal cord, brainstem, or hypothalamus may induce hiccups by
 Chronic Hiccups Reichenbach et al.

stimulating the hiccups reflex or decreasing the normal inhibition of the

neurons involved [10•].
Etiology and pathogenesis
The etiology of hiccups is very broad, and etiologies of hiccups can be divided
into central, peripheral, global, and medication derived causes (Table 1). Any
pathology or condition that disrupts the hiccups reflex, by either spatial disrup-
tion or a change in paracrine signaling, including inflammation and tumors, or
a change in chemical mediators, such as drugs, can precipitate hiccups [1, 2].
Persistent or intractable hiccups may be the first presentation of a serious
pathological condition and require further diagnostic testing [7, 16].

Central causes
Any disruption of the hiccups reflex from lesions in the brain can cause hiccups.
Cerebral vascular accidents (CVA) and other vascular defects such as aneurysms
have been shown to be correlated with hiccups, and they have resolved after
proper anticoagulation or vascular treatment, respectively [1]. One case report
showed a patient with antiphosophilipid syndrome (APS) developed hiccups
after suffering an infarction of the medulla [19]. Other reports have shown that
CNS structural abnormalities such as type I Arnold-Chiari malformations with
cervicothoracic syringomyelia and brain stem tumors, including astrocytomas
and cavernomas, have been implicated in hiccups [1, 14]. Traumatic injuries
may also cause disruption and hiccups [1]. Further, one report showed a patient
with vasogenic edema from aseptic meningitis presented with hiccups [20].
Additionally, hiccups may be a symptoms of Parkinsonism or may result from
dopamine replacement therapy as dopamine agonists have a high affinity for
D3 receptors and affect the reflex arc [1, 21]. Any disruption of the neuronal
circuits, by mass or alterations in nerve transmission, can lead to hiccups.

Peripheral and global causes

Peripheral causes stem from a myriad of etiologies but in general affect the
afferent limb of the reflex. Hiccups were most frequently encountered in the
setting of gastrointestinal pathology, and a statistically significant correlation
was found between male sex and gastrointestinal disorders [5••]. As many as
80% of patients with persistent hiccups seen in evaluation may be attributable
to GERD [4]. GERD has been shown to induce hiccups and in a review of
patients with GERD, 7.9% of males and 10% of females reported hiccups [1, 4,
6, 22]. Experimentally, studies where acid was infused into the stomach con-
firmed the onset of hiccups [1, 23]. Belching may also trigger hiccups and is
associated with GERD [1, 7, 24, 25]. Helicobacter pylori infection can precipitate
hiccups, and eradication of the infection has been reported to relieve symptoms
[1]. Increased acid production in the infectious state may explain the pathogen-
esis [1]. Singultus triggered by GERD tends to be most effectively treated with
the use of a PPI [16].
Persistent hiccups are often precipitated commonly by large hiatal hernias
[4, 6]. Manometry and pH-impedance revealed that hiccups can inhibit normal
esophageal motility and reduce LES tone [6]. Changes induced by hiccups can
Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

also alter the anatomy of the gastro-esophageal junction (GEJ), and these
combined changes promote GERD [6]. Since GERD can lead to more hiccups,
it seems the interplay of the hiatal hernia and hiccups may prove to be a self-
perpetuating problem. More so, reports of erosive esophagitis and eosinophilic
esophagitis (EoE) have also been noted to cause persistent hiccups [25, 26].
Lastly, the GI tract can trigger hiccups through bowel obstruction, gastric
volvulus, hepatitis, gallbladder diseases, and pancreatitis [1, 4].
Hiccups commonly arise from over distension of the stomach and may
follow a large meal or consumption of carbonated beverages and can be
exacerbated by overeating, aerophagia, or eating too rapidly [1, 4, 6, 7, 16].
Distention following recent abdominal surgery may also cause hiccups [8].
Post-operative gastroparesis with increasing stomach distention may be a likely
mechanism [1]. Dietary choices correspondingly play a role and the consump-
tion of hot or cold liquids, alcohol, and spicy foods tend to be more likely to
cause hiccups [4, 6, 14, 24, 25]. Smoking, both tobacco and cannabis can also
cause episodes [1, 6, 27].
Hiccups have been seen as a symptom of unrecognized esophageal cancer
and in a review of 99 patients with esophageal tumors, 27% had persistent
hiccups [1, 28]. Persistent hiccups may be the presenting complaint in as many
as 25% of patients [4, 6]. Either the direct effect of the tumor or dilation of the
esophagus may trigger the hiccup reflex [1, 28]. Esophageal stents implanted to
palliate tumors may in itself produce hiccups [7, 29].
Any peripheral irritation that aggravates the reflex arc can cause hiccups and
includes asthma, bronchitis, pleuritis, lymphadenopathy, myocardial infarction
(MI), and infections [1, 4]. A patient diagnosed with sarcoidosis had mediasti-
nal lymphadenopathy leading to hiccups [1, 30]. Angina pectoris and acute MI
can trigger hiccups [1, 7, 31]. This likely stems from inflammatory mediators in
the ischemic tissue that can irritate the hiccup reflex arc or from direct ischemic
injury to the sensory branches of nerves in the pleura, pericardium, and perito-
neum [1, 31]. Pulmonary embolism has also been reported to be a cause of
hiccups, and in one report, the pulmonary infarction was found adjacent to the
right diaphragm [12, 32].
Numerous infections have been shown to be associated with singultus
including herpes zoster (HZV), herpes simplex virus (HSV), influenza, malaria,
neurosyphilis, subphrenic abscess, and tuberculosis [4]. One report noted HZV
infection affecting the vagus nerve presented with hiccups and was corrected
with acyclovir [1, 4, 33].
Iatrogenic manipulation can also induce hiccups as the introduction of
central venous lines, bronchoscopy, and trans-venous pacing which have all
caused singultus [1, 7, 34, 35]. Less invasive actions such as men shaving or
stroking their chins have been reported to trigger hiccups [1, 36]. This likely
results from the sensory afferents in the chin that convey information to the
intermediate part of the spinal tract nucleus of CN V which also projects to the
medullary reticular formation and interplays with the phrenic nucleus
and nucleus ambiguous [1]. A patient’s emotional state can also affect
hiccups, and increased excitement, stress, and anxiety can generate hic-
cups especially if coupled with continuous laughter, hyperventilation, or
aerophagia [4, 6, 14, 27].
Multiple metabolic derangements can create a physiological state which
favors the induction of hiccups including hypocapnia, hypocalcemia,
 Chronic Hiccups Reichenbach et al.

hypokaelmia, hyponatremia, and uremia [4, 7]. Increasing pCO2 has been
shown to suppress the movement of muscles necessary for hiccup progression
[1, 16, 37]. Chronic renal failure or diabetes mellitus can also contribute to the
onset of hiccups [2].

Medication induced singultus

Multiple drugs, particularly chemotherapeutics, have been shown to induce
hiccups and one report showed that 3.9% of inpatients and 4.5% of outpatients
with cancer reported severe and chronic hiccups [1, 38]. A retrospective case
study revealed that 0.39% of patients treated with cisplatin, carboplatin, and
etoposide had hiccups, which was more common in men [1, 39]. In Japanese
patients undergoing cisplatin therapy, hiccups were reported in 6.1–10% of
patients, while a Taiwanese analysis showed that combination therapy with
cisplatin and dexamethasone caused hiccups in 41.2%, 97.4% of them were
male [1, 40, 41]. The effect of steroids remains controversial as it has been
postulated to induce hiccups but it has also been recommended as a treatment
[1]. In patients receiving cisplatin, enterochromaffin cells and enteric vagal
efferents may release serotonin and cause hiccups [10•, 42]. Activation of the
5-HT1A receptor and antagonism of the 5-HT2A receptor may increase activity of
the phrenic nerve and induce hiccups [10•, 43]. Steroids have been hypothe-
sized to lower the threshold of synaptic transmission in the midbrain and allow
for easier stimulation of the reflux [2].
Many other medications have been known to induce hiccups including
antibiotics, benzodiazepines, opioids, methohexital, antipsychotics, and dopa-
mine agents [16]. Benzodiazepines have a biphasic effect on hiccups and have
been postulated to induce them at low doses while high doses can be
therapuetic [4]. Anesthesia interrupts the inhibitory reflex of the phrenic nerve
and has also been reported to cause hiccups especially if barbiturates are used
for induction. [1, 16, 44].

Diagnosis
Acute hiccups do not require any additional work up other than an attempt to
understand the transient factors involved. In contrast, any episode of hiccups
lasting longer than 48 h should be met with diagnostic inquiry. Failure to
elucidate an etiology based on history and physical exam should not lead to
the diagnosis of idiopathic or psychogenic origin. A work up to exclude over
100 associated diseases is appropriate. Unfortunately, there are no widely
accepted guidelines to help guide practitioners.
A directed history and physical exam may reveal underlying pathology such
as GERD, gastric distension, esophageal disorders, psychologic components, or
a causative medication that can be targeted from the onset of investigation.
Social history including alcohol, recreational drug use, and tobacco use have all
been linked to chronic hiccups [6]. Nocturnal hiccups may be an indicator of
organic pathology. Hiccups with a fixed periodicity may be indicative of an
intracranial lesion [45, 46]. Physical exam can reveal neurologic deficit or
pathology of the external auditory canal (inflammation, foreign body, impact-
ed cerumen) for targeted work up or intervention [47].
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)
Table 2. Treatment of Hiccups
Treatment Mechanism of
action
Home remedies Behavioral Decrease gastric
distensions/irritation
Physical maneuver - Vagal stimulation/interruption
- Nasopharyngeal stimulation
- Respiratory interruption
- Diaphragmatic impedance
Pharmacologic Proton pumps inhibitor Control underlying
GERD/esophagitis
*Metoclopramide - Stimulation of gastrointestinal
motility
- Dopamine antagonist
*Baclofen Inhibition of hiccup reflex arc
- GABA-B receptor agonist
Gabapentin/pregabalin - Neuronal voltage-gated
Ca channels
- Modulates diaphragm/
inspiratory muscle
Chlorpromazine Dopamine(D), antagonist
Combination Therapy Combination PPI and any
of the above
Others Amantadine, Haldol, Midazolam,
Olanzapine, Carbamazepine,
Lidocaine, Nifedipine,
Phenytoin, Carvedilol,
Methylphenidate, Nimodipine,
Valproate
Interventional Phrenic nerve block Inhibition of sensory/motor
input of diaphragm
Vagus nerve stimulation Direct interruption/pacing
of hiccup reflex arc
Acupuncture Regulation of thoracic viscera
and effects on gastrointestinal
motility through modulation
Notes
Avoid carbonated beverages, slow eating,
cessation of EtOH, avoid
extremes in food temperature
- Based on historical theory
and anecdotal evidence
- Only role is in acute hiccups
- Empiric trial if work up
negative
- Titrate to bid dosing before
considering failure
-10 mg TID based on RTC
-First line in suspected
peripheral etiology
-Risk of significant side
effects (tardive
dyskinesia)
-10 mg TID based on RTC
-First line in suspected
central etiology
- Caution with use in
renal impairment
- No RTCs
- Wide range of doses reported
- Only US FDA approved
pharmacologic for
hiccups
- Efficacy based on historical
case studies only
Consider prior to
interventional treatment
Small case reports/case
series only
Avoid in patients and
respiratory compromise
- Invasive (surgical placement)
- Consider vagus nerve block prior
Based on poorly executed RCTs
 Chronic Hiccups Reichenbach et al.

Table 2. (Continued)
Treatment Mechanism of Notes
action
of local blood flow, neurotransmitter
signaling and inflammation

*Baclofen tested in patients with intractable hiccups of longer duration compared with metoclopramide (60 days compared with 30 days);
BID twice daily, RCT randomized control trial, TID three times daily, GABA-B γ-aminobutyric acid-B

Initial work up should always be guided by associated symptoms. For

example, brain imaging for associated neurologic symptoms, chest CT for
pulmonary disease, or EGD if gastrointestinal pathology is suspected. Esopha-
geal manometry and pH impedance may have a role based on initial work up
and associated symptoms. When hiccups are the sole complaint, a step-wise
approach is best. Obtaining basic blood work (CBC, BMP, LFTs), chest x-ray,
and EKG should be included in initial testing. If no abnormalities are found,
then EGD is a logical next step given that the prevalence of hiccups is related to
GERD and associated with GI pathology. CT imaging (chest, neck, ENT) and
MRI (brain) are warranted if all aforementioned studies have failed to identify a
cause. Ultimately, each patient should have a work up tailored to their symp-
toms and medical history.

Treatment (Table 2)
Treatment should always be directed at underlying pathology; intervention of
neurologic lesions, management of GERD, or cessation of offending medica-
tion. If these targeted interventions fail to control hiccups or no etiology is
identified, then the next options can be overwhelming. Behavioral modifica-
tions, physical maneuvers, and pharmacologic and non-pharmacologic inter-
ventions have all yielded inconsistent results. The majority of available litera-
ture involves only case reports or case series for non-pharmacologic methods of
treatment. Several systematic reviews have shed light on the paucity of quality
studies to direct pharmacologic management as well. Interestingly, initial man-
agement of idiopathic hiccups may depend on the specialty of the provider
involved [6].

Non-pharmacologic
Non-pharmacologic methods to treat hiccups range from lifestyle modification
and physical maneuvers to invasive procedures. Most supportive evidence for
physical maneuvers is anecdotal and the use of nerve blocks/stimulation is
limited to case reports [1, 3, 45, 48, 49]. Acupuncture for the treatment of
hiccups has been studied in RCTs, but a Cochrane review deemed these to be
low quality reports with no conclusions made about its efficacy [50]. Physical
maneuvers are usually harmless and can be attempted prior to any pharmaco-
logic treatment. More advance and invasive therapies (nerve blocks/stimula-
tion, acupuncture) should only be considered after failure of pharmacologic
management and on a case-by-case basis.
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

Physical Maneuvers and Anecdotes

The history of home remedies and maneuvers has been reviewed extensively [3,
45, 48, 49]. Reports of success are largely tied to episodes of transient hiccups
and efficacy for their use in chronic hiccups is lacking [1]. These maneuvers aim
to interrupt the hiccup reflex arc. Stimulation of the vagus nerve may be
achieved by nasopharyngeal irritation via uninterrupted drinking, noxious
stimuli, gargling water, or eating granulated sugar as examples. Vagal interrup-
tion is also a target through carotid massage, Valsalva maneuver, or orbital
pressure. Phrenic nerve disruption is achieved by tapping over the 5th cervical
vertebra or applying ice to the nerve’s cutaneous location. Inducing sneeze or
fright, hyperventilation, and breath holding aim to interrupt respiratory func-
tion rather than the hiccup reflex arc. One physiologic study identified that the
frequency of hiccups decreases as arterial pCO2 rises [50]. A Japanese group
built on this concept and induced hypercapnia using a controversial method
involving near suffocation to stop hiccups [37]. Physical maneuvers that push
against the diaphragm like pulling knees to chest have also been reported. The
maneuvers listed above are not an exhaustive list, as the number of home
remedies to stop hiccups rivals the amount of causes.

Vagus nerve
Recent studies have targeted the reflex arc for intervention after traditional
maneuvers and pharmacologic therapies fail. Surgical placement of a vagus
nerve stimulator has been reported as a cure for hiccups in a stroke patient
who had failed multiple medications and peripheral nerve blocks [51]. Pierluigi
et al. used vagal nerve stimulation (VNS) with less conclusive results as VNS
could not cure refractory hiccups but did reduce symptom burden [52]. To
contrast these positive studies, a trauma patient with intractable hiccups who
had failed multiple medications and interventions underwent VNS with no
improvement at all [53]. Authors postulated that the positive effects of VNS
may be limited to hiccups of central etiology [53]. The risks and complications
of surgical VNS implantation are not trivial and would have to be considered as
all cases involved surgical placement [54]. Cutaneous VNS devices are available,
but none have been studied for the treatment of hiccups.

Phrenic nerve
The phrenic nerve’s direct involvement in diaphragmatic function makes it an
excellent target for therapeutic intervention. A variety of therapies including
nerve blocks, stimulation, radiofrequency ablation, and clipping have been
investigated [55–60]. Though the majority of available literature on phrenic
nerve blockade for the treatment of hiccups is via case report, one small case
series in a group of 5 cancer patients reported excellent effectiveness with a
cervical approach [61]. A more recent series of 28 patients treated with contin-
uous epidural nerve block at the C3-C5 level achieved a 60% cure with one
block and 100% response with up to 3 blocks without significant adverse events
[62]. Respiratory compromise from phrenic nerve blockade is, however, a
theoretical concern. Cases of acute dyspnea and marginal respiratory compro-
mise after phrenic nerve blockade have been reported [63, 64]. However, when
phrenic nerve block was used in a RCT in shoulder arthroplasty, there was no
 Chronic Hiccups Reichenbach et al.

evidence of clinically significant respiratory compromise compared with

placebo [65].

Acupuncture
Acupuncture has been proposed to treat hiccups as well. Mechanisms of action
to support a role for acupuncture are related to its regulating effect on thoracic
viscera and gastrointestinal motility, though local changes to blood flow and
modulation of neurotransmitters/inflammation have been invoked as well
[66]. A case series performed at the National Institutes of Health developed
and validated a hiccup assessment instrument (HAI) and used it to show that 13
of 16 cancer patients achieved complete hiccup cessation with acupuncture
[67]. Despite this, several systematic reviews have failed to endorse acupuncture
as an effective treatment because conclusions cannot be drawn based on the
quality of available studies. Yue et al. reviewed acupuncture for use in stroke
patients and concluded that because of a limited number of studies and overall
poor methodology, no recommendations could be made [68]. The study did
ultimately suggest that acupuncture may be an effective treatment when used as
an adjunct with pharmacologic treatment [68]. Acupuncture point (GV26) was
common amongst positive studies, suggesting a potential connection with
vagal activity related to hiccups [68]. Similarly, Choi et al. performed a system-
atic review in cancer patients. While there were favorable outcomes in this
population, no conclusions were drawn because of poor methodological qual-
ity [69]. A Cochrane review was published in 2013 in which four studies met
inclusion criteria. Each study had a high risk of bias, did not use appropriate
placebo, and failed to report side effects [50]. Heterogeneity in methodology
between studies precluded a formal metanalysis [50].

Pharmacologic
Empiric PPI should be considered in most patients. Cabane et al. produced a
large case series of 184 patients with recurrent hiccups, 80% of which had an
identifiable upper digestive abnormality [70]. The treatment of GI related
disorders led to a 66% improvement in the subjective severity of hiccups,
though the results should be tempered as there was no control group [70].
Additionally, at least two case reports have questioned if GERD is actually a
sequela of hiccups instead of a cause [71, 72]. Nissen fundoplication treated
GERD and esophagitis, but not hiccups in one patient [71]. High resolution
esophageal manometry (HREM) in another patient revealed normal esophage-
al motility in the absence of hiccups but an incompetent lower esophageal
sphincter and absent esophageal peristalsis with increased acid exposure during
hiccup episodes [72]. Despite these reports, the majority of evidence supports
gastric acid suppression as part of the algorithm to cure hiccups [23]. PPI is a
common and relatively safe medication to use compared with other medica-
tions implicated in the treatment of hiccups.
Beyond PPI, an exhaustive list of medications have been used for the
treatment of hiccups and their mechanisms of action has been reviewed [3,
45, 48, 49]. The majority of pharmacologic therapy is directed at dopaminergic
and GABA-ergic receptors. Chlorpromazine is the only medication approved in
the USA for the treatment of hiccups. Baclofen and metoclopramide are the
only medications tested in small randomized controlled trials [73••, 74••].
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

Gabapentin has a relatively robust number of case series to support use, but no
RCTs to date. Medications such as Amitriptyline, Haldol, Midazolam, Nifedi-
pine, Nimodipine, Valproic acid, and others have all been discussed in small
case series or case reports [6, 9, 69].
Several recent systematic reviews underscore the paucity of quality data to
guide pharmacologic therapy. Steger et al. provide a review in which 15 studies
and 341 patient met inclusion criteria [6]. Polito et al. performed a similar
review with inclusion of 26 studies [9]. Moretto et al. had set out to include
pharmacologic therapy in their systematic review; however, only the four
acupuncture studies discussed previously met their inclusion criteria [69, 75].
None of these reviews were able to perform a meta-analysis. Proposed treat-
ment algorithms are based on these two RTC’s and case series.

Chlorpromazine
Chlorpromazine is an anti-psychotic medication that selectively antagonizes
dopamine D2 receptors. Its use in hiccups originates from two case series
produced in the 1950’s that showed IV chlorpromazine was effective [76, 77].
Studies to support its current use as oral maintenance therapy are not available.
Since these reports, there are additional studies that have shown no efficacy for
chlorpromazine [2]. Because it remains the only therapy approved by the US
FDA, it should remain in treatment algorithms as a second or third choice of
therapy.

Metoclopramide
Metoclopramide stimulates gastrointestinal motility through a variety of mech-
anisms. An RCT with 34 patients had cessation of hiccups in 2 of 17 patients
and overall improvement in 9 of 17 patients treated with metoclopramide
[74••]. Efficacy compared with placebo showed a relative risk (RR) of 2.75
[p = 0.03, CI 1.09–6.9] [74••]. Metoclopramide achieved relief across peripheral
and central causes [74••]. Reported side effects included fatigue (47%) and
mood disturbance (35%) over the 15-day treatment course, but the more
significant side effects associated with metoclopramide were rarely seen
[74••]. A small case series involving 14 patients with a variety of peripheral
hiccup etiologies achieved symptom relief in all participants given
metoclopramide, though “symptom relief” was not clearly defined by the
authors [78]. Metoclopramide should be considered a first line treatment
because of available RCT data, especially in patients with a peripheral etiology
of hiccups.

Baclofen
Baclofen is a GABA-B receptor agonist traditionally used to treat spasticity. Its
proposed mechanism of action related to hiccups is via an inhibitory effect on
the reflex arc [49]. An RCT in 30 stroke patients showed that baclofen induced
cessation of hiccups in 14 of 15 patients compared with 2 of 15 in the placebo
group (RR 7, p = G0.01 CI [1.9–25.6]) [73]. Treatment was only needed for
5 days to achieve this [73••]. The systematic review by Polito et al. identified 12
additional studies where baclofen was used as monotherapy [9]. In total, 78 of
the 84 patients included had symptoms improve and 66 achieved complete
control of their hiccups with dosages of baclofen ranging from 5 to 75 mg per
 Chronic Hiccups Reichenbach et al.

day [9]. Further review noted that baclofen worked within 6 days for the
majority of cases and after a single dose in one patient [2, 9]. Baclofen should
also be considered a first line pharmacotherapy.

Gabapentin
Gabapentin is a GABA-like molecule that acts through neuronal voltage-
gated calcium channels, possibly resulting in modulation of the dia-
phragm and inspiratory muscles [2]. No RCTs for gabapentin as mono-
therapy therapy for hiccups exist. Polito et al. found two case series
totaling 58 patients where cessation of hiccups was achieved in 52 of
the treated patients [9]. A separate review of gabapentin included addi-
tional reports and found improvement or cessation of hiccups in 81/83
patients with the longest treatment duration needed being 6 months and
a wide range of dosages used (200–1200 mg daily) [2]. Several individ-
ual case reports have used pregabalin as well [79–81].

Combination therapy
Data for the use of combination therapy is limited. Petroianu et al. pro-
duced two case series using combinations of baclofen, gabapentin, cisapride,
and omeprazole [82, 83]. The group noted 9 of 15 patients with cessation
or improvement in hiccups using the combination of baclofen, omeprazole,
and cisapride [82]. A follow-up case series of three patients who were
refractory to that combination ultimately responded to a regimen including
the addition of gabapentin or with gabapentin substituted for baclofen [83].
A step-wise model for combination was proposed by Guelaud et al. [84].
Fifty-five patients with GERD were recruited, of which 20 failed to respond
to PPI and ultimately underwent treatment with PPI plus baclofen [84]. Of
the 20 patients treated with combination therapy, 8 experienced complete
resolution after up-titration of baclofen if needed [84]. Individual case
reports of successful hiccup cure using either gabapentin or baclofen in
combination therapy with a variety of medications exist as well [2].

Treatment algorithm
Available treatment algorithms in the literature are based on two small RCTs
(metoclopramide and baclofen), case series, and case reports. Empiric PPI use
should be considered first in most cases of hiccups with an idiopathic etiology.
Careful use of metoclopramide is first-line if a peripheral etiology of hiccups is
suspected. When a central etiology is apparent, baclofen is the primary choice.
Either can be used in cases where the other has failed or should be attempted
prior to initiation of other medications. Gabapentin may be a second-line agent
in either central or peripheral causes based on the relatively large number of
cases studied compared with other alternative medications. Chlorpromazine
may be considered a third-line agent given its FDA approval for the treatment of
hiccups but lack of RCT data. Monotherapy is recommended prior to combi-
nation therapy or treatment with alternative medications. If hiccups fail to
resolve with medical management, then interventional approaches should be
considered. Recent evidence is building to support the safe and efficacious use
 Neurogastroenterology and GI Motiliy (H Parkman and R Schey, Section Editors)

of peripheral phrenic nerve block and C3-C5 targeted epidural for refractory
cases.
Conclusion
Hiccups are a tightly controlled reflex with both peripheral and central compo-
nents to the reflex arc. Any irritation or disruption of this pathway may cause
hiccups. Symptoms lasting longer than 48 h typically signify a more serious and
underlying pathology and warrant further investigation. In many instances,
GERD is causative but many patients have underlying esophageal cancer or
central nervous system disturbances. First-line therapy should involve the ad-
dition of a PPI and appropriate gastroenterology work up. An EGD is usually
warranted in these situations. Patients who do not respond to PPI or whose
history may suggest other symptoms will likely need further diagnostic studies.
Other medication strategies may be employed with baclofen, metoclopramide,
gabapentin, or chlorpromazine, and those refractory to medication may require
more invasive treatments such as phrenic nerve block. Other therapies such as
acupuncture can be tried, but data to support their use is lacking.

Compliance with ethical standards

Conflict of interest
Kerstin Austin declares he has no conflict of interest. Sara Bonnes declares she has no conflict of interest. Harrison
Daniel declares he has no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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