ArticlePDF AvailableLiterature Review

Neurotransmitters in hiccups

Authors:
  • CalMed-School of Medinine
  • Click Therapeutics

Abstract and Figures

Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3) the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic, psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepinephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at each anatomical level of the reflex arc to better target hiccups pharmacologically.
Content may be subject to copyright.
Nausheen et al. SpringerPlus (2016) 5:1357
DOI 10.1186/s40064-016-3034-3
REVIEW
Neurotransmitters inhiccups
Fauzia Nausheen1, Hina Mohsin2 and Shaheen E. Lakhan1,2*
Abstract
Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign
and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions
for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent
limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3)
the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic,
psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated
with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated
in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepi-
nephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at
each anatomical level of the reflex arc to better target hiccups pharmacologically.
Keywords: Hiccup, Neurotransmitters, Therapies
© 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Background
e term “singultus” (hiccup) comes from singult; a Latin
word that means ‘sob’ or ‘gasp’. It refers to the sounds
that are produced by the sudden involuntary contrac-
tions of the diaphragm and intercostal muscles followed
by an abrupt contraction of the glottis. e air strikes the
closed glottis and results in the characteristic “hiccup”
sound. Hiccups are usually benign and self-limiting. ey
generally start without any specific reason and disappear
in a few minutes. Brief episodes of hiccups are common
in healthy individuals after a large meal, intake of alco-
holic beverages, or sudden excitement.
is article provides a review of different neurotrans-
mitters that are related in the mechanism of action of
the most commonly used drugs to treat hiccups, and the
medications that induced hiccups. At the end, this paper
draws a conclusion about the neurotransmitters involved
in the pathophysiology of hiccups.
Epidemiology
e classification of hiccups is based on their duration.
An acute attack lasts less than forty-eight hours. Persis-
tent hiccups last more than 2days. Intractable hiccups
are present if the attack lasts more than 1month. Per-
sistent hiccups are most likely to be associated with an
underlying pathological, anatomic or organic disease
process (Cymet 2002). Intractable hiccups that continue
for more than 1month are usually indicative of a seri-
ous organic disturbance (Vaidya 2000). If left untreated,
intractable hiccups can cause severe discomfort, depres-
sion, reduced physical strength, and even death (Con-
sults 2011). According to a report by William H. Dobelle,
approximately 4000 hospital admissions due to hiccups
are reported each year in the United States (Dobelle
1999). e intractable hiccups are more common in men
(82%) than in women. Most of the men suffering from
hiccups are 50years of age or older (Cymet 2002). Psy-
chogenic hiccups have been reported to occur more
commonly in women. e usual rate for hiccups is four
to sixty per minute with fairly constant frequency in an
individual (Howes 2012). Pathological hiccups can be
explained as a form of epilepsy or a failure of supra-spinal
inhibition (Launois et al. 1993; Lewis 1985). e inci-
dence and prevalence of persistent and intractable hic-
cups in the community has not been studied.
Open Access
*Correspondence: slakhan@gnif.org
1 Department of Medical Education, California University of Science
and Medicine - School of Medicine, 1405 W. Valley Blvd, Suite 101, Colton,
CA 92343, USA
Full list of author information is available at the end of the article
Page 2 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
Pathophysiology
e pathophysiological mechanism of hiccups is related
to lesions in its reflex arc as shown in Fig.1. e reflex arc
is comprised of three components:
1. e afferent limb including phrenic, vagus, and sym-
pathetic nerves to pass on somatic and visceral sen-
sory signals;
2. e central processing unit in the midbrain; and
3. e efferent limb travelling in motor fibers of phrenic
nerve to diaphragm and accessory nerves to the
intercostal muscles, respectively.
e central component is located in the periaque-
ductal grey, subthalamic nuclei (Hansen and Rosenberg
1993) among the brain stem respiratory center, phrenic
nerve nuclei, reticular formation and hypothalamus.
e central component for hiccups lies in the medulla
and is thought to be entirely separate from the pathways
involved in rhythmic breathing (Davis 1970). Dopamine,
gamma-amino-butyric-acid (GABA), serotonin, gluta-
mate, and glycine neurotransmitters can regulate this
central mechanism. e hiccup arc has modulatory input
from catecholaminergic and serotonergic afferents.
e release of 5-hydroxyl-tryptamine (5HT) from the
gut enterochromaffin cells and enteric vagal afferents
may also lead to hiccups as seen in a case report following
administration of cisplatinum, a chemotherapeutic agent
(Jatoi 2009). e mental branch of the trigeminal nerve
was also postulated to develop hiccups when stimulated
via chin shaving (Todisco etal. 2004). Significant nega-
tive intrathoracic pressure may occur during hiccups that
may result in hypotension, bradycardia, pneumomedi-
astinum, and subcutaneous emphysema (Rousseau 1995).
e mechanism of action of hiccups might be mediated
through agonizing 5-HT1A and antagonizing 5-HT2A
receptors to enhance the activity of the phrenic nerve,
thereby inducing hiccups. is concept was supported in
Fig. 1 Hiccup reflex arc with neurotransmitters
Page 3 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
a case report in which quetiapine was successfully used
to resolve the aripirazole-induced hiccups. is may sug-
gest the partial agonist and relatively high 5-HT1A recep-
tors binding affinities in the pathophysiology of hiccups
(Gilson and Busalacchi 1998). It is postulated in a study
that the GABA-containing cells in the nucleus raphe
are the source of GABA-nergic inhibition of the hiccup
center (Musumeci etal. 2000).
e most commonly used pharmacological treatments
include metoclopramide which reduces the intensity of
esophageal contraction, chlorpromazine (Twycross etal.
2002), baclofen, nifedipine which reverses the abnor-
mal depolarization in the hiccups reflex, valproic acid
that enhances GABA transmission centrally (Smith and
Busracamwongs 2003), antipsychotics, glucagon, GABA
analogue which acts by activating an inhibitory neuro-
transmitter, and dimethlamine derivative of phenothia-
zine which acts centrally by dopamine blockade in the
hypothalamus (Friedman 1996). Baclofen (GABA-ago-
nist) is among the substances that act through the nerv-
ous system and has by far the best ability to treat chronic
hiccups (Guelaud etal. 1995; Oshima etal. 1998; Petroi-
anu etal. 1997; Steger etal. 2015). However, a Cochrane
systemic review found insufficient evidence as to which
pharmacological agent is best for hiccups (Moretto etal.
2013). Hiccups are the manifestation of diaphragmatic
myoclonus and are considered to be a form of physiologic
myoclonus.
Etiology
In the review of recent literature, a variety of hiccups
etiologies have been reported (idiopathic, organic, psy-
chogenic, and medication-induced) induced have been
reported. Table1 provides an overview of pathology that
has been reliably linked to this condition. It has been sug-
gested that damage to the cervical cord, brainstem, hypo-
thalamus, and supra-tentorial area precipitate hiccups by
stimulating the hiccups reflex arc or decreasing the nor-
mal inhibition of hiccup neurons. It is suggested that all
potentially successful therapeutic drugs used to treat hic-
cups either decrease the input from gastrointestinal tract
(GIT) to the hiccups center or decrease the excitability
and output from the hiccups center (Burke etal. 1988;
Petroianu etal. 1997).
Neurotransmitters targets inhiccups
e exact etiology of hiccups is unclear, and it is
unknown why diverse drugs like dopamine blocking
agents (DBA), baclofen, clonazepam, and phenytoin,
which have widely varying mechanisms of action, can
be effective in the treatment of hiccups (Peleg and Peleg
2000). Table2 summarize drugs which induce and treat
hiccups and their potential neurotransmitters.
Gama‑amino butyric acid (GABA)
ere is strong evidence that the GABA is one of the
neurotransmitters involved in the hiccups reflex at the
central level. GABA functions as an inhibitory media-
tor at the interneuron level in the brain and in the spinal
cord (presynaptic inhibition) by altering trans-membrane
potential. Glutamic acid is decarboxylated to produce
GABA by the enzyme -glutamate decarboxylase (Rod-
well 2012). e inhibition of synapses by GABA has been
shown in the cerebellar cortex, hippocampus, olfactory
bulb, cuneate nucleus, caudate nucleus, substantia nigra,
septal nucleus, and between the vestibular and trochlear
Table 1 Common causes ofhiccups
Central nervous system Vascular Stroke, Infarct, SLE related vascular disorders and aneurysm
Infectious Meningitis and Encephalitis
Structural Brain injury, Intracranial tumors
Inflammation Neuromyelitis optica and multiple sclerosis
Miscellaneous Seizure, Parkinson’s Syndrome
Peripheral Nervous System (phrenic, vagal
and sympathetic nerves) Gastrointestinal Hiatus hernia, Esophageal cancer, Gastro-esophageal reflex
disease, stomach volvulus and H.pylori infection, Pancreatitis,
Abdominal abscess and Abdominal tumors
Thoracic Cardiovascular Myocardial Ischemia, Pericarditis, Thoracic Aneurysm
Pulmonary Bronchitis, Pneumonia, Asthma, Bronchial carcinoma, Tuberculosis
Ear, Nose and Throat Rhinitis, Otitis, Pharyngitis, Foreign body in nose or ear
Other causes Toxic metabolic Electrolyte imbalance, Alcohol, Chronic renal failure, Diabetes
mellitus
Pharmacological Steriods, benzodiazepines, chlordiazepoxide, diazepam, antibiot-
ics, sulfonamides, opioids, cisplatinum (Jatoi 2009), analeptic
agent, Methyldopa, l-dopa, Dopamine
Psychosomatic Anxiety, sleep deprivation, stress and fear
Page 4 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
Table 2 List ofdrugs which induce andtreat hiccups andtheir potential neurotransmitters
Location Neurotransmitters Drug‑induced hiccups Treatment ofhiccups
Central neurotransmitters; Respiratory center, medul-
lary reticular formation, phreni**c nerve nuclei,
hypothalamus, temporal lobes
Gama-amino butyric acid (GABA) Propofol (Jones et al. 1995) Valproic acid (Smith and Busracamwongs 2003)
Benzodiazepine (Jones et al. 1995) Baclofen (Guelaud et al. 1995; Oshima et al. 1998;
Petroianu et al. 1997; Smith and Busracamwongs
2003; Zhang et al. 2014)
Barbiturates (MacDonald et al. 1989) Gabapentin (Petroianu et al. 1998, 2000; Moretti et al.
2004; Liang et al. 2005; Porzio et al. 2010)
Midazolam (Smith and Busracamwongs 2003)
Dopamine Aripiprazole (Ray et al. 2009) Metaclopramide (Smith and Busracamwongs 2003;
Stav et al. 1992; Bateman 1983)
Chlorpromazine (Smith and Busracamwongs 2003)
Dopamine agonists (pirebedil, pergolide, pramipexo)
(Sharma et al. 2006; Lester et al. 2007)Baclofen (Martinez-Ruiz et al. 2004)
Clonazepam (Martinez-Ruiz et al. 2004)
Levodopa (Luquin et al. 1992) Phenytoin (Martinez-Ruiz et al. 2004)
Pramipexol (Vaidya 2000; Martinez-Ruiz et al. 2004)
Serotonin Olanzapine (Alderfer and Arciniegas 2006)
Amantadine (Wilcox et al. 2009; Askenasy et al. 1988)
Sertraline (Vaidya 2000)
Tandospirone (Takahashi et al. 2004)
Risperidone (Nishikawa et al. 2015)
Peripheral neuro transmitters; diaphragm, glottis,
scalene muscle, respiratory muscle, GIT Histamine Omeprazole (Petroianu et al. 1997)
Epinephrine Norepine-phrine Methylphenidate (Marechal et al. 2003; Pollock et al.
2009)
Acetylcholine Metoclopramide (Butterworth IV et al. 2005; Smith
and Busracamwongs 2003)
Page 5 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
motor neurons. ere are three main types of GABA
receptors—GABA-A, -B, and -C. GABA-A are the most
abundant receptors and the site of action of many neuro
active drugs such as benzodiazepines, barbiturates, etha-
nol and volatile anesthetics (Molinoff 2011). Valproic
acid enhances GABA transmission centrally (Smith and
Busracamwongs 2003) and is one of the most commonly
suggested therapies for hiccups. It is postulated in a study
that the GABA-containing cells in the nucleus raphe are
the source of GABA-ergic inhibition of the hiccup center
(Musumeci etal. 2000).
Dopamine
ere are many studies to support the convincing role
of dopamine as the central neurotransmitter involved
in hiccup pathogenesis. Dopamine is found in the brain
and peripherally in the adrenal medulla, plexuses of the
GI tract, and the enteric nervous system. Dopamine is
an adrenergic agonist that is non-selective (Morgan etal.
2005). ere are five dopamine receptor subtypes that
have been delineated by pharmacological analysis that
are the bases of a subtype of selective drugs. ere are
three major dopaminergic pathways in the central nerv-
ous system:
1. the niagrostriatal pathway which is important in Par-
kinson’s disease;
2. the mesolimbic pathway which plays a role in psychi-
atric disorders; and
3. the tuberoinfundibular pathway, which is related to
the regulation of the endocrine system.
Dopamine is an immediate precursor of norepineph-
rine. e synthesis of dopamine can be increased by
giving DOPA (Smith and Busracamwongs 2003; Ash-
ley and Krych 1995). ere are many studies, in which
patients have been treated successfully by using dopa-
mine blocking drugs such as metochlopromide and
chlorpromazine (Smith and Busracamwongs 2003) which
supports the evidence that dopamine acts as the central
neurotransmitter.
5‑Hydroxyl tryptamine (5HT; serotonin)
Many studies support the role of 5HT (serotonin) as the
neurotransmitter of hiccups. Serotonin is an important
central nervous system neurotransmitter and a local hor-
mone. It is also found in high concentrations in entero-
chromaffin cells throughout the GIT that are the site of
synthesis and storage of 5 HT from tryptophan. It regu-
lates the smooth muscles in the GIT to increase the tone
and facilitate the peristalsis via 5HT2 receptors (Katzung
2012). It is a powerful vasoconstrictor mainly through
5HT2 receptor but it dilates the blood vessels of the
heart and skeletal muscles (Katzung 2012). It is produced
in two steps: in step 1, tryptophan in converted to 5HT
and in the next step, the 5HT is converted to serotonin.
Increasing the concentration of tryptophan in the brain
can increase the high concentration of 5HT and sero-
tonin. Drugs that increase serotonin levels were most
commonly used as appetite suppressants. ey regulate
the smooth muscles in the GIT and cardiovascular sys-
tem. ere are fourteen subtypes of receptor of 5HT
recognized. ere are the 5HT1 subfamily and 5HT2
subfamilies of receptors. 5HT3 subfamilies were origi-
nally described in the periphery. ere are fourteen sub-
types of receptor of 5HT recognized. Cases of intractable
hiccups have been successfully treated with olanzapine
(Alderfer and Arciniegas 2006). Olanzapine has a com-
plex pharmacology and its major effect is to antago-
nize the postsynaptic serotonergic receptors. Similarly,
another case was reported describing the successful
treatment of hiccups with sertraline, a selective seroto-
nin reuptake inhibitor (SSRI), for the first time (Benowitz
2012; Vaidya 2000). In one case study, intractable hic-
cups were treated successfully with a tandospirone, a new
anxiolytic and 5HTA1 receptor agonist (Takahashi etal.
2004). Interestingly, a case report of intractable hiccups
that was refractory to the typical antipsychotic haloperi-
dol, however, responsive to atypical antipsychotic risp-
eridone which acts on 5HT2A, 5HT1A, 5HT1C, 5HT1D,
and D2 receptors (Nishikawa etal. 2015). All these stud-
ies are evidence that serotonin is involved in the patho-
physiology of hiccups.
Histamine
Histamine is produced by decarboxylation of histadine,
an amino acid, by the enzyme histadine decarboxylases
(Biomedical Aspects of Histamine 2011).
Histamine is released by the various triggers from mast
cells and basophils and has various biological effects
through four receptors H1R, H2R, H3R, H4R. Hista-
mine causes smooth cell contractions, vasodilatation,
and gastric acid secretion. Hyperhistaminemia can cause
an anaphylactic reaction (Hershko etal. 2001). ere is
evidence for the use of H2-receptor blockers and proton
pump inhibitors (i.e. omeprazole) for the treatment of
hiccups thought to act via decreasing the input from the
GIT to the hiccup center (Petroianu etal. 1997).
Epinephrine andnorepinephrine (NE)
Noreepinephrine (NE) is the neurotransmitter of the
post ganglionic autonomic nervous system that is
involved in the reduction of gastrointestinal motility.
NE is synthesized from tyrosine that is produced from
phenyle alanine. Dopamine is converted to NE by dopa-
mine beta hyroxylases. Norepinephrine is converted
Page 6 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
to epinephrine by the enzyme phenyle ethanolamine-
N-methyltransferase. e action of neurotransmit-
ter catecholamines is terminated by the re-uptake
and metabolism by the enzymes monoamine oxidases
(MOA) and catecolaminotransferases (COMT). e
inhibitors of these enzymes are used in the treatment
of Parkinson’s disease. Adreno receptors have four sub-
types, alpha1, alpha2, and beta1 for NE mainly and B2
is for epinephrine mainly. ere are studies about the
successful treatment of hiccups with methylphenidate
(a psycho-stimulant) generally used in attention deficit
disorders (Marechal etal. 2003; Pollock etal. 2009). e
methylphenidate is considered as the receptor modula-
tor of dopamine and norepinephrine. erefore relation-
ship may exist between norepinephrine and epinephrine
to the pathophysiology of hiccups.
Acetylcholine
Acetylcholine is a naturally occurring neurotransmit-
ter for the muscarinic receptors. It is a neurotransmitter
of all the preganglionic autonomic fibres, most post-
ganglionic parasympathetic, and a few post-ganglionic
sympathetic fibers (Westfall and Westfall 2011). Meto-
clopramide, an anticholinergic, is recommended for the
symptomatic relief of hiccups. ere are studies that
show that metoclopramide acts peripherally to reduce
the intensity of esophageal contraction (Consults 2011).
It has also been observed that metoclopramide have been
used to treat hiccups (Smith and Busracamwongs 2003)
which may explain the relation of acetylcholine as the
peripheral neurotransmitter involved in the pathophysi-
ology of hiccups.
Conclusion
Largely through case studies involving medications, we
implicate the neurotransmitters involved in hiccups. e
reflex arc is potentially mediated by central neurotrans-
mitters (GABA, dopamine, and serotonin) and peripheral
neurotransmitters (epinephrine, norepinephrine, acetyl-
choline, and histamine). Lesions across any of these neu-
roanatomical structures, for instance, from the brainstem
down to the diaphragm, may be responsible for the devel-
opment of hiccups. Further research is needed to char-
acterize the neurotransmitters involved in hiccups for
potential new therapeutic targets.
Authors’ contributions
Conceived and designed the paper: FN, HM, SEL. All authors participated in
the preparation of the manuscript. All authors read and approved the final
manuscript.
Author details
1 Department of Medical Education, California University of Science and Medi-
cine - School of Medicine, 1405 W. Valley Blvd, Suite 101, Colton, CA 92343,
USA. 2 Department of Neurology, California University of Science and Medicine
- School of Medicine, Colton, CA, USA.
Acknowledgements
We would like to extend our thanks to the Chair, Professor and Associate
Dean for Clinical Research, Department of Cellular Biology and Pharmacol-
ogy Florida International University, Dr. Georg Petroianu. Without his help
and guidance this review would have not been possible. It is our pleasure to
convey our gratitude to him in our humble acknowledgement. Also, we wish
to thank Ellen Wilkinson and Nancy Bethel of California University of Science
and Medicine for their editing support, guidance, and suggestions.
Competing interests
The authors declare that they have no competing interests.
Received: 9 March 2016 Accepted: 10 August 2016
References
Alderfer BS, Arciniegas DB (2006) Treatment of intractable hiccups with olan-
zapine following recent severe traumatic brain injury. J Neuropsychiatry
Clini Neurosci 18(4):551–552. doi:10.1176/jnp.2006.18.4.551
Ashley MJ, Krych DK (1995) Traumatic brain injury rehabilitation, 1st edn. CRC-
Press, Boca Raton
Askenasy JJ, Boiangiu M, Davidovitch S (1988) Persistent hiccup
cured by amantadine. N Engl J Med 318(11):711. doi:10.1056/
NEJM198803173181118
Bateman DN (1983) Clinical pharmacokinetics of metoclopramide. Clin Phar-
macokinet 8(6):523–529
Benowitz NL (2012) Antidepressants, general (noncyclic). In: Olson K (ed) Poi-
soning and drug overdose, 6th edn. McGraw-Hill Professional, New York
Biomedical Aspects of Histamine (2011). Springer Netherlands, Dordrecht
Burke AM, White AB, Brill N (1988) Baclofen for intractable hiccups. N Engl J
Med 319(20):1354. doi:10.1056/NEJM198811173192016
Butterworth IV JF, Mackey DC, Wasnick JD (2005) Adjuncts to anesthesia. In:
Morgan G, Mikhail M, Murray M (eds) Clinical anesthesiology, 4th edn.
McGraw-Hill, New York
Consults D (2011) Hiccups—etilogy and treatment. http://hslibrary.ucdenver.
edu/. Accessed Sept 2011
Cymet TC (2002) Retrospective analysis of hiccups in patients at a community
hospital from 1995-2000. J Natl Med Assoc 94(6):480–483
Davis JN (1970) An experimental study of hiccup. Brain 93(4):851–872
Dobelle WH (1999) Use of breathing pacemakers to suppress intractable hic-
cups of up to thirteen years duration. ASAIO J 45(6):524–525
Friedman NL (1996) Hiccups: a treatment review. Pharmacotherapy
16(6):986–995
Gilson I, Busalacchi M (1998) Marijuana for intractable hiccups. Lancet
351(9098):267. doi:10.1016/S0140-6736(05)78270-2
Guelaud C, Similowski T, Bizec JL, Cabane J, Whitelaw WA, Derenne JP (1995)
Baclofen therapy for chronic hiccup. Eur Respir J 8(2):235–237
Hansen BJ, Rosenberg J (1993) Persistent postoperative hiccups: a review. Acta
Anaesthesiol Scand 37(7):643–646
Hershko AY, Dranitzki Z, Ulmanski R, Levi-Schaffer F, Naparstek Y (2001)
Constitutive hyperhistaminaemia: a possible mechanism for recurrent
anaphylaxis. Scand J Clin Lab Invest 61(6):449–452
Howes D (2012) Hiccups: a new explanation for the mysterious reflex. BioEs-
says 34(6):451–453. doi:10.1002/bies.201100194
Jatoi A (2009) Palliating hiccups in cancer patients: moving beyond recom-
mendations from Leonard the lion. J Support Oncol 7(4):129–130
Jones MV, Harrison NL, Pritchett DB, Hales TG (1995) Modulation of the GABAA
receptor by propofol is independent of the gamma subunit. J Pharmacol
Exp Ther 274(2):962–968
Katzung BG (2012) Histamine, serotonin, and the ergot alkaloids. In: Katzung
BG, Masters SB, Trevor AJ (eds) Basic and clinical pharmacology. McGraw-
Hill, New York
Launois S, Bizec JL, Whitelaw WA, Cabane J, Derenne JP (1993) Hiccup in
adults: an overview. Eur Respir J 6(4):563–575
Lester J, Raina GB, Uribe-Roca C, Micheli F (2007) Hiccup secondary to
dopamine agonists in Parkinson’s disease. Mov Disord 22(11):1667–1668.
doi:10.1002/mds.21583
Lewis JH (1985) Hiccups: causes and cures. J Clin Gastroenterol 7(6):539–552
Page 7 of 7
Nausheen et al. SpringerPlus (2016) 5:1357
Liang C, Tsai K, Hsu M (2005) Gabapentin therapy for persistent hiccups and
central post-stroke pain in a lateral medullary infarction—two case
reports and literature review. Tzu Chi Med J 17:365–368
Luquin MR, Scipioni O, Vaamonde J, Gershanik O, Obeso JA (1992) Levodopa-
induced dyskinesias in Parkinson’s disease: clinical and pharmacological
classification. Mov Disord 7(2):117–124. doi:10.1002/mds.870070204
MacDonald RL, Rogers CJ, Twyman RE (1989) Barbiturate regulation of kinetic
properties of the GABAA receptor channel of mouse spinal neurones in
culture. J Physiol 417:483–500
Marechal R, Berghmans T, Sculier P (2003) Successful treatment of intractable
hiccup with methylphenidate in a lung cancer patient. Support Care
Cancer 11(2):126–128. doi:10.1007/s00520-002-0411-y
Martinez-Ruiz M, Fernandez Riestra Fde A, Quesada Rubio R (2004) Pramipex-
ole for intractable hiccups. Med Clin 123(17):679
Molinoff PB (2011) Neurotransmission and the central nervous system. In: The
pharmacological basis of therapeutics, 12th edn. McGraw-Hill Profes-
sional, New York
Moretti R, Torre P, Antonello RM, Ukmar M, Cazzato G, Bava A (2004) Gabapen-
tin as a drug therapy of intractable hiccup because of vascular lesion: a
three-year follow up. Neurologist 10(2):102–106
Moretto EN, Wee B, Wiffen PJ, Murchison AG (2013) Interventions for treating
persistent and intractable hiccups in adults. Cochrane Database Syst Rev.
doi:10.1002/14651858.CD008768.pub2
Morgan JGE, Mikhail MS, Murray MJ (2005) Adrenergic Agonists and Antago-
nists. In: Morgan G, Mikhail M, Murray M (eds) Clinical Anesthesiology, 4th
edn. McGraw-Hill, New York
Musumeci A, Cristofori L, Bricolo A (2000) Persistent hiccup as presenting
symptom in medulla oblongata cavernoma: a case report and review of
the literature. Clin Neurol Neurosurg 102(1):13–17
Nishikawa T, Araki Y, Hayashi T (2015) Intractable hiccups (singultus) abolished
by risperidone, but not by haloperidol. Ann Gen Psychiatry 14:13.
doi:10.1186/s12991-015-0051-5
Oshima T, Sakamoto M, Tatsuta H, Arita H (1998) GABAergic inhibition of
hiccup-like reflex induced by electrical stimulation in medulla of cats.
Neurosci Res 30(4):287–293
Peleg R, Peleg A (2000) Case report: sexual intercourse as potential treatment
for intractable hiccups. Can Fam Physician Medecin de famille canadien
46:1631–1632
Petroianu G, Hein G, Petroianu A, Bergler W, Rufer R (1997) Idiopathic chronic
hiccup: combination therapy with cisapride, omeprazole, and baclofen.
Clin Ther 19(5):1031–1038
Petroianu G, Hein G, Petroianu A, Bergler W, Rufer R (1998) ETICS study: empiri-
cal therapy of idiopathic chronic singultus. Z Gastroenterol 36(7):559–566
Petroianu G, Hein G, Stegmeier-Petroianu A, Bergler W, Rufer R (2000)
Gabapentin “add-on therapy” for idiopathic chronic hiccup (ICH). J Clin
Gastroenterol 30(3):321–324
Pollock BG, Semla TP, Forsyth CE (2009) Psychoactive drug therapy. In: Halter JB,
Ouslander JG, Tinetti ME, Studenski S, High KP, Asthana S (eds) Hazzard’s
geriatric medicine and gerontology, 6th edn. McGraw-Hill, New York
Porzio G, Aielli F, Verna L, Aloisi P, Galletti B, Ficorella C (2010) Gabapen-
tin in the treatment of hiccups in patients with advanced cancer: a
5-year experience. Clin Neuropharmacol 33(4):179–180. doi:10.1097/
WNF.0b013e3181de8943
Ray P, Zia Ul Haq M, Nizamie SH (2009) Aripiprazole-induced hiccups:
a case report. Gen Hosp Psychiatry 31(4):382–384. doi:10.1016/j.
genhosppsych.2008.09.014
Rodwell VW (2012) Conversion of amino acids to specialized products. In:
Rodwell V, Bender D (eds) Harper’s illustrated biochemistry. McGraw-Hill,
New York
Rousseau P (1995) Hiccups. South Med J 88(2):175–181
Sharma P, Morgan JC, Sethi KD (2006) Hiccups associated with dopamine
agonists in Parkinson disease. Neurology 66(5):774. doi:10.1212/01.
wnl.0000201267.78431.f0
Smith HS, Busracamwongs A (2003) Management of hiccups in the palliative
care population. Am J Hosp Palliat Care 20(2):149–154
Stav A, Weksler N, Berman M, Lemberg L, Ribak L, Segal A, Machamid E, Ovadia
L, Sternberg A (1992) Premedication with metoclopramide decreases
the frequency of methohexital induced hiccup. J Anesth 6(1):17–20.
doi:10.1007/s0054020060017
Steger M, Schneemann M, Fox M (2015) Systemic review: the pathogenesis
and pharmacological treatment of hiccups. Aliment Pharmacol Ther
42(9):1037–1050. doi:10.1111/apt.13374
Takahashi T, Murata T, Omori M, Tagaya M, Wada Y (2004) Successful treatment
of intractable hiccups with serotonin (5-HT)1A receptor agonist. J Neurol
251(4):486–487. doi:10.1007/s00415-004-0377-4
Todisco T, Todisco C, Bruni L, Donato R (2004) Chin stimulation: a trig-
ger point for provoking acute hiccups. Respiration 71(1):104.
doi:10.1159/000075661
Twycross R, Wilcock A, Charlesworth S, Dickman A (2002) Palliative care formu-
lary, 2nd edn. Radcliffe Medical Press, Oxford
Vaidya V (2000) Sertraline in the treatment of hiccups. Psychosomatics
41(4):353–355. doi:10.1176/appi.psy.41.4.353
Westfall TC, Westfall DP (2011) Neurotransmission: the autonomic and somatic
motor nervous systems. In: Brunton L, Chabner B (eds) Goodman and
Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-
Hill, New York
Wilcox SK, Garry A, Johnson MJ (2009) Novel use of amantadine: to
treat hiccups. J Pain Symp Manag 38(3):460–465. doi:10.1016/j.
jpainsymman.2008.10.008
Zhang C, Zhang R, Zhang S, Xu M, Zhang S (2014) Baclofen for stroke patients
with persistent hiccups: a randomized, double-blind, placebo-controlled
trial. Trials 15:295. doi:10.1186/1745-6215-15-295
... The hiccup reflex is characterized by sudden inspiration immediately followed by an active closure of the glottis. 1 The reflex arc for hiccups involves phrenic, glossopharyngeal, vagal, and sympathetic pathways as afferents, a central pattern generator in the lower brainstem, and motor neurons that supply the diaphragm and the other respiratory muscles as the efferent. [10][11][12] The neurotransmitters involved in hiccups include gamma-aminobutyric acid (GABA), dopamine, and serotonin, and hence, blocking these has proved to be useful in the treatment of hiccups. 12,13 There are central and peripheral causes for hiccups. ...
... [10][11][12] The neurotransmitters involved in hiccups include gamma-aminobutyric acid (GABA), dopamine, and serotonin, and hence, blocking these has proved to be useful in the treatment of hiccups. 12,13 There are central and peripheral causes for hiccups. Cerebrovascular accidents, trauma, and space occupying lesions include some of the central causes, and peripheral causes include gastro-esophageal reflux, lesions along the afferent pathway such as tumors, herpes infection or myocardial ischemia and drugs like steroids, anti-Parkinsonism and chemotherapeutic agents. 1 Medullary lesions are known to result in hiccups, and lateral medullary infarction is an important cause for intractable hiccups. ...
... 14,15 The function of hiccups continues to remain poorly understood. 1,12 Phylogenetically, hiccups are similar to the gill ventilation that occurs in fish and tadpoles. In tadpoles, gill ventilation precedes lung ventilation which is similar to that of humans where, embryologically, hiccups occur during the latter part of gestation, even before the onset of fetal respiration. ...
Article
Full-text available
Background Hiccups is a known presentation of lateral medullary infarction. However, the region in the medulla associated with this finding is not clearly known. In this study, we aimed to study the neural correlates of hiccups in patients with lateral medullary infarction (LMI). Materials and Methods This retrospective study included all patients who presented with lateral medullary infarction between January 2008 and May 2018. Patients with hiccups following LMI were identified as cases and those with no hiccups but who had LMI were taken as controls. The magnetic resonance imaging of the brain was done viewed and individual lesions were mapped manually to the template brain. Voxel-based lesion-symptom mapping employing nonparametric permutation testing was performed using MRIcron. Results There were a total of 31 patients with LMI who presented to the hospital during the study period. There were 11 (35.5%) patients with hiccups. Using the voxel-based lesion-symptom mapping analysis, the dorso-lateral region of the middle medulla showed significant association with hiccups. Conclusion In patients with LMI, we postulate that damage to the dorsolateral aspect on the middle medulla could result in hiccups.
... These contractions usually are accompanied by a short inhalation, which is interrupted by closure of the glottis (9, 10). The hiccup response appears to involve a reflex arc that arises from the interaction of three neuroanatomical facets (29)(30)(31)). An "afferent limb" composed of the phrenic and vagus nerves as well as sympathetic nerve fibers from the thoracic chain T6-T12, which mediates the outflow of visceral and somatic sensory inputs. ...
Article
Full-text available
Symptoms, such as fever, dry cough, dyspnoea, and respiratory distress, are commonly described in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recently, a growing number of cases pertained to persistent hiccups have been reported by SARS-CoV-2 infected patients. The aim of this systematic review was to screen the current literature and provide a summary of the reported cases of SARS-CoV-2 infected patients presenting with persistent hiccups. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Scopus, and Web of Science databases were searched from inception until October 2021. Case reports or case series that provided a separate clinical description for patients with presenting complaints of persistent hiccups before or after COVID-19 diagnosis were retrieved. The critical appraisal checklist for case reports provided by the Joanna Briggs Institute (JBI) was employed to evaluate the overall quality of the eligible studies. We identified 13 eligible studies that included 16 hospitalized COVID-19 patients who complained of persistent hiccups. The mean duration of hiccups was 4.6 days reported in 88% (14/16) patients. Hypertension was the most common comorbidity present in 50% (8/16) of patients followed by diabetes mellitus (4/16). Moreover, 44% (7/16) of patients received only one medication for managing the hiccups with metoclopramide (5/16) followed by chlorpromazine and baclofen (4/16) used as primary treatment. Equally, 44% of patients (7/16) received dexamethasone followed by azithromycin (5/16), ivermectin (4/16), and ceftriaxone (4/16) for managing the infection from SARS-CoV-2. The majority of patients (14/16) improved after initiation of treatment. Persistent hiccups are possibly a rare symptom that clinicians may expect to encounter in patients infected with SARS-CoV-2. Although there is not ample proof to propose causation, increased awareness about the diversity of presentations of SARS-CoV-2 infection could be crucial in the early recognition of the disease.
... The second component is the central processing unit, which involves the brain stem, medulla oblongata, temporal lobes, chemoreceptors, glossopharyngeal and phrenic nerve nuclei, and hypothalamus [1][2][3][4][5][6]. Moreover, the central neurotransmitters related to the central processing unit include gamma-aminobutyric acid (GABA), dopamine, and serotonin [7]. The last component is the efferent component, which includes the phrenic nerve supplying the diaphragm and the accessory nerves supplying the intercostal muscles [1]. ...
Article
Full-text available
The possibilities of coronavirus disease 2019 (COVID-19) to present with atypical manifestations have reported. Information of COVID-19 atypical signs and symptoms is still emerging globally. One of these presentations is persistent hiccups. One of the hypotheses is that COVID-19 has been linked to several neurological manifestations and effects. Some observations noticed phrenic nerve paralysis after COVID-19 infection leading to pulmonary failure. We report one case of COVID-19-positive patient where he presented with persistent hiccups. Many predisposing factors might lead to the development of hiccups in COVID-19 infection such as a history of smoking, phrenic and vagus nerve damage or irritation, high inflammatory markers, lower lobe pneumonia, ground-glass-like appearance on x-rays. We hypothesize that hiccups are the first sign of serious deterioration of patients with COVID-19 and such patients are at high risk of developing kidney injury and intubation.
... Refleks arkı boyunca yer alan sinirlerin uzun seyrinden dolayı hıçkırığın nedenini bulmanın zor olabileceği belirtilmiştir. 6 Prince ve ark. 7 ...
Article
Hiccups are experienced by people of all ages. While acute hiccups are benign and self-limited, persistent and intractable hiccups can sometimes signal a serious disease. We present a young previously healthy man who complained of only hiccups for 4 months and later developed a severe headache and projectile vomiting. His systemic examination was within normal limits. Brain imaging revealed a diffuse pontine glioma with mild hydrocephalus.
Article
Full-text available
In this study, we used the large number of cases in the FDA adverse-event reporting system (FAERS) database to investigate risk factors for drug-induced hiccups and to explore the relationship between hiccups and gender. From 11,810,863 adverse drug reactions reported between the first quarter of 2004 and the first quarter of 2020, we extracted only those in which side effects occurred between the beginning and end of drug administration. Our sample included 1454 adverse reactions for hiccups, with 1159 involving males and 257 involving females (the gender in 38 reports was unknown). We performed univariate analyses of the presence or absence of hiccups for each drug and performed multivariate analysis by adding patient information. The multivariate analysis showed nicotine products to be key suspect drugs for both men and women. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon.
Article
Hiccups are a common phenomenon experienced by many people and are usually short-lived with spontaneous resolution of symptoms. Certain anesthetic medications have been associated with the development of hiccups, though the underlying pathophysiology and reflex arcs remain poorly understood. We describe a patient who developed hiccups lasting 9 days following an orthopedic surgery and again developed hiccups during a subsequent surgery after only having received midazolam; flumazenil administration led to sustained cessation of his hiccup symptoms immediately.
Article
Full-text available
Hiccups are involuntary and spasmodic contractions of the diaphragm, and multiple etiological factors have been suggested to be involved. Medications, such as dexamethasone, as well as some diseases, such as pneumonia, can cause persistent (>48 h) hiccups. Here, we report a 58-years-old male who had a fever, myalgia, cough, and ground-glass view in the chest computed tomography, and his PCR test for Covid-19 was positive. During the treatment course, persistent hiccups were developed after taking dexamethasone and lasted for six days. All cardiac and neurologic examinations were performed, and all of them were normal. After evaluating all of the possible underlying causes, dexamethasone was replaced by prednisolone. Upon a change in his treatment regimen, hiccups began to stop, and his symptoms also disappeared. Hiccups may occur in patients who have pneumonia and other infectious diseases. Dexamethasone can also stimulate hiccups along with infections.
Article
Full-text available
Hiccups or singulata are rhythmic involuntary movements of the diaphragm, caused by a variety of conditions that interfere with the functions of the nerve nuclei in the medulla and supra-spinal hiccup center. Although neurotransmitters and receptors involved in the pathophysiology of hiccups are not defined well, dopamine has been considered to play an important role. In some cases, chlorpromazine or other antipsychotics are used for the treatment of intractable hiccups but their efficacy is often limited. This report involves an 18-year-old patient who experienced two episodes of intractable hiccups triggered by stress, which lasted for weeks or even months. In both episodes, haloperidol was initially used, but there was no significant effect. In contrast, risperidone, the second-generation antipsychotic that possesses a dopamine-serotonin antagonist property, completely abolished the hiccups 6 hours after administration. This is one of few case reports in which two antipsychotics were challenged for a single patient with hiccups, and the effects of the drugs were obviously different. Our finding suggests that, in addition to dopaminergic system, the serotonergic systems may be involved in the pathophysiology of some hiccup cases and that the serotonin-acting antipsychotics such as risperidone should be considered as a choice in the drug treatment of intractable hiccups.
Article
Full-text available
The results of preclinical studies suggest that baclofen may be useful in the treatment of stroke patients with persistent hiccups. This study was aimed to assess the possible efficacy of baclofen for the treatment of persistent hiccups after stroke. In total, 30 stroke patients with persistent hiccups were randomly assigned to receive baclofen (n = 15) or a placebo (n = 15) in a double-blind, parallel-group trial. Participants in the baclofen group received 10 mg baclofen 3 times daily for 5 days. Participants assigned to the placebo group received 10 mg placebo 3 times daily for 5 days. The primary outcome measure was cessation of hiccups. Secondary outcome measures included efficacy in the two groups and adverse events. All 30 patients completed the study. The number of patients in whom the hiccups completely stopped was higher in the baclofen group than in the placebo group (relative risk, 7.00; 95% confidence interval, 1.91–25.62; P = 0.003). Furthermore, efficacy was higher in the baclofen group than in the placebo group (P < 0.01). No serious adverse events were documented in either group. One case each of mild transient drowsiness and dizziness was present in the baclofen group. Baclofen was more effective than a placebo for the treatment of persistent hiccups in stroke patients. Trial registration Chinese Clinical Trials Register: ChiCTR-TRC-13004554
Chapter
Acetylcholine (ACh) is the neurotransmitter at all autonomic ganglia, all postganglionic parasympathetic nerves, postganglionic sympathetic nerves innervating eccrine sweat glands, the neuromuscular junction, and neurons in the central nervous system. ACh is synthesized by the acetylation of choline and acetyl coenzyme A by choline acetyltransferase. Depolarization of cholinergic neurons releases ACh by exocytosis into the various synapses where it acts on muscarinic (M 1-M 5) metabotropic receptors or nicotinic (N m or N n) ionotropic receptors. ACh is inactivated by acetylcholine esterase to acetic acid and choline. Following reuptake into cholinergic neurons, choline is reused for ACh synthesis.
Article
Hiccups are familiar to everyone, but remain poorly understood. Acute hiccups can often be terminated by physical manoeuvres. In contrast, persistent and intractable hiccups that continue for days or months are rare, but can be distressing and difficult to treat. To review the management of hiccups, including a systematic review of reported efficacy and safety of pharmacological treatments. Available articles were identified using three electronic databases in addition to hand searching of published articles. Inclusion criteria were any reports of pharmaceutical therapy of 'hiccup(s)', 'hiccough(s)' or 'singultus' in English or German. Treatment of 341 patients with persistent or intractable hiccups was reported in 15 published studies. Management was most effective when directed at the underlying condition. An empirical trial of anti-reflux therapy may be appropriate. If the underlying cause is not known or not treatable, then a range of pharmacological agents may provide benefit; however, systematic review revealed no adequately powered, well-designed trials of treatment. The use of baclofen and metoclopramide are supported by small randomised, placebo-controlled trials. Observational data suggest that gabapentin and chlorpromazine are also effective. Baclofen and gabapentin are less likely than standard neuroleptic agents to cause side effects during long-term therapy. This systematic review revealed no high quality data on which to base treatment recommendations. Based on limited efficacy and safety data, baclofen and gabapentin may be considered as first line therapy for persistent and intractable hiccups, with metoclopramide and chlorpromazine in reserve. © 2015 John Wiley & Sons Ltd.
Article
Hiccups and pain are well known although often overlooked complications of a stroke. Persistent hiccups in patients with a stroke can be associated with potentially fatal consequences, such as aspiration pneumonia, malnutrition, and respiratory arrest. We present 2 patients who suffered from persistent hiccups due to a lateral medullary infarction. We treated them with gabapentin, and both responded quite promptly. Central post-stroke pain (CPSP) is particularly prevalent after a lateral medullary infarction, and only partially responds to conventional treatment. One of the 2 patients had CPSP and failed to respond to a variety of oral analgesics; but within 2 weeks of the inception of gabapentin therapy, his average pain intensity was significantly reduced. This report suggests a potential advantage of gabapentin in the treatment of persistent hiccups and CPSP in patients with a lateral medullary infarction.
Article
Background: Persistent and intractable hiccups (typically defined as lasting for more than 48 hours and one month respectively) can be of serious detriment to a patient's quality of life, although they are relatively uncommon. A wide range of pharmacological and non-pharmacological interventions have been used for the treatment of persistent and intractable hiccups. However, there is little evidence as to which interventions are effective or harmful. Objectives: The objective of this review was to evaluate the effectiveness of pharmacological and non-pharmacological interventions used in the treatment of persistent and intractable hiccups of any aetiology in adults. Search methods: Studies were identified from the following databases: CENTRAL, CDSR, DARE, MEDLINE, EMBASE, CINAHL, PsychINFO and SIGLE (last search March 2012). The search strategy for all the databases searched was based on the MEDLINE search strategy presented in Appendix 1. No additional handsearching of journals was undertaken. Investigators who are known to be carrying out research in this area were contacted for unpublished data or knowledge of the grey literature. Selection criteria: Studies eligible for inclusion in this review were randomised controlled trials (RCTs) or controlled clinical trials (CCTs). Inclusion criteria: adults (over 18 years old) diagnosed with persistent or intractable hiccups (hiccups lasting more than 48 hours), treated with any pharmacological or non-pharmacological intervention. Exclusion criteria: less than ten participants; no assessment of change in hiccup frequency or intensity in outcome measures. Data collection and analysis: Two independent review authors assessed each abstract and title for relevance. Disagreement on eligibility was resolved by discussion. Where no abstract was available the full paper was obtained and assessed. We obtained full copies of the studies which met the inclusion criteria for further assessment. Two review authors independently collected data from each appropriate study and entered them into the software Review Manager 5. Two independent review authors assessed the risk of bias using the RevMan 5 'Risk of bias' table following guidance from the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2009). Main results: A total of four studies (305 participants) met the inclusion criteria. All of these studies sought to determine the effectiveness of different acupuncture techniques in the treatment of persistent and intractable hiccups. All four studies had a high risk of bias, did not compare the intervention with placebo, and failed to report side effects or adverse events for either the treatment or control groups. Due to methodological differences we were unable to perform a meta-analysis of the results. No studies investigating pharmacological interventions for persistent and intractable hiccups met the inclusion criteria. Authors' conclusions: There is insufficient evidence to guide the treatment of persistent or intractable hiccups with either pharmacological or non-pharmacological interventions.The paucity of high quality studies indicate a need for randomised placebo-controlled trials of both pharmacological and non-pharmacological treatments. As the symptom is relatively rare, trials would need to be multi-centred and possibly multi-national.