Olanzapine and Baclofen for the Treatment of Intractable
Amy N. Thompson,1,* Julie Ehret Leal,2and Walter A. Brzezinski3
1Department of Clinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy,
Medical University of South Carolina, Charleston, South Carolina;2Clinical Pharmacy Specialist in
Ambulatory Care, Department of Pharmacy Services, Medical University of South Carolina, Charleston,
South Carolina;3College of Medicine, Medical University of South Carolina, Charleston, South Carolina
Intractable hiccups are a relatively uncommon condition characterized by involuntary, spasmodic con-
tractions of the diaphragm. This type of hiccups generally has a duration of more than 1 month. We
describe a 59-year-old kidney transplant recipient with a complicated medical history (atrial fibrilla-
tion, chronic renal failure, type 2 diabetes mellitus, gastroesophageal reflux, gout, hypertension, hyper-
lipidemia, and obstructive sleep apnea) who developed intractable hiccups that significantly affected
his quality of life. Despite an extensive gastrointestinal and pulmonary evaluation, and treatment fail-
ures with several different drug regimens—metoclopramide, desipramine, amantadine, cyclobenzap-
rine, phenytoin, and lorazepam—his hiccups were eventually controlled with a combination of
baclofen and low-dose olanzapine therapy. Baclofen is a c-aminobutyric acid (GABA) analog that con-
tains a phenylethylamine moiety. It is hypothesized that having both GABA and phenylethylamine
properties activates inhibitory neurotransmitters, most notably GABA, which may in turn block the
hiccup stimulus. The exact mechanism through which olanzapine is effective in patients with hiccups
is not fully understood. It is thought that the effect is, in part, due to serotonin augmenting phrenic
motoneuronal activity on the reflex arcs involved in the generation of hiccups within the spinal cord.
In addition, since olanazapine is a dopamine antagonist, particularly a dopamine D2-receptor antago-
nist, this could also have played a role in its effectiveness in treating our patient. Strong evidence for a
specific treatment regimen for intractable hiccups is lacking in the primary literature. Our case report
adds to the available literature, as there are currently no published data on the use of combination
therapy for the treatment of intractable hiccups, and the combination of baclofen and olanzapine sig-
nificantly improved our patient’s quality of life.
KEY WORDS baclofen, intractable hiccups, olanzapine.
(Pharmacotherapy 2014;34(1):e4–e8) doi: 10.1002/phar.1378
Intractable hiccups are a relatively uncommon
condition characterized by involuntary, spas-
modic contractions of the diaphragm that result
in sudden closure of the glottis, producing the
characteristic “hic” sound. This type of hiccups
generally has a duration of more than 1 month.
Although the pathophysiology of intractable hic-
cups is not fully understood, it is thought to be
the result of injury, irritation, or inflammation
of a nerve involved in the hiccup reflex arc.
Many causes of intractable hiccups have been
suggested, including gastrointestinal conditions,
metabolic abnormalities, vagus nerve irritation,
central nervous system conditions, certain drugs,
diaphragm. However, in many cases, the exact
Assistant Professor, Department of Clinical Pharmacy and
Outcome Sciences, South Carolina College of Pharmacy –
MUSC Campus, 43 Sabin Street, QE 213-E, Charleston, SC
29425-1320; e-mail: email@example.com.
? 2013 American College of Clinical Pharmacy
for correspondence:AmyN. Thompson,
intractable hiccups is not well established due to
the lack of randomized controlled trials; thus,
potential treatment regimens are based mainly
describe the case of a man who developed
intractable hiccups who failed several different
drug regimens but was eventually controlled
with olanzapine and baclofen.
A 59-year-old kidney transplant recipient pre-
sented to his transplant nephrologist 4 months
after transplantation with complaints of persis-
tent hiccups that were quite bothersome. The
patient reported a previous history of hiccups
that was at one point controlled with chlor-
promazine, but the drug had to be discontinued
due to cholestatic jaundice. He also reported
that the hiccups were very frequent and persis-
tent, and would resolve on their own with no
intervention. He stated that the most recent epi-
sode of hiccups started shortly after his trans-
plant surgery. He reported that they lasted
throughout the day, resolved once he was
asleep, then returned several hours after waking
in the morning. The patient’s medical history
was significant for atrial fibrillation, chronic
renal failure, type 2 diabetes mellitus, gastro-
esophageal reflux, gout, hypertension, hyperlip-
complete list of drug therapy is shown in
At this visit, the transplant nephrologist pre-
scribed over-the-counter aluminum hydroxide–
magnesium trisilicate tablets, and instructed the
patient to continue metoclopramide 5 mg 3
times/day, which the patient was already taking
for gastroparesis. The patient called the trans-
plant clinic 2 days later complaining of contin-
ued hiccups that were interfering with sleep and
work. The transplant nephrologist discontinued
metoclopramide, and baclofen 10 mg/day was
started. Two days later, the patient presented to
his primary care physician, still complaining of
hiccups, but no changes in therapy were made
at this visit.
again presented to his transplant nephrologist
with complaints of persistent hiccups along with
nausea and vomiting. He was admitted to the
hospital, with plans for an upper endoscopy to
evaluate the cause of the hiccups. On the day of
the scheduled procedure, however, the patient’s
heart rate dropped into the 30 beats/minute
range, so the procedure was postponed. The car-
diology service was consulted, and the patient’s
atrial fibrillation was treated with cardioversion.
Of interest, the patient’s nausea, vomiting, and
hiccups resolved spontaneously without any
intervention. However, the inpatient team still
scheduled the patient to be evaluated by the gas-
troenterology service as an outpatient, which
occurred 3 weeks later. The gastroenterologist
suggested that gastroparesis was the cause for the
patient’s hiccups, and desipramine 25 mg/day
was started. The gastroenterologist also ordered
an endoscopy, gastric-emptying study, and com-
puted tomography (CT) scans of the chest and
abdomen, which were all unremarkable.
One month later, the patient returned to the
gastroenterologist stating that the hiccups con-
tinued despite the addition of desipramine, so
the drug was discontinued. The gastroenterolo-
gist could not offer any additional drug therapy
but suggested a low-fat, low-residue diet and
small, infrequent meals, and the patient was
referred to the pulmonology service. The patient
5 days later. Amantadine
started, and a CT scan of the neck and magnetic
resonance imaging of the brain were ordered,
which were both unremarkable. Two months
later, the patient returned to the gastroenterolo-
gist with continued complaints of persistent
Table 1. The Patient’s Drug Therapy Before His Hospital-
ization for Intractable Hiccups
Drug Dose and Frequency
+ vitamin D
200 mg once/day
81 mg once/day
0.25 mcg once/day
Calcium 500 mg–vitamin
D 400 mg twice/day
20 mg twice/day
36 units in the morning
24 units at bedtime
40 mg once/day
800 mg twice/day
5 mg 3 times/day
2.5 mg once/day
50 mg twice/day
1000 mg twice/day
40 mg twice/day
5 mg once/day
5 mg on Tuesday, Thursday,
and Saturday; 2.5 mg on Monday,
Wednesday, Friday, and Sunday
Human NPH insulin
OLANZAPINE AND BACLOFEN FOR INTRACTABLE HICCUPS Thompson et ale5
hiccups; both amantadine and baclofen were dis-
continued. He was prescribed cyclobenzaprine
5 mg 3 times/day for a 1-month trial, which
Five months later, the patient returned to his
primary care physician with continued com-
plaints of severe hiccups that continued to
interfere with his daily life. Phenytoin 200 mg/
day was started, titrated up to 300 mg/day, but
after 2 weeks of therapy, the patient experi-
enced no relief of his hiccups. The primary care
physician discontinued phenytoin, and loraze-
pam 0.5 mg twice/day was started. Around this
same time, the patient’s nephrologist increased
his dialysis time by 30 minutes to see if
this intervention would help. Neither of these
treatments relieved the patient’s hiccups, and
lorazepam was discontinued.
Given the patients’
chlorpromazine, the primary care physician pre-
scribed olanzapine 2.5 mg/day as a last resort
drug before consideration of more invasive
diagnostic procedures. The patient continued to
have intractable hiccups that would occasion-
ally result in vomiting. When he returned to
the pulmonologist for follow-up, olanzapine
was increased to 5 mg twice/day, and baclofen
was restarted at 10 mg four times/day. The
patient’s hiccups finally ceased with this regi-
men; however, he developed concerning extra-
involuntary movements, unsteadiness, and a
swollen tongue. He was instructed by the pul-
monologist to discontinue the drugs, which
resolved the adverse effects, but the hiccups
quickly returned. The pulmonologist advised
restarting baclofen at a lower dose of 5 mg
twice/day, which the patient tolerated without
any adverse effects. Several days later, the
patient resumed olanzapine, which was pre-
scribed at a lower dose of 2.5 mg/day, which
adverse effects did not recur with the lower
doses of baclofen and olanzapine.
The patient continued baclofen and olanza-
noted in his hiccups. He was assessed for
adverse effects at each follow-up clinic visit.
He reported that although he still experienced
hiccups frequently, they no longer began on
awakening, nor did they last all day. His hic-
cups typically started later in the afternoon and
only lasted for a short period of time. In addi-
tion, they no longer interfered with his quality
There are several case reports in the literature
regarding hiccups in transplant recipients. One
study reported that hiccups in the early post-
transplant period are typically due to infections
or adverse effects of drugs such as steroids and
anesthetics.1They state that in later periods, the
most common causes are infections and tumors.
Our patient’s hiccups began to occur before
his transplantation but then returned more
persistently approximately 4 month after trans-
Strong evidence for a specific treatment regi-
men for intractable hiccups is lacking in the pri-
mary literature. However, several case reports
have been previously published that describe
various successful pharmacotherapeutic
these cases describe successful use of baclofen or
gabapentin in various clinical settings.2–10Addi-
tional cases specifically involve patients with
cancer who were successfully treated with gaba-
pentin, baclofen, or methylphenidate.11–14Other
case reports describe successful use of chlor-
promazine, olanzapine, sertraline, nimodipine,
amantadine, and midalozam as monotherapy.15–21
Several nonpharmacotherapeutic treatment regi-
mens have also been effective, including simple
strategies such as nebulized normal saline,22the
Heimlich maneuver,23and sexual intercourse,24
to more complicated treatments such as acu-
puncture,25–28nerve stimulation or block,29–31
stim,33and suboccipital release.34
We were able to find one case report describ-
ing cardioversion that successfully treated a
reported a case of a 67-year-old man who had
three-vessel bypass surgery after myocardial
infarction. After his procedure, he had complica-
tions involving ileus, pulmonary embolus, hic-
cups, and recurrent ventricular tachycardia. Of
note, the authors reported that the hiccups were
unaffected by chlorpromazine, prochlorperazine,
diazepam, and lorazepam. The authors reported
that the most debilitating problem was the
patient’s ventricular tachycardia, for which he
underwent cardioversion. The patient went into
normal sinus rhythm immediately after the
procedure. In addition, the patient’s hiccups
ceased. The patient had intermittent hiccups for
approximately 2 hours, and then they perma-
nently resolved. Although the exact mechanism
of how cardioversion could have contributed to
e6 PHARMACOTHERAPY Volume 34, Number 1, 2014
cessation of the patient’s hiccups is unclear, the
authors theorized that the cardioversion may
have depolarized the afferent or efferent neural
limbs, resulting in cessation of the hiccups.
To our knowledge, there are no case reports
in the literature describing the combination of
baclofen and olanzapine for intractable hiccups.
There are many case reports describing baclofen
alone as a successful treatment option, and there
is one case report describing olanzapine alone as
successful treatment. That report described a
patient with intractable hiccups after severe trau-
matic brain injury and successfully treating his
hiccups with olanzapine 2.5 mg/day.16
The exact mechanism through which olanza-
pine is effective in patients with hiccups is not
fully understood. It is thought that the effect is,
in part, due to serotonin augmenting phrenic
involved in the generation of hiccups within
the spinal cord.36, 37In addition, since olanaza-
pine is a dopamine antagonist, particularly a
dopamine D2-receptor antagonist, this could
also have played a role in its effectiveness in
treating our patient.38Given the risk of meta-
bolic effects from the atypical antipsychotics
and the patient’s history of diabetes and hyper-
lipidemia, routine monitoring of his hemoglobin
A1cand lipid panel is justified. After 30 months
of monitoring, no changes to his therapies were
Baclofen is a c-aminobutyric acid (GABA)
analog that contains a phenylethylamine moi-
ety.39It is hypothesized that having both GABA
and phenylethylamine properties activates inhib-
itory neurotransmitters, most notably GABA,
which may in turn block the hiccup stimulus.39
To our knowledge, baclofen is the only agent
that has been studied in a double-blind, random-
ized, controlled, crossover trial in patients with
intractable hiccups.40Although the study was
very small (only four men who had failed previ-
ous treatment with chlorpromazine, diazepam,
symptomatic relief with baclofen therapy. Hic-
cup-free periods were extended by 69% with ba-
clofen 15 mg/day and by 120% with baclofen
Our case report adds to the available litera-
ture, as there are currently no published data on
the use of combination therapy for the treatment
of intractable hiccups. Although our patient’s
hiccups did not completely resolve, the combi-
nation therapy of baclofen and olanzapine signif-
icantly improved his quality of life.
the patients reported
This report describes a man with a compli-
cated medical history who experienced intracta-
ble hiccups despite an extensive gastrointestinal
and pulmonary evaluation. His symptoms ulti-
mately were controlled on a combination of
baclofen and low-dose olanzapine therapy.
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e8PHARMACOTHERAPY Volume 34, Number 1, 2014