This case report describes two patients with chronic, refractory cough who experienced improvement in symptoms after treatment with the drug baclofen. Both patients underwent a double-blind, placebo-controlled study where they received either baclofen or placebo for 14 days, followed by a crossover. Both patients reported decreased cough frequency and severity during baclofen treatment, with effects persisting for 2 weeks after. Cough sensitivity tests also showed increased cough thresholds after baclofen. The study provides preliminary evidence that baclofen may effectively treat chronic cough.

1. Case Report
Respiration 1998;65:86–88 Received: March, 1997
Accepted: June 3, 1997
Peter V. Dicpinigaitis
Khalid Rauf
Treatment of Chronic, Refractory
Department of Medicine, Division of Cough with Baclofen
Pulmonary Medicine, Albert Einstein
College of Medicine, Bronx, Bronx, N.Y.,
USA
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Key Words Abstract
Cough Chronic, nonproductive cough may result from enhanced sensitivity of the
Baclofen cough reflex. Often, this debilitating symptom is refractory to standard anti-
GABA tussive therapy. Baclofen, an agonist of Á-aminobutyric acid (GABA), has
Capsaicin been shown, in animals, to have antitussive activity via a central mechanism.
Recently, in normal subjects, we have demonstrated the ability of baclofen to
inhibit capsaicin-induced cough, as well as cough due to angiotensin-convert-
ing enzyme (ACE) inhibitors. Herein, we describe two patients with chronic,
refractory cough who obtained symptomatic improvement after a 14-day
course of low-dose, oral baclofen, administered in a double-blind, placebo-
controlled manner. In addition, both subjects demonstrated significant in-
creases in cough threshold to inhaled capsaicin after treatment with baclofen.
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Introduction Á-Aminobutyric acid (GABA), an inhibitory neuro-
transmitter of the central nervous system, has recently
Cough is the most common symptom in pulmonary been detected in the lung, as well as in other peripheral
disease, and among the most frequent complaints for tissues [2]. Baclofen, a GABA agonist, is a commonly used
which patients seek medical attention. In the United agent for the relief of muscle spasm, especially in patients
States, ‘over-the-counter’ cough preparations account for with multiple sclerosis or spinal cord injury. Baclofen has
over a half billion dollars in annual sales [1]. been shown, in animals, to inhibit cough via a central
Chronic, nonproductive cough may result from in- mechanism [3], with a potency comparable to or exceed-
creased sensitivity of the cough reflex [1]. Often, this ing, that of codeine [4]. We have recently demonstrated
debilitating symptom is refractory to standard antitussive the antitussive activity of low-dose oral baclofen in
therapy. Although codeine may be an effective cough sup- healthy human subjects [5], and have shown the ability of
pressant, possible side effects such as sedation, nausea, this agent to suppress the cough induced by angiotensin-
constipation, and potential for abuse limit its usefulness converting enzyme (ACE) inhibitors [6].
for control of chronic cough. Therefore, a nonnarcotic Herein, we report the successful therapeutic use of
agent able to diminish the sensitivity of the cough reflex baclofen in two subjects suffering from chronic, nonpro-
could have significant therapeutic value. ductive cough refractory to standard antitussive therapy.
© 1998 S. Karger AG, Basel Peter V. Dicpinigaitis, MD
ABC 0025–7931/98/0651–0086$15.00/0 Albert Einstein Hospital
Fax + 41 61 306 12 34 1825 Eastchester Road
E-Mail karger@karger.ch This article is also accessible online at: Bronx, NY 10461 (USA)
www.karger.com http://BioMedNet.com/karger Tel. (718) 904 2676, Fax (718) 904 2827

2. Case Reports
Subject 1
A 69-year-old woman presented with a 10-year history of persis-
tent, nonproductive cough, which frequently occurred in severe,
uncontrollable paroxysms. She had discontinued the use of tobacco
15 years earlier, after having smoked approximately 20 cigarettes
daily for 30 years. Despite pulmonary function studies demonstrat-
ing mild obstructive impairment (FEV1 70% predicted; FEV1/FVC
0.70) without significant reversibility after bronchodilators, she re-
ported excellent exercise tolerance. Her chest radiograph was within
normal limits. Other medical history included mastectomy for carci-
noma of the breast 12 years earlier, hypertension (never treated by
ACE inhibition or ß-blockade), and hypothyroidism.
During the previous several years, the patient had been treated
with courses of numerous medications aimed at alleviating her
chronic cough, without success. These included: inhaled albuterol,
ipratropium bromide, nedocromil sodium, and corticosteroids (oral
and nasal inhalers), as well as oral prednisone (unknown dose), oral
antihistamine/decongestant preparations, benzonatate (Tessalon),
and prolonged therapy with ranitidine. Symptomatic relief was
obtained only from codeine preparations, which the patient used
prior to social occasions when cough suppression was essential.
Subject 2
A 37-year-old woman, a lifetime nonsmoker without prior history
of respiratory disease, presented with a 1-year history of persistent,
nonproductive cough that was refractory to various nonprescription Fig. 1. Daily number of coughing episodes during the 4-week
antitussive preparations. Physical examination was unremarkable. treatment period (day 0–28) and the subsequent 2 weeks (day 28–
The patient was unable to perform pulmonary function studies 42). Subject 1 (P) received baclofen on days 0–14 and placebo on
because a forced expiratory effort would cause severe paroxysms of days 14–28. Subject 2 ([) received placebo on days 0–14 and baclof-
coughing, even after pretreatment with codeine. Chest radiograph en on days 14–28.
revealed bilateral interstitial infiltrates of the lower lung zones, a
finding which was confirmed by computed tomography. A serologi-
cal evaluation for collagen vascular disease was negative. Flexible
fiberoptic bronchoscopy revealed normal endobronchial anatomy.
Transbronchial biopsies revealed chronic, nonspecific interstitial until the concentration inducing five or more coughs (C5) was
inflammation; bronchial washings and brushings were nondiagnos- attained. Subjects were unaware that the number of coughs induced
tic. A 14-day course of oral prednisone, 40 mg daily, and subsequent was the endpoint of the study.
trial of inhaled albuterol, had no significant effect on the patient’s No other antitussive agents were used for several weeks prior to,
cough, or her chest radiograph. or during, the study.
Results
Methods
After providing informed consent, subjects underwent cough Random assignment resulted in Subject 1 receiving
challenge studies with inhaled capsaicin, to establish the sensitivity blaclofen first, followed by placebo, while Subject 2 ini-
of their cough reflex at baseline. Subjects were then randomly tially received placebo, followed by baclofen. Both sub-
assigned, in a double-blind manner, to receive oral baclofen, 10 mg
jects reported a decrease in the frequency (fig. 1) as well as
three times daily, or identically appearing placebo, for 14 days, after
which subjects crossed over to the other regimen for 14 days. Capsai- the severity of cough during baclofen therapy, which per-
cin cough challenge was repeated at the end of each 14-day period. sisted for approximately 2 weeks after cessation of the
Subjects kept diaries documenting the number of coughing episodes drug. Cough frequency and severity eventually returned
occurring during each 24-hour interval for the duration of the treat- to their previous baseline levels.
ment period (28 days), as well as the subsequent 14 days.
After the placebo treatment period, cough sensitivity
Capsaicin cough challenge studies were performed by methods
previously described [5]. Briefly, subjects inhaled single breaths of to inhaled capsaicin was unchanged from baseline in both
capsaicin solutions, given in ascending, doubling concentrations with subjects. However, after 14 days of baclofen therapy, cap-
normal saline randomly interspersed to increase challenge blindness, saicin cough threshold was increased by three doubling
Treatment of Chronic Cough with Baclofen Respiration 1998;65:86–88 87

3. cough due to ACE inhibition [6], and that it inhibits cap-
saicin-induced cough in healthy volunteers [5]. In the
present report, we demonstrate both subjective and objec-
tive responses in two subjects with chronic, refractory,
nonproductive cough. A 14-day course of low-dose baclof-
en resulted in decreased frequency and severity of cough,
as well as a significant increase in the cough threshold to
inhaled capsaicin.
Of note, both subjects required approximately 2 weeks
of therapy with baclofen before achieving subjective im-
provement in cough frequency and severity. In addition,
both subjects reported persistent suppression of symp-
toms for about 2 weeks after completion of the 14-day
course of baclofen. This response is very similar to our
experience with ACE-inhibitor-induced cough, in which
Fig. 2. Cough sensitivity to inhaled capsaicin before and after a the optimal antitussive effect of baclofen was attained
14-day course of baclofen and placebo. C5 = Concentration of capsai- after 5–14 days of therapy, and a prolonged antitussive
cin inducing 5 or more coughs. P = Subject 1; [ = subject 2. effect of several weeks was reported after completion of a
28-day course of the drug [6]. Similarly, the inhibitory
effect of baclofen on bronchial hyperresponsiveness has
been demonstrated only after chronic administration [7].
concentrations (8-fold) in Subject 1, and five doubling Subsequent studies of the effect of baclofen on chronic
concentrations (32-fold) in Subject 2 (fig. 2). cough, therefore, should include a longer treatment
Neither subject reported any adverse reactions during course, as well as an adequate washout period.
the study period. We herein provide the first evidence that low-dose oral
baclofen may be effective in the treatment of chronic,
pathologic cough. These results, in addition to our recent
Discussion findings in healthy volunteers and in subjects with ACE-
inhibitor-induced cough, support further investigation of
The GABA agonist baclofen has been shown to inhibit a potential therapeutic role for baclofen, or other GABA
the cough reflex in animals via a central site of action [3]. agonists, in the management of chronic, pathologic
Recently, we have demonstrated that baclofen suppresses cough.
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88 Respiration 1998;65:86–88 Dicpinigaitis/Rauf