Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections

Abstract

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200–400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin’s effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.

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R E V I E W Open Access
Role of guaifenesin in the management of
chronic bronchitis and upper respiratory
tract infections
Helmut H. Albrecht
1
, Peter V. Dicpinigaitis
2
and Eric P. Guenin
3*
Abstract
Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive.
It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally
marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold
medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication).
Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus
hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and
possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric
populations. Its dosing range (200–400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of
plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-
release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience
with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant
for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been
demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable
symptoms. Progress is being made to establish clinical models and measures that are more appropriate for
studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and
high-quality data needed to optimize guaifenesin’s effectiveness in established uses, and in new respiratory indications
associated with mucus hypersecretion.
Keywords: Guaifenesin, Mucus, Cough, Expectorant, Chronic bronchitis, Respiratory tract infections, Mucociliary
clearance; over-the-counter (OTC), Extended-release (ER) formulation, Mucoactive agents
Background
Respiratory conditions have been known throughout most
of recorded medical history, and today mortality and
morbidity associated with respiratory conditions repre-
sent a substantial global health burden. Statistics show
over a hundred million people living with chronic respira-
tory conditions worldwide [1], while acute respiratory
infections are among the most common reasons for
physician office visits [2].
Pathological hypersecretion of mucus is a common
feature in many acute and chronic respiratory conditions.
Expectorants are used empirically to treat cough with an
underlying cause of pathological mucus, by targeting vari-
ous mechanisms that promote increased mucus hydration
and clearance from the respiratory tract. Guaifenesin, or
glyceryl guaiacolate ether (GGE), is an oral expectorant
and a common ingredient in prescription and over-the-
counter (OTC) medicines for respiratory conditions. Des-
pite its wide use for the symptomatic management of
chest congestion and cough associated with acute upper
respiratory tract infections (URTIs), such as the common
cold, guaifenesin’s precise mechanism of action has not
been fully elucidated.
The use of guaifenesin as a natural remedy dates back
to the 1500s, when guaiac tree extracts were used by Native
Americans to treat various illnesses (Table 1). The drug
was first accepted in 1952 by the US Food and Drug
* Correspondence: eric.guenin@rb.com
3
Reckitt Benckiser, LLC, 399 Interpace Parkway, Parsippany, NJ 07054, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access 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. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31
DOI 10.1186/s40248-017-0113-4

Administration (FDA); in 1989, it was included in the Final
Monograph for ‘Cold, Cough, Allergy, Bronchodilator, and
Anti-asthmatic Drug Products for Over-the-Counter
Human Use’[3], 21 CFR 341. Inclusion in the Mono-
graph established guaifenesin as a safe and effective
expectorant for the symptomatic treatment of acute
URTIs and also allowed use of the drug in stable chronic
bronchitis. Today, guaifenesin is still the only OTC expec-
torant legally marketed in the US.
The purpose of this article is to review scientific evi-
dence for the use of guaifenesin in different respiratory
conditions and to summarize the key clinical studies. As
a single-ingredient product, guaifenesin has an acceptable
safety profile in both adult and pediatric populations. We
describe recent advances in the understanding of guaifene-
sin’s mechanism of action and briefly discuss the rationale
for its use in the context of its pharmacology, pharmacody-
manics, and clinical efficacy profile.
Mucus in airway function and disease
The respiratory tract is covered with a layer of mucus,
which maintains airway humidification and acts as a pro-
tective barrier to inhaled particles and microorganisms.
Mucus entraps inhaled particles and is then transported
out of the lungs by the sweeping movements of epithelial
cilia—a process termed mucociliary clearance (MCC)
[4]—before being swallowed or expectorated. A dynamic
balance of production, secretion, and clearance of mucus
is needed to maintain airway function and health.
Respiratory conditions can dramatically alter airway
mucus composition and properties. Upregulation of mucins,
high molecular-weight extracellular mucopolysaccharides
that are critical components of mucus, increases mucus
viscosity; this can worsen congestion [5]. Pathological
overproduction and hypersecretion of mucus feature prom-
inently in chronic respiratory conditions such as chronic
bronchitis, chronic obstructive pulmonary disease (COPD)
and asthma [4, 6]. In fact, mucus hypersecretion has
been described as a hallmark of the chronic bronchitis
“phenotype”[7]. Since excessive respiratory mucus dra-
matically hinders MCC and serves as a trigger for cough
[4], normalization of pathological mucus is a central goal
of many therapeutic interventions in respiratory disease.
Guaifenesin: multiple effects on pathological mucus
Therapy with mucoactive drugs is an important factor in
the treatment of respiratory conditions in which mucus
hypersecretion is prevalent. A large number of drugs
acting directly or indirectly on mucus have been well
studied and reviewed [5, 8–12].
There are four main classes of mucoactive drugs with
different mechanisms of action (Table 2). Out of these,
only mucolytic and expectorant drugs act directly on
mucus properties or its secretion. Earlier studies showed
that guaifenesin has multiple effects on mucus, such as in-
creasing the volume of bronchial secretions and decreas-
ing mucus viscosity. This modulation of airway secretions
enhances their clearance by promoting more effective
expectoration. Guaifenesin may also have direct effects
on respiratory tract epithelial cells, including suppressed
mucin production, reduced mucus viscoelasticity, and im-
proved MCC [13]. One study indicated that guaifenesin
does not act directly on mucus viscosity [14]. The effects of
guaifenesin are not limited to affecting mucus consistency
(e.g., increasing mucus hydration or altering viscoelasticity);
it appears that the drug directly or indirectly targets
multiple processes, including the inhibition of cough
reflex sensitivity [15, 16].
Pharmacology
Pharmacokinetics
Guaifenesin [3-(2- methoxyphenoxy)-1,2-propanediol] has
been well characterized chemically [17]. Animal studies
showed that guaifenesin is generally well absorbed and has
an established pharmacokinetic profile. In rats, when
administered by various routes including intravenous
(IV) bolus, oral gavage (50 mg/kg, 25 mg/mL), and gastric,
jejunal or cecal infusions (50 mg/kg, 50 mg/mL), guaifenesin
achieved a maximum plasma concentration (C
max
)of15–
33 μg/mL [18]. The time to reach C
max
(T
max
)inratswas
fasterwhengivenasanoralbolus(27min)thanwith
gastric, jejunal or cecal infusions (120 min) [18]. In rats,
the bioavailability of guaifenesin for all gastrointestinal
(GI) routes was ~70%, and the terminal half-life of IV
administration (~45 min) was identical to that associ-
ated with various GI routes of administration (45–
54 min) [18].
Table 1 Brief history of guaifenesin and its regulatory path in
the US
Time Key events
Pre-1500s Used as natural remedy by Native Americans
1500s Guaiac extract used as stimulant remedies, e.g. for
sore throat, syphilis
1800s Guaiac extract used to treat respiratory diseases
in Europe
1952 First accepted by US Food and Drug Administration
(FDA)
1989 Guaifenesin was reclassified to Category I (generally
recognized as safe and effective) and was included
in the Final Monograph (Cold, Cough, Allergy,
Bronchodilator, and Antiasthmatic Drug Products for
Over-the-Counter Human Use, 21 CFR 341) as an
expectorant for the symptomatic treatment of colds
and stable chronic bronchitis.
2002 12-h extended-release (ER) guaifenesin bi-layer tablets
were approved by the FDA. From 2007, the FDA
removed all marketed, but unapproved, timed-release
guaifenesin products from the market.
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 2 of 11

Guaifenesin is well absorbed from the human GI tract.
Following a single oral dose of guaifenesin in pediatric
subjects, C
max
was reached in approximately 0.5 h and
the plasma elimination half-life was approximately 1 h
[19]. In adult subjects, C
max
was achieved in 1.69 h fol-
lowing a single oral dose of IR guaifenesin; the terminal
exponential half-life is approximately 0.86 h [20], and
the compound is no longer detectable in the blood at
8 h post dose.
Once absorbed, guaifenesin is efficiently metabolized
and subsequently excreted in the urine. Guaifenesin is
not known to interfere with the cytochrome P450 (CYP)
system, nor is it an inhibitor or inducer of this system.
Guaifenesin appears to undergo both oxidation and
demethylation. The drug is rapidly metabolized in the
liver via oxidation to β-(2-methoxyphenoxy)-lactic acid
[21]. The demethylation of GGE (hydroxyguaifenesin) is
performed by O-demethylase, localized in liver micro-
somes;approximately40%ofadoseisexcretedasthis
metabolite in the urine within 3 h. O-demethylase seems to
be the main enzyme for the metabolism of GGE [22, 23].
Following oral dosing (400 mg), more than 60% of a dose is
hydrolyzed within 7 h, with no parent drug detectable in
the urine [24]. The major metabolites of guaifenesin (both
inactive) are beta-2-methoxyphenoxy-lactic acid [21, 25]
and hydroxy-guaifenesin [22].
In vitro and animal studies investigating the mechanism of
action
To date, several mechanisms of action have been described
for guaifenesin. It has been postulated that guaifenesin ex-
erts its expectorant activity via a neurogenic mechanism: a
stimulation of vagal afferent nerves in the gastric mucosa
activates the gastro-pulmonary reflex, and increases the
hydration of airway mucus [26, 27]. In support of this
hypothesis, a study in rats demonstrated that oral but
not intravenous guaifenesin administration increased
respiratory secretions [18].
The viscoelastic behavior of bronchial mucus has im-
portant consequences for mucociliary clearance. This mucus
is an adhesive, viscoelastic gel, the biophysical properties of
which are largely determined by entanglements of long poly-
meric gel-forming mucins: MUC5AC (expressed in goblet
cells) and MUC5B (originating from submucosal glands)
[11]. Inflammatory airway diseases and infections cause
mucus (including mucin glycoproteins) overproduction and
hypersecretion from metaplastic and hyperplastic gob-
let cells which contributes to mucus obstruction of air-
ways [6]. Medications that decrease viscoelasticity, such
as certain mucolytics, may benefit ciliary clearance.
Recent in vitro studies using differentiated human air-
way epithelial cells, grown at an air-liquid interface to
mimic physiological conditions in the respiratory tract,
revealed direct effects of guaifenesin on the airway epi-
thelium [13, 28]. At clinically relevant doses, guaifenesin
was found to significantly decrease mucin (MUC5AC)
production, mucus viscosity and elasticity, and to enhance
MCC [13]. These results were replicated in another study
on airway epithelial cells pre-treated with an inflammatory
mediator,IL-13,toincreasesecretionspriortotreat-
ment with guaifenesin, N-acetylcysteine, or ambroxol
[28]. Guaifenesin was more effective than N-acetylcysteine
or ambroxol at increasing MCC rates, inhibiting mucin se-
cretion, and improving mucus rheology. Figure 1 shows
some of these putative mechanisms of action (Fig. 1a,-d).
Additional in vivo pharmacology and clinical studies will be
needed to further elucidate these findings and determine
how these mechanisms can be most effectively recruited to
produce clinically relevant effects in the target populations.
Human studies investigating the mechanism of action of
guaifenesin
Studies in patients with chronic bronchitis demonstrated
that guaifenesin increases MCC [29] and reduces sputum
viscosity [30]. Bennett and coworkers compared the effects
of guaifenesin and placebo on in vivo MCC by measuring
the rate of removal of inhaled radioactive tracer particles
from the lungs of healthy, non-smoking adults. Guaifenesin
enhanced small airway clearance with a strong trend to-
ward statistical significance (p= 0.07) [31]. In a similar
study with a crossover design to assess the effects of guaife-
nesin on MCC and cough clearance (MCC/CC) in adults
with acute RTIs, it was reported that the effect of a single
dose of guaifenesin on MCC/CC could not be differentiated
from that of placebo in that study population [32].
A study in healthy volunteers with a history of sinus
disease did not detect significant differences between
guaifenesin and placebo treatment in terms of their ef-
fects on in vivo nasal MCC [33]. Saccharin particle tran-
sit time (STT) was similar with guaifenesin and placebo,
and it was suggested that additional factors could have
an impact on MCC and/or ciliary motility.
Table 2 Main classes of mucoactive drugs
Mucoactive drug classes Proposed mechanism of action (example)
Expectorants Increase mucus secretion volume and/or hydration for more productive cough (e.g. guaifenesin)
Mucolytics Reduce mucus viscosity by breaking down tertiary structures within mucus (e.g. N-acetylcysteine)
Mucokinetics Increase mucus transportability by mucociliary transport and cough mechanisms (e.g. ambroxol)
Mucoregulators Affect the regulation of mucus synthesis and reduce mucus hypersecretion (e.g. anticholinergic agents)
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 3 of 11

Guaifenesin has been shown to make coughs more
productive [34], and additionally has been found to inhibit
cough reflex sensitivity in subjects with acute URTIs
[15, 16]. Two double-blind, randomized and placebo-
controlled studies investigated the effect of a single
dose of guaifenesin (400 mg and 600 mg, respectively)
on participants’response to a nebulized capsaicin cough
challenge. Guaifenesin significantly reduced cough reflex
sensitivity in patients with viral URTIs [15, 16], but not in
healthy volunteers. The authors suggested that this effect
was limited to patients with URTIs due to their transiently
increased cough receptor sensitivity.
Details of clinical studies mentioned in this section are
in Table 3.
Clinical efficacy studies in respiratory diseases
Clinical uses of guaifenesin
Despite the large number of clinical studies on different
clinical aspects of guaifenesin therapy, its expectorant
indication is currently the only one that the FDA con-
siders to be supported by sufficient medical evidence.
The “Cough-Cold”Final OTC Monograph covers the
use of guaifenesin in adults and children 2 years and older,
and is based on a subset of clinical studies in chronic
respiratory diseases that were available when the mono-
graph was developed. The Monograph indication for
guaifenesin is limited to symptomatic treatment of acute
URTIs and stable chronic bronchitis [3]. The FDA ap-
proved labels for guaifenesin include an OTC label for its
Fig. 1 Putative effects of guaifenesin on mucus in chronic or acute hypersecretory respiratory conditions. aThe airway is composed of a mucus
gel layer covering the epithelium, which includes ciliated cells, Clara cells, goblet cells and submucosal glands. The mucociliary complex can be
subdivided into two layers –an upper mucus gel layer containing MUC5AC and MUC5B mucins, and a lower layer of periciliary fluid containing
cell surface-tethered mucins. Mucociliary clearance (MCC) is effected by the rhythmic sweeping motion of cilia. Prolonged exposure to irritants
such as cigarette smoke or allergens can lead to overproduction and hypersecretion of mucus. Guaifenesin has been postulated to promote mucociliary
clearance via a number of mechanisms. (1) Indirect activation/stimulation of gastrointestinal vagal afferent nerves triggers reflex parasympathetic glandular
secretion from submucosal glands and goblet cells (green stars), increasing hydration of mucus layer for more effective mucociliary clearance. Guaifenesin
also affects secretion from goblet and Clara cells (red stars), resulting in (2) decreased mucin production and secretion (green circles, goblet cells; blue
squares, Clara cells), and (3) reduced viscoelasticity of mucus, which increases the ability of ciliary movement to remove mucus. Together these changes
serve to enhance MCC and mucus clearance. b–dGuaifenesin has direct effects on MCC-related processes in airway epithelial cells. In cultured
human differentiated tracheobronchial epithelial cells, 24-h treatment with guaifenesin (2 or 20 μg/mL) significantly suppressed mucin production and
mucin secretion (b), while 6-h treatment with guaifenesin (2–200 μg/mL) significantly enhanced mucociliary transport rates (c). At 1 h and 6 h after
guaifenesin treatment (0–200 μg/mL), significant dose-dependent decreases were observed in mucus viscosity and elasticity at typical ciliary
beat frequency (1 rad/s) (d), as measured by G*1 (vector sum of viscosity and elasticity at 1 rad/s). Panels b-d adapted from Seagrave et al., 2011 [13]
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 4 of 11

Table 3 Pharmacology studies
First Author (Year) Objectives of study Intervention Results
Chodosh (1973) To evaluate sputum changes associated
with guaifenesin in chronic bronchial
conditions
Double-blind crossover study:
1 week known placebo +800 mg/day
or 2400 mg/day for 4 weeks +1 week
unknown placebo +1000 mL extra
oral water intake
Significantly uniform and beneficial changes, such
as sputum adhesiveness and dry weight, occurred
with 2400 mg/day guaifenesin
Thomson (1973) To assess the effect of guaifenesin on
mucociliary clearance (MCC) in the human
lung from the rate of removal of inhaled
radioactive tracer particles
Double-blind crossover study:
600 mg guaifenesin vs placebo
Significant improvement in mucociliary clearance
with guaifenesin in patients with chronic bronchitis
but not in healthy subjects
Sisson (1995) To examine:
(i) The effect of guaifenesin on nasal MCC
in vivo (assessed by saccharin transit time
[STT]) and nasal ciliary beat frequency (CBF;
assessed by nasal brushing and ex vivo
microscopy), and
(ii) whether a relationship exists between
nasal CBF and nasal STT
Double-blind crossover study:
400 mg guaifenesin vs placebo 5× daily
from days 1 to 7, or days 14 to 21
No significant differences between guaifenesin- or
placebo-treated groups in change from baseline
values of STT or CBF
No relationship observed between STT and CBF
from regression analysis
Dicpinigaitis (2003) To evaluate the effect of guaifenesin on
cough reflex sensitivity to inhaled capsaicin
in healthy subjects and subjects with acute
URTIs
Randomized double-blind study:
Single dose of 400 mg guaifenesin
vs placebo
Cough reflex sensitivity was statistically significantly
decreased with guaifenesin in patients with URTIs
but not in healthy subjects
Dicpinigaitis (2009) To evaluate the antitussive effect of the
combination of benzonatate and guaifenesin
in subjects with acute URTI
Randomized double-blind crossover
study (n= 23):
Each subject received 3 of 4 possible
study drug/combinations:
600 mg guaifenesin (G), 200 mg
benzonatate (B), their combination
(B + G), and placebo (P)
•Guaifenesin (p= 0.01) significantly inhibited cough
reflex sensitivity relative to placebo
•B + G combination suppressed capsaicin-induced
cough significantly more than B (p< 0.001) or G
(p= 0.008) alone
Bennett (2010) To determine whether guaifenesin improves
MCC in the healthy lung by assessing the
rate of removal of inhaled radioactive tracer
particles
Open-label randomized crossover
study (n= 8):
Single dose of 1200 mg guaifenesin
vs placebo over 3 weeks; minimum
7-day washout period
Strongtrendtowardstatisticalsignificance(p=0.07)
for enhanced small airway clearance with guaifenesin
vs placebo
Bennett (2015) To determine the effect of guaifenesin on
MCC and cough clearance in non-smoking
adults with acute URTI by assessing the rate
of removal of inhaled radioactive tracer
particles
Randomized double-blind crossover study:
Single dose of 1200 mg guaifenesin
vs placebo
No significant effect of single dose guaifenesin on
mucociliary and cough clearance compared to
placebo
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 5 of 11

use in the treatment of chest congestion associated with
an URTI but also a professional label for chest congestion
associated with stable chronic bronchitis for its detailing
to healthcare professionals. This professional label indica-
tion mirrors the outcome of clinical studies conducted on
chronic bronchitis patients. The exact wording of the indi-
cations is listed below:
Guaifenesin “helps loosen phlegm (mucus) and thin
bronchial secretions -
○to rid the bronchial passageways of bothersome
mucus and make coughs more productive”(OTC
uses)
○in patients with stable chronic bronchitis”
(professional indication).
A review of the literature supporting the clinical utility
of guaifenesin shows effects across three categories of
respiratory conditions: chronic bronchitis and chronic re-
spiratory conditions (Table 4), URTIs (Table 5), and rhino-
sinusitis (Table 6). Almost all studies discussed here were
conducted in adults, with the exception of one published
study in children on the use of guaifenesin for relieving
cough symptoms [35].
It should be noted that stable chronic respiratory condi-
tions, such as chronic bronchitis, have proved more reliable
as clinical models for studying the effects of expectorants
and other mucoactive drugs. Mucus production and associ-
ated cough symptoms tend tobemorestableinchronic
respiratory conditions, allowing the effects of guaifenesin to
be observed more consistently.
Table 4 Clinical efficacy studies: Chronic bronchitis and chronic respiratory conditions
Author (Year) Objectives of study Intervention Results
Hayes (1956) To determine the effectiveness of Robitussin®
as an expectorant in productive cough due
to chronic pulmonary disease
1–2 g Robitussin® (containing
100 mg guaifenesin and 1 mg
desoxyephedrine HCl per 5 mL)
vs placebo every 2–3 h, as required
Statistically significant changes compared
to placebo:
•Reduction in chronic productive cough
•Decreased frequency of cough and
sputum viscosity
Chodosh (1964) To investigate the efficacy and mechanism
of action of guaifenesin in bronchopulmonary
diseases
Double-blind study:
100 mg guaifenesin tablet 4×
daily vs placebo for 14 days
(after placebo run-in)
Statistically significant changes compared
to placebo:
•Increase in ease of expectoration
•Decrease in the measured sputum surface
tension
Hirsch (1973) To investigate the expectorant effect of
guaifenesin in patients with chronic bronchitis
Single-blind crossover study:
800 mg or 1600 mg guaifenesin
vs placebo alternating for 5 weeks
Double-blind crossover study:
1600 mg guaifenesin vs placebo
daily for 5 days
No significant difference between
guaifenesin and placebo in reducing
sputum consistency, increasing
sputum volume, improving ventilatory
function or ease of expectoration
Wojcicki (1975) To investigate the effect of guaifenesin on:
(i) Severity and frequency of cough, and
(ii) Tenaciousness of sputum
Double-blind crossover study:
120 mg guaifenesin vs 17 mg
narcotine HCl, vs combination
(120 mg guaifenesin +17 mg
narcotine HCl), vs placebo, 3×
daily for 7 days (per treatment)
Guaifenesin + narcotine HCl combination
associated with statistically significant
decreases in:
•Cough severity
•Cough frequency
Finiguerra (1982)
(unpublished;
data on file)
To determine the efficacy of guaifenesin for:
(i) Modifying the volume and viscosity of
tracheobronchial secretions, and in
(ii) Providing symptomatic relief of difficult
expectoration and cough in chronic bronchitis
Randomized double-blind parallel-
group study:
190 mg guaifenesin vs placebo,
3× daily for 15 days
Statistically significant changes:
•Decrease in sputum volume and viscosity
•Decrease in cough severity
•Improvement in ease of expectoration
Parvez (1996) To determine the usefulness of a
multidimensional cough quantitation system
for evaluating guaifenesin’seffectsoncough
and sputum
Randomized double-blind parallel-
group study:
300 mg guaifenesin vs placebo,
4× daily for 14 days
Differences between guaifenesin and
placebo groups:
•Guaifenesin significantly increased
sputum volume; 37% difference on day
14 (p< 0.05)
•Significant reduction in fucose, a
biomarker for sputum glycoprotein,
in the guaifenesin group at day 14
(p< 0.01)
•Subjective measure of average
intensity/cough at day 4 (p< 0.05)
•Trend for greater improvement in
ease of expectoration at days 10 and
14 in the guaifenesin group but did
not reach significance in the subgroup
with productive cough (p< 0.01)
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Chronic bronchitis and chronic respiratory conditions
The inclusion of guaifenesin in the 1989 Final OTC
Monograph was essentially supported by four clinical
studies in patients with chronic bronchitis [36–39]. All of
these definitive studies demonstrated statistically superior
efficacy of guaifenesin versus controls in improving ease
of expectoration, decrease in sputum surface tension and
viscosity, or reduction in the frequency and severity of
cough (Table 4).
An early study in chronic bronchitis patients reported
that guaifenesin’s effects on sputum consistency and
volume were comparable to that of placebo [40]. Other
studies, however, support the drug’seffectsonsputum.
Although results for cough assessments in patients with
chronic bronchopulmonary disease were mixed, guaifenesin-
treated patients reported increased sputum volume
compared with placebo, as well as greater ease of ex-
pectoration [41]. These findings are consistent with an
earlier study on objective sputum changes in patients
with chronic bronchitis; guaifenesin was found to sig-
nificantly decrease sputum adhesiveness and quantity
(dry weight), and was also reported to improve expec-
toration [30].
Acute upper respiratory tract infections (URTIs)
The efficacy of guaifenesin as an expectorant has also
been examined in the context of acute URTIs (Table 5).
Robinson and coworkers showed that guaifenesin im-
proved acute URTI symptoms based on patient-assessed
subjective measures (cough frequency and intensity) and
physicians’evaluation of global effectiveness [42]. In adults
with acute URTIs, guaifenesin significantly reduced spu-
tum thickness and quantity compared to placebo [41].
A large placebo-controlled pilot study explored a range
of objective and subjective outcome measures in patients
with acute URTIs. The most promising measures included
a daily diary for patient-reported outcome (PRO) parame-
ters. These described symptoms such as severity of chest
congestion, mucus thickness and cough. Some of these 11
exploratory parameters showed strong trends or statistically
significant differences between guaifenesin and placebo. A
PRO validation process served to qualify more focused sub-
sets of 4 and 8 questions. Based on post-hoc analyses (p=
0.038), an 8-question PRO tool (SUM8) was validated and
proposed for use in future respiratory studies [43]. To ex-
plore effects on sputum as objective endpoints, laboratory
analyses were performed on patient mucus samples from
Table 5 Clinical efficacy studies: Upper respiratory tract infections
First Author (Year) Objectives of study Intervention Results
Robinson (1977) To confirm that guaifenesin was
superior to placebo in facilitating
expectoration of sputum and
ameliorating dry cough in patients
with an acute upper respiratory
infection
Randomized double-blind
parallel-group study:
200 mg guaifenesin in
10-mL doses vs placebo,
4× daily for 3 days
Subjective measures compared to placebo:
•Cough frequency reduced at 48 h, 72 h (all: p< 0.01)
•Cough intensity reduced at 48 h, 72 h (all: p< 0.01)
•Chest discomfort reduced at 24 h, 48 h, 72 h (all: p< 0.01)
•Sputum volume increased (only in patients with
productive cough) at 48 h (p< 0.01)
•Ease of raising sputum increased at 24 h, 48 h, 72 h (all:
p< 0.01)
Kuhn (1982) To evaluate the efficacy of guaifenesin
in reducing cough frequency in adults
with acute respiratory disease
Double-blind study:
2400 mg guaifenesin
vs placebo syrup vehicle
in 30-mL doses every
6 h for 30 h
•Objective cough counts: No significant differences
between guaifenesin and placebo
•Significantly greater decrease in sputum viscosity
compared to baseline in patients with productive cough
(p= 0.001)
•Greater decrease in sputum quantity (p= 0.07)
Albrecht (2012) Pilot study to determine the efficacy
of extended-release (ER) guaifenesin
with placebo for treatment of URTI,
using objective and subjective efficacy
assessments
Randomized double-
blind study:
1200 mg ER guaifenesin
vs placebo 2× daily for
7 days
Subjective measures of efficacy (patient-reported
outcomes; PROs) showed the most prominent differences
between treatment groups at Day 4, in favor of guaifenesin.
Based on post-hoc analyses focusing on subsets of these
PROs, an 8-question PRO tool (SUM8) was validated.
Table 6 Clinical efficacy studies: Rhinosinusitis
First Author (Year) Objectives of study Intervention Results
Wawrose (1992) To evaluate the role of guaifenesin in
decreasing symptoms of postnasal
drainage and nasal congestion in HIV+
patients with chronic rhinosinusitis
Double-blind parallel-group study:
1200 mg guaifenesin vs placebo
2× daily for 3 weeks
Significantly less nasal congestion and
thinner postnasal drainage reported after
3 weeks of treatment with guaifenesin
vs placebo (p< 0.05)
Rosen (2005) To evaluate the effect of guaifenesin
on mucociliary clearance time (MCT)
and sinonasal symptoms in HIV+ patients
Randomized double-blind parallel-
group study:
1200 mg guaifenesin vs placebo
2× daily for 3 weeks
Significant improvement in sinonasal
symptom survey (SNOT-16) score in HIV+
patients treated with guaifenesin vs placebo
(p< 0.05)
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 7 of 11

the pilot study. The laboratory analyses could not demon-
strate differences in mucus properties with guaifenesin
compared to placebo; however, it should be noted that
methodological issues with mucus sample collection and
shipping were present, raisingsomequestionsaboutthein-
terpretation of the laboratory results [44].
Rhinosinusitis
Guaifenesin was reported to be effective for improving
symptomatic rhinitis and sinusitis by decreasing nasal
congestion and postnasal discharge in immunocom-
promised HIV positive patients [45, 46]. Despite some
conflicting data available, some patients with rhinitis
benefit from using guaifenesin [12]. Further research is
needed to clarify guaifenesin’s effects on congestion and
mucus clearance from the nasal passages and sinuses in
the general patient population.
Clinical safety
As a single agent, guaifenesin has a well-established and
favorable safety and tolerability profile. Its safety record
is supported by data from published clinical studies and
a history of post-marketing surveillance safety reports
covering more than 50 years in the US and around the
world. Common side effects reported for the drug in-
clude dizziness, headache, and gastrointestinal distur-
bances at high doses [17].
Retrospective and ongoing prospective pediatric safety
data analyses confirm guaifenesin’s favorable safety pro-
file as an OTC drug in children [47, 48]. In a continuous
safety surveillance analysis of 8 common cough and cold
drugs conducted from 2008 through 2014, guaifenesin
showed the lowest number of “at least potentially re-
lated”non-fatal adverse event (AE) cases (1%) out of a
total of 5610 index drug reports [48]. Guaifenesin had
the lowest frequency of mentions for non-fatal AEs by
system organ class (SOC) at estimated supra-therapeutic
and even at estimated unknown dosing; and the second
lowest frequency of mentions for non-fatal AEs by SOC
at estimated therapeutic dosing. More importantly, guai-
fenesin was not mentioned in any “potentially related”
fatal cases during the 1991–2008 surveillance period, or
during the 2008–2014 detection period.
The few published reports of serious adverse events
related to the use of guaifenesin have mostly been in the
context of overdose and use as part of multiple-drug com-
binations for various cough and cold indications. Pub-
lished reports include renal stone formation with chronic
guaifenesin overdose [49], and acute fatal intoxication by a
combination of guaifenesin, diphenhydramine, and chlor-
pheniramine, although the relative contribution of guaife-
nesin to the fatality could not be determined [50].
Pregnancy category C status for GGE was determined
by the FDA based on the absence of definitive studies
assessing potential risks to the fetus [3, 51]. Results of a
recently published study in female, pregnant rats, after
testing very high doses of guaifenesin, suggest that the
risk of fetal abnormalities cannot be ruled out [52]. The
medical literature and safety databases do not show
meaningful signals suggesting a significant risk of fetal
development issues after pregnant women used guaife-
nesin. Thus, caution regarding the use of GGE in preg-
nant women is warranted [51]. The current labeling (“if
pregnant, ask a health professional before use”) is in line
with the FDA OTC Monograph and seems to be an ap-
propriate warning telling women to avoid taking the
drug during pregnancy.
Guaifenesin drug products and dosing
Immediate-release (IR) and extended-release (ER) guaife-
nesin are available in single-agent formulations (Table 7).
There are also many popular guaifenesin-containing com-
bination OTC and prescription products available on the
market, but these are outside the scope of this article. The
dual dosing range of guaifenesin in the US allows patients
the flexibility to titrate doses to achieve optimal efficacy.
Table 7 Examples of currently available over-the-counter guaifenesin formulations and recommended doses in the US and Canada
Formulation Population Recommended doses Available dosage form –Product example(s)
Immediate-release Children –2 to <6 years US: 50–100 mg up to 4-hourly; max
600 mg/day
Canada: Not recommended
Syrup –CVS Health® Children’s Mucus
Relief Chest Congestion
Soft chews –Kids-EEZE® Chest Relief
Immediate-release Children –6 to <12 years US: 100–200 mg up to 4-hourly; max
1200 mg/day
Canada: Not recommended
Syrup –CVS Health® Children’s Mucus
Relief Chest Congestion
Soft chews –Kids-EEZE® Chest Relief
Immediate-release Adults and children 12 years and older US: 200–400 mg up to 4-hourly; max
2400 mg/day
Canada: 200–400 mg up to 6-hourly;
max 1600 mg/day
Tablet –Bidex®
Syrup –Robitussin® Mucus & Chest
Congestion; Scot-Tussin Expectorant
Soft chews –Kids-EEZE® Chest Relief
Extended-release Adults and children 12 years and older US: 600–1200 mg up to 12-hourly; max
2400 mg/day
Canada: 600 mg (1 tablet) up to
12-hourly; max 1200 mg/day (2 tablets)
Tablet –Mucinex®
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 8 of 11

In the US, adults and children above 12 years old may take
guaifenesin in oral doses of 200 to 400 mg every 4 h, up to
a maximum of 2400 mg over 24 h [17]. Pediatric doses
cater to children aged 2–12 years, and differ according to
age groups, i.e. 2–6yearsand6–12 years (Table 7). In
Canada, guaifenesin is not recommended for children
aged 12 years and below. Dosing regimens and daily max-
imum doses for adults and children above 12 years old in
Canada (daily dose of 1600 mg maximum) also differ from
those in the US [53].
Because of guaifenesin short half-life, frequent dosing
with IR guaifenesin is required to maintain therapeutic
levels of the drug in the body (Fig. 2). Subsequently 12-h
extended release form of guaifenesin were designed to
provide bioequivalent pharmacokinetic characteristics to
generic IR guaifenesin products [20] and are currently
approved as 12-h tablet ER guaifenesin formulation in
the US market. An example of such ER products is a bi-
layer tablet formulation containing 600 mg of guaifene-
sin and comprising an IR layer that allows rapid release
of guaifenesin to achieve an early C
max
, and an ER layer
that allows sustained release of guaifenesin to produce a
steady plasma concentration over a 12-h period (Fig. 2).
Following approval of this extended release form of guai-
fenesin (NDA-21-282) in 2002, the FDA required the re-
moval of all marketed, but unapproved, timed-release
guaifenesin products from the market by 2007.
Conclusions
This review provides an updated and comprehensive per-
spective on the use of guaifenesin in treating respiratory
disorders in which excessive mucus is an important clinical
feature. Excessive mucus secretion and local accumulation
in the airway occurs in both acute URTIs and chronic
respiratory disorders with an underlying inflammatory
etiology (such as chronic bronchitis and COPD). The
expectorant properties of guaifenesin, which help to thin
bronchial secretions and promote mucus clearance, were
demonstrated in studies involving patients with chronic
bronchitis or other chronic respiratory conditions. These
studies played an important role in the FDA’s decision to
include guaifenesin as an expectorant in the respective
Final OTC Monograph labeled for the relief of mucus-
related symptoms of acute URTIs and stable chronic bron-
chitis. Additional studies have been performed to clarify the
mode of action and assess guaifenesin’s efficacy and safety
in other clinical indications [13, 28, 29, 42, 45, 46, 54].
Recent advances in the understanding of guaifenesin’s
mechanism of action add to the understanding of the drug’s
potential in the management of hypersecretory respiratory
conditions. Studies in symptomatic chest congestion and
acute cough, as well as in acute rhino-sinusitis indications,
have yielded mixed results. This may be understand-
able, given the context of rapidly changing symptoms
in acute URTIs, which are challenging to study under
standard clinical trial conditions. Some studies showed
evidence of efficacy based on improvements in subject-
ive measures as patients assessed their cough, mucus
clearance, or chest congestion symptoms. However, in
many cases the methods were not validated or results
were not confirmed by subsequent studies. For this rea-
son, the effects of guaifenesin have been more consist-
ently demonstrated in stable chronic respiratory disease
models. Further research is needed to clarify the anti-
tussive effectiveness of guaifenesin and its ability to re-
lieve chest congestion in acute URTIs in children and
adults, and the utility of the drug in improving symp-
toms of rhino-sinusitis.
To date, the approved indications for guaifenesin have
not changed from those included in the 1989 Final
Monograph. Interestingly, the secondary indication for
stable chronic bronchitis remains largely underutilized
or unrecognized even among US medical professionals.
Further progress will require improved assessment tools
and appropriately designed, modern studies, to confirm
guaifenesin’s utility in acute and chronic hypersecretory
respiratory conditions.
A large body of AE reporting data supports the safety
of guaifenesin for adult and pediatric use. Unlike certain
other OTC cough and cold medications, guaifenesin has
not been reported to cause many serious side effects or
abuse/dependence problems, and has been proven safe
in studies for use in conditions such as URTIs and stable
chronic bronchitis.
Well-established as a safe expectorant drug, guaifenesin
has achieved common usage for the relief of mucus-
IR guaifenesin
ER guaifenesin
10000
1000
100
10
024 6 81012
Time after dosing (hours)
Plasma concentration (ng/mL)
Fig. 2 Schematic pharmacokinetic profile of extended-release (ER) vs
immediate-release (IR) guaifenesin formulations. Extended-release (ER)
guaifenesin (blue line) attained bioequivalent plasma concentrations to
those obtained with 3 immediate-release (IR) guaifenesin doses (orange
line). The unique bi-layer tablet formulation comprises an IR layer that
permits immediate release of guaifenesin to rapidly attain maximum
plasma concentrations (C
max
), and an ER layer that permits sustained
release of guaifenesin to maintain prolonged blood plasma levels of
guaifenesin over 12 h. Figure adapted from Vilson and Owen, 2013 [20]
Albrecht et al. Multidisciplinary Respiratory Medicine (2017) 12:31 Page 9 of 11

related symptoms of acute URTIs and for patients with
mucus-related symptoms in the context of stable chronic
bronchitis. Additional, up-to-date, and high-quality data
are needed to explore the full potential of this compound
in established uses, and in new respiratory indications
associated with mucus hypersecretion.
Abbreviations
AE: Adverse event; CC: Cough clearance; COPD: Chronic obstructive
pulmonary disease; CYP: Cytochrome P450; ER: Extended-release; FDA: Food
and Drug Administration; GGE: Glyceryl guaiacolate ether; GI: Gastrointestinal;
HIV: Human immunodeficiency virus; IL-13: Interleukin 13; IR: Immediate-
release; IV: Intravenous; MCC: Mucociliary clearance; NDA: New drug
application; OTC: Over-the-counter; PRO: Patient-reported outcome;
STT: Saccharin particle transit time; URTI: Upper respiratory tract infection
Acknowledgements
The authors would like to thank the subjects, clinicians, and scientists who
participated in the design, conduct, and analysis of the studies described in
this review paper. The authors would also like to thank Geraldine Toh, Wei Yi
Kwok and the team at Tech Observer for their medical writing support and
editorial assistance; this support was funded by Reckitt Benckiser, LLC.
Funding
Medical writing and editorial support in the preparation of this review article
was funded by Reckitt Benckiser, LLC. There are no other sources of funding
to declare.
Availability of data and materials
Not applicable.
Authors’contributions
All authors participated in drafting the manuscript, and have read and
approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
HHA is a paid consultant to Reckitt Benckiser, LLC, and to Alitair
Pharmaceuticals, Inc. PVD is a consultant to Reckitt Benckiser, Merck, and
Vernalis. EPG is an employee of Reckitt Benckiser, LLC.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Florida International University, Herbert Wertheim College of Medicine,
11200 SW 8th St., GL 495, Miami, FL 33199, USA.
2
Albert Einstein College of
Medicine and Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY
10461, USA.
3
Reckitt Benckiser, LLC, 399 Interpace Parkway, Parsippany, NJ
07054, USA.
Received: 3 May 2017 Accepted: 13 November 2017
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