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CREDIT:
2.0
Continuing Education
EARN CE CREDIT FOR THIS ACTIVITY AT WWW.DRUGTOPICS.COM
AN oNgoiNg cE progrAm oF THE uNiVErsiTY oF coNNEcTicuT
scHooL oF pHArmAcY AND DRUG TOPICS
educationaL oBJectiVeS
Goal: To provide pharmacists with an overview
of management options for the most common
causes of cough in outpatient settings.
After participating in this activity,
pharmacists will be able to:
●
●
●
Describe the major etiologies of cough in
adult and pediatric primary care settings.
Summarize the pharmacology of commonly
prescribed medications for cough symptoms.
Describe the place in therapy of medications
commonly prescribed for cough symptoms
for both adult and pediatric patients.
Discuss essentials of pharmacist triage for
the patient with cough.
The university of connecticut school of
pharmacy is accredited by the Accreditation
council for pharmacy Education as a provider
of continuing pharmacy education.
Pharmacists are eligible to participate in the
knowledge-based activity, and will receive up to 0.2
cEus (2 contact hours) for completing the activity,
passing the quiz with a grade of 70% or better, and
completing an online evaluation. statements of credit
are available via the cpE monitor online system and
your participation will be recorded with cpE monitor
within 72 hours of submission.
ACPE# 0009-9999-15-037-H01-P
Grant funding: This activity is supported by an independent educational grant from Boehringer ingelheim
pharmaceuticals, inc.
supported by an educational grant from genentech
Novartis pharmaceuticals corporation
Activity Fee: There is no fee for this activity.
Initial release date: December 10, 2015
Expiration date: December 10, 2018
To obtain cpE credit, visit www.drugtopics.com/cpe
and click on the “Take a Quiz” link. This will direct
you to the uconn/Drug Topics website, where you will
click on the online cE center. use your NABp E-profile
iD and the session code: 15DT37-ZJK56 to access
the online quiz and evaluation. First-time users must
pre-register in the online cE center. Test results will
be displayed immediately and your participation will
be recorded with cpE monitor within 72 hours of completing the requirements.
For questions concerning the online CPE
activities, e-mail: [email protected]
MTM essentials for
cough management
Devra K. Dang, PharmD, BCPS, CDE, FNAP
ASSOCIATE ClINICAl PROFESSOR, UNIVERSITY OF CONNECTICUT SCHOOl OF PHARMACY, STORRS, CONN.
Abstract
Cough is the most common presenting symptom encountered in the ambulatory
care setting. It can range from mild to severe, adversely affecting quality of life.
Assessment of the underlying cause(s) of the cough should be the first step of the
treatment plan, as cough is not a medical condition in itself but rather a symptom
of an underlying condition or disease process. Various cough medications are
popular with both healthcare providers and patients but their efficacy in various
conditions is questionable and safety concerns exist. This article provides an
overview of the most common causes of cough and a review of commonly prescribed
antitussives and expectorants. This article also summarizes pertinent aspects of the
2006 American College of Chest Physicians guideline for the management of cough
as they apply to primary care settings.
Faculty: devra K. dang, Pharmd, BcPS, cde, FnaP
Dr. Dang is an associate clinical professor at the University of Connecticut School of Pharmacy, Storrs,
Conn.
Faculty Disclosure: Dr. Dang has no actual or potential conflict of interest associated with this article.
Disclosure of Discussions of Off-Label and Investigational Uses of Drugs: This activity may contain discussion
of unlabeled/unapproved use of drugs in the United States and will be noted if it occurs. The content and
views presented in this educational program are those of the faculty and do not necessarily represent
those of Drug Topics or University of Connecticut School of Pharmacy. Please refer to the official
information for each product for discussion of approved indications, contraindications, and warnings.
66
DrugTopics | DECEMBER 2015 | DrugTopics.com
imAgE: gETTY imAgEs / NicoLE HiLL /
●
continuing education
CPE SERIES: MTM FOR THE PATIENT WITH RESPIRATORY
DISEASE
Welcome to the CPE series, Medication
Therapy Management for the Patient
with Respiratory Disease, which was
designed for pharmacists who take care
of patients with respiratory disease.
Beginning in April 2015 and continuing
through December 2015, pharmacists
can earn up to 18 hours of CPE credit
with 9 monthly knowledge-based activities from the University of Connecticut
School of Pharmacy and Drug Topics.
C
ough is the most common presenting symptom in primary care.1-3 The
duration and severity of cough range
from self-limiting and mild to chronic and
severe. Given the common nature of cough
as a presenting symptom, the complexity
of diagnosis and treatment is sometimes
underappreciated by healthcare professionals, leading to suboptimal management. A
number of guidelines from various countries exist, including the comprehensive,
evidence-based “Diagnosis and Management of Cough” from the American College
of Chest Physicians (ACCP) in the United
States, hereafter referred to as the ACCP
guideline.4 This guideline was published in
2006 and included 36 sections. The guideline was in the process of being updated at
the time of writing. The information provided
in this article is from the 2006 version.
Cough is a protective mechanism to
clear the airway of inhaled or aspirated irritants and sputum. The cough reflex arc
consists of an afferent sensory limb (consisting of the vagus, trigeminal, and glossopharyngeal nerves) in the respiratory tract,
the cough center in the medulla of the
brainstem, and an efferent limb innervating not just the larynx and tracheobronchial
tree but also the intercostal, diaphragm,
abdominal, and pelvic muscles.5 The cough
receptors in the afferent limb are sensitive
to a wide variety of mechanical, chemical,
inflammatory, and immunological stimuli.5
Cough can also be voluntarily suppressed,
indicating that areas outside the brainstem,
such as the cortex, are also involved.6
This series kicked off in April and
May with MTM essentials for asthma
management—Part 1 and Part 2.
In June and July, the focus shifts to
MTM essentials for chronic obstructive
pulmonary disease (COPD) management.
The August CE activity is a primer on
inhalers and nebulizers. In September,
pharmacists have the opportunity to
learn about allergic rhinitis management.
In October, the CE activity covers MTM
Cough is not a medical condition in
itself but rather a symptom of an underlying condition or disease process. Therefore,
the first step in the management of cough
is a thorough medical history and physical examination to determine the etiology.
Knowing the duration of the cough can
also assist in determining its cause. The
ACCP guideline classifies cough as acute,
subacute, or chronic. An acute cough is
one that has been present for less than
three weeks, a subacute cough has been
present for three to eight weeks, and a
chronic cough has been present for more
than eight weeks.4 These timeframes are
somewhat arbitrary3 but nevertheless are
useful frameworks from which to establish
the underlying etiology (Table 1).7, 8
An acute cough is most commonly
due to an upper respiratory tract infection (URI), most commonly viral in nature
(eg, the common cold or flu). This type of
cough is typically mild to moderate in nature and is self-limiting but may be severe
and long-lasting in immunosuppressed,
elderly, and other at-risk patients. A subacute cough is also most commonly the
result of a URI. This postinfectious cough
is caused by increased sensitivity and inflammation of the airway after a URI.9
The most common causes of chronic
cough in immunocompetent patients who
are not smokers or taking angiotensin-converting enzyme (ACE) inhibitors are upper
airway cough syndrome (UACS), asthma,
nonasthmatic eosinophilic bronchitis
(NAEB), and gastroesophageal reflux dis-
essentials for cold, flu, and sinusitis
management. The November CE activity
includes drug-induced pulmonar y
disease recognition and management
and idiopathic pulmonary fibrosis. The
series concludes in December with a
focus on MTM essentials for cough
management.
The series also offers applicationbased and practice-based activities in
2016.
The most
common causes of
chronic cough in
immunocompetent
patients who
are not smokers
or taking ACE
inhibitors are
upper airway
cough syndrome,
asthma,
nonasthmatic
eosinophilic
bronchitis, and
GERD.
ease (GERD).10 Cough may be the only presenting symptom for these conditions (eg,
cough-variant asthma, silent GERD), and
more than one condition may be present
in a patient and contribute to the cough.10
Overview of common
causes and treatment of
cough in adults
Upper airway cough syndrome
UACS, called postnasal drip syndrome
before the publication of the 2006 ACCP
DrugTopics.com | DECEMBER 2015 | DrugTopics
67
Continuing Education
MtM eSSentiaLS FoR cougH ManageMent
guideline, is the most common cause of
chronic cough.5 Patients may report feeling
postnasal drainage, a tickle in the throat,
and/or nasal congestion or rhinorrhea. Interestingly, some patients with UACS do
not subjectively feel the postnasal drip and
therefore do not report this during the history and evaluation.11 There is no objective
test to determine whether the postnasal
drip is the cause of the cough.
UACS can be caused by a number of
rhinosinus conditions, including bacterial
and fungal sinusitis, allergic and nonallergic rhinitis, and rhinitis medicamentosa.5,11
If the cause is known, therapy should be
directed toward treating the underlying
cause (eg, allergen avoidance and antihistamine or intranasal corticosteroid for
allergic rhinitis). Empiric therapy with a
first-generation antihistamine-decongestant combination can be quite effective,
and the patient’s response to therapy can
confirm the diagnosis of UACS.5, 11
Asthma
This is the second most common cause
of chronic cough in adults, as well as a
common cause of cough in children.10 All
patients with asthma experience cough as
a symptom at some point, and cough is
the only presenting symptom in a subset
of asthma patients (cough-variant asthma).5 The ACCP guideline recommends
that cough in an asthmatic patient be
treated with standard therapy for asthma,
including inhaled corticosteroids and bronchodilators.12 In patients with cough that
is refractory to these medications, a leukotriene receptor antagonist may be added
before proceeding to (short-term) oral corticosteroid therapy.12
Nonasthmatic eosinophilic bronchitis
NAEB is distinguished from asthma in that
it is not associated with bronchial hyperresponsiveness or with abnormal spirometry.
It is diagnosed by the presence of eosino-
Guaifenesin,
dextromethorphan,
and a combination
of the two
are popular
medications for
cough due to
the common
cold, but neither
guaifenesin nor
dextromethorphan
has demonstrated
efficacy in this
clinical scenario.
philia in the sputum, after other common
causes of chronic cough have been ruled
out, and may be due to an inhaled allergen
or irritant. Avoidance of these allergens/
irritants is the best treatment; inhaled
corticosteroid therapy to treat the chronic
cough can also be used. Oral corticosteroid therapy may be needed if the cough
persists with high-dose inhaled corticosteroid treatment.13
Gastroesophageal reflux disease
The proposed mechanisms of GERD-induced cough are aspiration of esophageal
content into the lower respiratory tract and
direct acid reflux into the lower esophagus,
stimulating vagus nerve-mediated cough
reflex.5 The diagnosis of GERD-induced
cough in adults is typically made after the
other causes of chronic cough (smoking,
ACE inhibitor use, UACS, asthma, and
NAEB) have been ruled out.14 Some pa-
Pause&Ponder
What are the most popular cough products prescribed/
taken at your practice setting, and are these products
used according to the recommendations made in the
accP cough guideline?
68
DrugTopics | DECEMBER 2015 | DrugTopics.com
tients do not experience the typical GERD
gastrointestinal symptoms and only experience chronic cough (silent GERD).14 The
ACCP guideline recommends that patients
with chronic cough due to GERD be treated
with dietary and lifestyle modification and
acid suppression therapy. An adequate
time period (one to three months) should
be given before therapy is reassessed,
as it may take two to three months to
see improvement in the cough in some
patients.14
Common cold
This is the most common etiology of cough
in the general population, and a large variety of over-the-counter (OTC) products designated for the management of cough and
cold exist. Many patients self-treat with an
OTC product containing guaifenesin, dextromethorphan, or a combination of the
two, but neither drug has demonstrated
efficacy in this clinical scenario. A 2014
Cochrane systematic review of OTC medications for acute cough in children and
adults in community settings concluded
that “there is no good evidence for or
against the effectiveness of OTC medicines in acute cough.”15 The authors stated
that “this lack of evidence of effectiveness
also has implications for regulatory bodies
and brings into question how these products can continue to be promoted using
language that implies that their effectiveness is not in doubt.”15
It has been postulated that the cough
associated with the common cold is most
likely due to postnasal drip, and so the
ACCP guideline recommends treatment
with a combination of a first-generation antihistamine and a decongestant (pseudoephedrine).16 This combination decreased
cough, cough severity, throat clearing, and
postnasal drip in patients with uncomplicated common cold in a double-blind, placebo-controlled study.17 The mechanisms
of first-generation antihistamines in the
treatment of cough due to the common
cold are not completely understood, but
their anticholinergic (decreased nasal mucus secretion) and sedative effects are
potential contributors.18 They may also decrease nerve transmission relating to the
control of cough in the central nervous
system.6,18 Second-generation antihista-
continuing education
mines are not effective for cough due to
the common cold.15,16
The ACCP guideline additionally noted
that, based on a randomized, double-blind,
placebo-controlled study, naproxen can also
be used to treat cough due to the common
cold. The proposed mechanism for this
nonsteroidal anti-inflammatory drug is that
inflammation due to a viral URI can lead to
increased sensitivity of the afferent limb of
the cough reflex arc.16
Despite the publication of the comprehensive ACCP cough guideline in 2006,
the popularity of cough products containing dextromethorphan, guaifenesin, and
codeine for treatment of the self-limiting
cough associated with a viral URI among
both patients and healthcare professionals remains high approximately 10 years
later. Many patients report symptomatic
relief with these products, despite several randomized, controlled clinical trials
that demonstrated no greater efficacy
compared to placebo. It has been postulated that the effect of cough medications
is due to several components, including
the drug itself, the physiological components of the medication formulation having a demulcent effect, and the placebo
effect.19 Many cough medications are formulated as a syrup, and the syrupy liquid
and its content (eg, sugar, honey, lemon)
are thought to encourage saliva production and swallowing and to coat sensory
nerve endings, which may suppress a dry,
nonproductive cough.19These physiological
components may also increase airway secretions, which can have an expectorant
effect for a productive (wet) cough.20 A
strong placebo effect has also been demonstrated in studies with antitussives; the
mean placebo response (calculated as a
percentage of the change in cough demonstrated by the active treatment arm)
across six studies was 85%.19 Additionally, acute and subacute coughs are selflimiting, and the cough will likely resolve
on its own even without the medication.19
Drug-induced cough
A drug-induced cause is important to
consider in patients with either acute or
chronic cough. The November 2015 continuing education article in this respiratory
medication therapy management series
table 1
Potential Etiologies of Cough in Adults*
Upper respiratory tract infection including common cold
Upper airway cough syndrome (previously called postnasal drip syndrome)
Allergic rhinitis
Nonallergic rhinitis including vasomotor rhinitis and rhinitis medicamentosa
Bacterial sinusitis
Fungal sinusitis
Acute bronchitis
Community-acquired pneumonia
Postinfectious cough
Bordetella pertussis infection
Asthma
Chronic obstructive pulmonary disease
Smoking
Gastroesophageal reflux disease
Nonasthmatic eosinophilic bronchitis
Drug-induced cough (most commonly caused by angiotensin-converting enzyme inhibitors)
Cardiac causes (eg, heart failure)
Bronchiectasis
Bronchiolitis and other nonbronchiectatic suppurative airway disease
Tuberculosis
Interstitial lung disease
Lung cancer
Aspiration
Inhaled irritants (eg, exposure to second-hand smoking, occupational exposure)
Somatic cough syndrome and tic cough
Unexplained (refractory) chronic cough
*Not an all-inclusive list.
provides a detailed description of druginduced pulmonary reactions.21 Given the
prevalence of hypertension, diabetes, coronary artery disease, and heart failure in the
United States, the most common cause of
cough that pharmacists will likely encounter is from ACE inhibitors. A review of the
literature reported that the prevalence of
cough is 5% to 20% in patients treated
with ACE inhibitors. A more recent review
of randomized controlled trials concluded
that the incidence of ACE-induced cough,
as well as the withdrawal rate because
of this adverse drug reaction, is much
greater than what is described in the FDAapproved product labeling.22 For example,
the incidence and withdrawal rate for enalapril from the literature are 11.48% and
2.57%, respectively, while those reported
in the product labeling are 1.3% and 0.1%,
respectively. The authors also posited that
the real-world percentages are likely to be
even higher than study data.22
The cough caused by an ACE inhibitor is a dry, persistent cough that occurs
within a few hours to several months after the first dose.23 The cough is not dosedependent and women, nonsmokers, and
Source: Ref 7,8
Chinese patients appear to be at higher
risk.23 The incidence of ACE inhibitor-induced cough in Chinese patients has been
reported to be as high as 44%.24
As with the evaluation of cough in general, a thorough history should be obtained
to rule out other potential etiologies. Discontinuation of the medication typically
leads to resolution of the cough within one
to four weeks, but the cough may linger
for as long as three months in some patients.23 In practice, many clinicians switch
the patient to an angiotensin receptor
blocker (ARB), as these agents have many
of the same treatment indications as the
ACE inhibitors. This approach is a sound
one, but another option also exists. A randomized, double-blind trial showed that
approximately 30% of patients who had
experienced cough with two previous ACE
inhibitors did not have the same reaction
when treated with a third ACE inhibitor.23 A
repeat attempt with another ACE inhibitor
is endorsed as a grade A recommendation by the 2006 ACCP cough guideline23
and may be particularly useful for patients
who are unable to afford the higher cost
of ARBs.
DrugTopics.com | DECEMBER 2015 | DrugTopics
69
Continuing Education
TABlE 2
MtM eSSentiaLS FoR cougH ManageMent
Potential etiologies of Cough
in ChildRen aged 14 yeaRs and youngeR*
Acute upper respiratory tract infection
upper airway cough syndrome
Asthma
protracted bacterial bronchitis
Bordetella pertussis infection
chronic suppurative lung disease (eg, cystic fibrosis)
Tobacco smoke
medications (angiotensin-converting enzyme inhibitors, asthma medications)
inhaled foreign body
psychogenic cough
otogenic cough
*Not an all-inclusive list.
Commonly prescribed
antitussives and
expectorants
Medications used in the treatment of
cough have traditionally been categorized
as cough suppressants (antitussives) and
expectorants. Theoretically, antitussives
suppress nonproductive coughs (also
called dry or nuisance coughs) and expectorants thin sputum and make a cough
that is productive (also referred to as a
wet cough) easier to expectorate. Antitussives are further classified by their site of
action. The centrally acting antitussives
are thought to act on the cough center in
the medulla to increase the cough threshold, whereas the peripherally acting antitussives suppress cough by acting on the
peripheral pulmonary receptors.
Antitussives
Dextromethorphan is the d-isomer of the
opioid analgesic levorphanol.25 At recommended doses for the treatment of cough,
it is well tolerated and does not have analgesic, sedative, respiratory depressant,
or addictive effects. Dextromethorphan’s
active metabolite dextrorphan is a strong
antagonist of the N-methyl-D-aspartate
(NMDA) receptor and possesses properties similar to those of phencyclidine (PCP)
and ketamine; dissociative hallucinations
can occur with these agents.25,26 Psychosis, tachycardia, lethargy, ataxia, hypertension, and mydriasis can also occur.26 An
alarming increase in the abuse of dextromethorphan (so called “robotripping”), especially by adolescents, has been reported
over the past two decades.26
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DrugTopics | DECEMBER 2015 | DrugTopics.com
Source: Ref 41,42
Dextromethorphan is a popular ingredient in both prescription and OTC cough
products. It is available in a wide variety
of formulations, including liquid, liquidfilled capsules, orally disintegrating strips,
lozenges, and tablets. OTC formulations
of dextromethorphan products provide
dosing for adults and children aged as
young as four years for the treatment of
cough due to the common cold. However,
as noted previously, the ACCP guideline
recommends that this type of cough in
adults be treated with a first-generation
antihistamine-decongestant combination.
Centrally acting antitussives such as dextromethorphan and codeine are not recommended because of their questionable
efficacy in treating cough due to a URI.6 Of
note, the author of a 2009 review article
on antitussives reported that he was unable to find any published English-language
studies that demonstrated the efficacy of
dextromethorphan or codeine in cough due
to the common cold.27 The ACCP guideline
does recommend that these agents can
be considered for the short-term symptomatic relief of chronic bronchitis in adults
as they have been reported to suppress
cough counts by 40% to 60%.6 As will be
discussed in the pediatric section of this
article, OTC cough and cold medications
are not recommended for the management of cough in children because of a
lack of efficacy and an increased risk of
adverse reactions. The Cochrane review
of OTC medications for acute cough in
children and adults in community settings
described earlier reported that all four of
the randomized, controlled trials of dex-
tromethorphan’s efficacy in children found
that the drug was no more effective than
placebo.15
Codeine is an opiate that is indicated
for both pain and cough and is available
in a variety of liquid formulations, typically
coformulated with guaifenesin, pseudoephedrine, or a first-generation antihistamine. Cough formulations containing no
more than 200 mg of codeine per 100
milliliters or per 100 grams are classified
as schedule V controlled substances.28
Codeine has been called the gold standard by which other antitussives are compared based on animal models and older
studies in humans demonstrating its effectiveness.29 However, more recent studies reported that codeine was no more
effective than placebo in both adults and
children.29-31 As previously discussed, the
ACCP guideline states that centrally acting antitussives can be considered for the
short-term symptomatic relief of chronic
bronchitis in adults.6 Some clinicians have
proposed that codeine’s analgesic and
sedative effects may be useful in the management of painful cough.18
As with other opiates, sedation, nausea, vomiting, constipation, respiratory depression, and potential abuse are potential
adverse reactions associated with codeine
use, but the risk of these events occurring
may be lower compared to more potent
opiates. The dosing of codeine for cough
suppression is lower than that required to
achieve analgesia and can be as low as
less than 15 mg per dose.32
In July 2015, the FDA announced
that it is investigating the safety of using
codeine-containing medications to treat
cough and cold in children aged younger
than 18 years because of the potential
for serious adverse events, including respiratory depression. The FDA warned
that children with breathing problems are
at an increased risk of serious adverse
drug reactions with codeine. The European
Medicines Agency has prohibited the use
of codeine to treat cough and cold in children aged younger than 12 years and has
recommended against its use in children
and adolescents aged between 12 and 18
years who have respiratory conditions.33
Other opioids, mainly hydrocodone
and morphine, have also been used for
continuing education
table 3
Recommended Pharmacologic Treatment of Cough
in Adults (2006 American College of Chest Physicians Cough Guideline)
Condition
Drug treatment
Comment
Common cold
First-generation antihistamine-decongestant (pseudoephedrine) combination
Naproxen
Second-generation
antihistamines are ineffective
Upper airway cough
syndrome
Specific therapy directed at underlying cause, if known
First-generation antihistamine-decongestant (pseudoephedrine) combination as empiric therapy
Acute bronchitis
Antitussives for short-term symptomatic relief “are occasionally useful”
Chronic bronchitis
Central cough suppressants such as codeine and dextromethorphan for short-term symptomatic No evidence that expectorants
relief of coughing
are effective and therefore not
Inhaled ipratropium bromide
recommended
Long-acting beta-2 agonist plus inhaled corticosteroid to control chronic cough in stable patients
Short-acting beta-2 agonist to control bronchospasm and relieve dyspnea may reduce chronic
cough in stable patients
Nonasthmatic
eosinophilic bronchitis
Inhaled corticosteroid (if avoidance of allergen or sensitizer is not possible)
Oral corticosteroid if cough is persistent or severe despite use of high-dose inhaled
corticosteroid
Postinfectious cough
For postinfectious cough not due to bacterial sinusitis or early in a pertussis infection, while the
optimal treatment is not known:
Inhaled ipratropium bromide
Inhaled corticosteroid
Short-term oral corticosteroid if cough is severe
Centrally acting antitussive as last resort
Asthma
Treat according to asthma guidelines
Mucokinetic agents are not
recommended
Determine and treat
underlying cause of
postinfectious cough first
Source: Ref 4
the management of cough. These are potent opiates, and in light of the risks of
significant side effects and addiction with
these agents, they are typically reserved
for cases of severe, intractable cough due
to a severe underlying condition such as
lung cancer.34,35
Peripherally acting antitussives include
benzonatate, levodropropizine, and moguisteine. Both levodropropizine and moguisteine have demonstrated efficacy in
controlling cough due to acute and chronic
bronchitis and COPD.6 However, neither
drug is available in the United States.
Benzonatate is chemically related to tetracaine, an anesthetic. It suppresses cough
by producing an anesthetic effect on the
pulmonary stretch receptors of the afferent
limb of the cough reflex arc.36 The ACCP
guideline does not specifically discuss
benzonatate and only states that peripherally acting cough suppressants are not
recommended for cough due to a URI.6 In a
recent systematic review and meta-analysis
of treatments for chronic unexplained or refractory cough, benzonatate was not found
to be more effective than placebo in one
study and was not found to be more effective than opioids in two others.37
Benzonatate has FDA-approved dosing
for adults and children aged older than 10
years.36 It is relatively well tolerated; the
most commonly reported adverse drug
reaction is nausea. The capsules should
be swallowed whole, as mouth, tongue,
and throat numbness can occur if they
are chewed or otherwise broken. Choking is also a risk with these capsules.38
In 2010, the FDA warned that deaths
from accidental ingestion of benzonatate
by children aged younger than 10 years
have been reported. Benzonatate’s round/
oval, liquid-filled gelatin capsules may be
attractive to children. Overdose can occur
with ingestion of just one to two capsules
in children aged younger than two years
of age and restlessness, tremors, convulsions, coma, and cardiac arrest may occur,
with signs and symptoms occurring within
15 to 20 minutes after ingestion and
death occurring within hours.38 Overdoses
have also been reported in adolescents
and adults.38 The product labeling also
states that isolated incidents of bizarre
behavior, including mental confusion and
visual hallucinations, have been reported
when benzonatate was taken in combination with other prescribed medications.36
Expectorants
The potential efficacy of expectorants is in
the management of a productive cough.
Guaifenesin is the only FDA-approved expectorant available in the United States.
This agent’s purported mechanism is in
increasing the volume and reducing the
viscosity of bronchial secretions, making
it easier for the patient to cough up the
sputum.39 Studies of guaifenesin’s efficacy
in acute and chronic cough in adults are
conflicting, with several studies showing
efficacy in acute URI but others showing
no difference compared to placebo.6,15 The
2006 ACCP guideline states that medications that alter mucus characteristics are
not recommended for cough suppression
in patients with chronic bronchitis and that
an antihistamine-decongestant combination is recommended for cough due to the
common cold.6 A 2009 study found that
guaifenesin inhibits cough-reflex sensitivity
in adult patients with acute viral URI, suggesting that guaifenesin may have an antitussive as well as an expectorant effect.39
Guaifenesin is available in single-ingredient and multi-ingredient products and in
tablet and liquid formulations. It is typically
coformulated with dextromethorphan or
DrugTopics.com | DECEMBER 2015 | DrugTopics
71
Continuing Education
MtM eSSentiaLS FoR cougH ManageMent
codeine and/or an oral decongestant in
both prescription and OTC products. Guaifenesin is generally well tolerated at recommended doses, with the most common
adverse reactions being nausea, vomiting,
and gastrointestinal discomfort.40
Cough in children
Similar to the evaluation of cough in
adults, the first step in the management
of cough in children is obtaining a thorough medical history and physical exam.
Children with chronic cough should be
evaluated with a chest radiograph and
spirometry (if the child is old enough to do
so).41 The etiologies of cough in children
are somewhat different than in adults (Table 2).41,42 Acute cough in children is most
commonly due to a URI.43 Chronic cough
in children, which is defined as a cough
lasting more than four weeks,41 is most
commonly due to asthma and asthmalike symptoms, protracted bronchitis, or
UACS.44 GERD as an underlying cause accounts for less than 5% of cases.44 Pertussis infection, inhaled foreign body, chronic
suppurative lung disease, nonasthmatic
eosinophilic bronchitis, tobacco smoke,
psychogenic cough, and otogenic cough
are other potential causes.41,42 If the underlying cause is known, therapy should
be directed toward treating this condition
(eg, inhaled corticosteroid for asthma).
However, the results of drug treatment in
adults cannot be extrapolated to children.
For example, a Cochrane systematic review concluded that empiric antihistamine
therapy cannot be recommended for children with chronic cough given “minimal, if
any” efficacy and the potential for adverse
drug reactions.45The ACCP guideline advises against using cough suppressants and
other OTC cough medications because of
an increased risk of morbidity and mortality, especially in young children.41 Adolescents aged 15 years and older may be
treated according to the guidelines for
adults.4,41
In 2007 and 2008, the FDA warned
that OTC cough and cold medications
should not be used for infants and children
aged younger than two years because serious and potentially life-threatening side
effects, including death, convulsions,
72
DrugTopics | DECEMBER 2015 | DrugTopics.com
The American
Academy of
Pediatrics has
stated that OTC
cough and cold
medications are
not effective for
children aged
younger than six
years.
tachycardia, and decreased levels of consciousness, have been reported.46 The
agency emphasized that there are no data
regarding the effectiveness of OTC products in children aged younger than two
years.46 In response, manufacturers of OTC
cough and cold products announced in
2008 that they would voluntarily withdraw
formulations that referred to “infants” and
would also revise product labeling to state
that the medications should not be used in
children aged younger than four years.47,48
Even though the labeling of the OTC
cough medications dextromethorphan and
guaifenesin contains dosing instructions for
children aged as young as four years, the
American Academy of Pediatrics (AAP) has
stated that OTC cough and cold medications are not effective for children aged
younger than six years.49 The AAP states
that honey, staring with one-half to one teaspoon, can be given to children aged older
than one year to ease nighttime cough
and sleeplessness.50 Corn syrup may be
substituted if honey is not available.50
A recent study of 300 children aged one
to five years with acute URI and nocturnal
cough found that honey was more effective than placebo in improving subjective
(parent-reported) measures of nocturnal
cough, child sleep, and parental sleep.51
Role of pharmacists
Pharmacists have a potentially large role
to play in the management of this very
common medical condition, especially
given that community pharmacists are the
most accessible healthcare professionals.
An evaluation of potential drug-induced
causes of cough should be considered
in the management of both acute and
chronic cough. Pharmacists should also
discuss the lack of efficacy of various OTC
products for the management of cough in
adults and children and any potential safety concerns, especially in young children.
Patients should be advised that many OTC
cough and cold products contain several
ingredients, increasing the possibility of a
drug-drug or drug-disease interaction (eg,
a first-generation antihistamine in a patient
with benign prostatic hyperplasia). Many
patients self-treat their chronic cough but
should be aware that doing so may delay
diagnosis and treatment of the underlying
cause of the cough. Conversely, cough due
to an acute mild URI in an immunocompetent nonsmoking person is generally selflimiting and typically requires only adequate
hydration and rest, not treatment with various OTC products. Pharmacists can also
assist in the selection of appropriate drug
treatment for common conditions associated with cough (Table 3)4 and can engage
in smoking cessation education, as both
first- and second-hand smoking can lead
to chronic cough.
Conclusion
The management of this very common
condition is multifaceted and complex.
Taking a thorough history, including a
medication and smoking history, is a
crucial step in the evaluation of cough.
Therapy should be directed toward treating the underlying cause of the cough, not
just masking the symptom.
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Free CPE Activities
continuing education
test questions
1.
A chronic cough is one that has been present for
a. Three or more weeks
b. Four or more weeks
c. Eight or more weeks
d. 12 or more weeks
2.
Which of following is the most common cause
of acute cough in both adults and children?
a. Upper respiratory tract infection
b. Heart failure
c. Gastroesophageal reflux disease
d. Inhaled foreign bodies
3.
Which of the following is a common cause of
chronic cough in adults but not in children?
a. Asthma
b. Upper airway cough syndrome
c. Bronchitis
d. Gastroesophageal reflux disease
4.
The 2006 ACCP cough guideline recommends
that cough due to the common cold in adults
be treated with _______.
a. Guaifenesin and dextromethorphan
combination
b. Dextromethorphan only
c. A first-generation antihistamine and an
oral decongestant
d. A second-generation antihistamine and
an oral decongestant
5.
Robotripping refers to abuse of high doses of
a. Diphenhydramine
b. Guaifenesin
c. Dextromethorphan d. Codeine
6.
In a patient experiencing ACE inhibitorinduced cough, management option(s) include
a. Discontinuation of the offending ACE
inhibitor and changing to an ARB
b. Continuation of the offending ACE inhibitor
and suppressing the cough with an antitussive
c. Discontinuation of the offending ACE inhibitor
and changing to a different ACE inhibitor
d. Either a or c
7.
Which of the following medications is
structurally related to tetracaine and can
cause numbness of the mouth, tongue, and
throat if the capsule is broken?
a. Guaifenesin
b. Dextromethorphan
c. Codeine
d. Benzonatate
Match the medication with its purported
mechanism of effect for the treatment of
cough:
8. Dextromethorphan a. Works in the brainstem
to increase the cough
threshold
9. Codeine
b. Anesthetizes pulmonary
stretch receptors
10. Guaifenesin
c. Increases sputum volume
and decreases sputum
viscosity
11. Benzonatate
d. Disrupts the cough-reflex
arc
12. Which of the following is true regarding the
use of OTC cough and cold medications in
young children?
a. They are safe and effective.
b. They are safe but have not been proven
effective.
c. They are recommended for children aged
two years and older.
d. None of the above.
13. According to the 2006 ACCP cough
guidelines, dextromethorphan and codeine
can be used in which of the following
conditions?
a. Short-term symptomatic relief of cough
in acute bronchitis
b. Short-term symptomatic relief of cough
in chronic bronchitis
c. The common cold
d. A and B
14. In the management of cough due to
nonasthmatic eosinophilic bronchitis, which
of the following is effective?
a. Avoidance of allergen or irritant
b. Inhaled anticholinergic
c. Expectorant
d. All of the above
15. In the evaluation of cough, which of the
following statements is true?
a. A thorough history and physical
examination is an important first step.
b. A potential drug-induced cause should
be investigated.
c. More than one cause for the cough may
be present.
d. All of the above.
16. Which of the following statements regarding
codeine is true?
a. It has a well-deserved reputation as the
gold standard cough medication given
its strong efficacy in treating many cough
conditions.
b. The FDA is investigating the safety of
using codeine-containing medications to
treat coughs and colds in children aged
younger than 18 years because of the
potential for serious adverse events.
c. It is most effective when combined with
dextromethorphan.
d. All of the above.
17. Benzonatate is FDA approved for children
older than
a. Six years of age
b. Eight years of age
c. 10 years of age
d. 12 years of age
18. Which of the following statements regarding
the treatment of cough due to the common
cold is true?
a. Inflammation of the respiratory tract may
play a role in causing the cough.
b. There is a strong placebo effect in cough
studies.
c. The vehicle for the cough medication
(eg, syrup) can act as a demulcent and
contribute to the therapeutic effect.
d. All of the above.
19. The most common cause of a subacute
cough is
a. A cardiac condition
b. Postinfectious cough
c. Psychogenic cough
d. None of the above
20. Pharmacists’ role in the evaluation and
management of cough involves:
a. Assessment for a drug-induced cause
b. Smoking cessation education
c. Educating patients on the efficacy, or
lack thereof, of cough medications
d. All of the above.
DrugTopics.com | DECEMBER 2015 | DrugTopics
73
Continuing Education
MtM eSSentiaLS FoR cougH ManageMent
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