1. health and fitness
2. disease
3. asthma

9
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
Current Drugs for the Treatment of Dry Cough
L Padma*
Abstract
Cough is one of the commonest symptoms of respiratory tract infections and is a frequent problem encountered
in general practice as well as in hospital practice. A wide range of disease processes may present with cough and
definitive treatment depends on identifying the cause and diagnosis. Specific treatment of the cause should control
the cough, but this may not occur in all cases and in a sizeable proportion of patients, no associated cause can
be found. An increased sensitivity of the cough reflex can be observed in patients with dry cough. Symptomatic
relief must be considered when the cough interferes with the patient’s daily activities and this is effectively
treated with antitussive preparations which are available as combinations of codeine or dextromethorphan with
antihistamines, decongestants and expectorants
Antitussives are used for effective symptomatic relief of dry or non-productive cough. First generation antihistamines like chlorpheniramine and centrally acting opioid derivatives like codeine are often used alone or in
combination in the management of nonspecific cough. Sedation caused by these is valuable , particularly if the
cough is disturbing the sleep.
Although there is extensive experimental data on single agent antitussives and antitussive combinations, there
is a major paucity of published literature on these combinations in nonspecific cough.
Treatment of dry cough remains a challenge in some patients and this article reviews the scope of the current
drugs and combination of Codeine and Chlorpheniramine in the effective management of dry cough
Introduction
C
ough is a reflex response to mechanical, chemical, or
inflammatory irritation of the tracheobronchial tree which
is mediated by sensory neurons in the airways reflexly through
neurons present in the brainstem. It is a physiologic function
to clear airways of obstructive or irritating material or to warn
about noxious substances in inspired air.1 It is important to
note that cough should not be suppressed indiscriminately.
However, there are many situations when cough does not serve
any useful purpose and may be annoying to the patient, disturb
sleep or hinder the adherence to otherwise beneficial medication
regimens (e.g., angiotensin-converting enzyme (ACE) inhibitorinduced cough). Additionally, this kind of chronic cough can lead
to fatigue, especially in elderly patients. In such circumstances,
the drug may be replaced with another without this side-effect
profile (e.g., an Angiotensin receptor blocker instead of an
ACE inhibitor) or add an antitussive agent that will reduce the
frequency or intensity of the coughing.2
Cough, apart from being classified as productive (wet)
and non-productive (dry), can also be classified based on the
Receptor
Afferent
Larynx and suprapharyngeal
area
•
Tracheabronchial tree
•
Auditory canal and tympanic
membrane
•
Pleura, pericardium and
diaphragm
•
Esophagus and stomach
Efferents
Modulation at
CNS cortex
Cough Receptor Location
•
CNS Center
Effector organ
Larynx, trachea
and bronchi
Vagus
Vagus
Cough Center:
Medulla,
Nucleus
tractussolitarius
Phrenic
Diaphragm
Spinal
motor
Expiratory muscles
Fig. 1: Cough Reflex Arc12
Professor and Head Depatment of Pharmacology, Dr. BR Ambedkar
Medical College, Bangalore
*
duration into acute, subacute and chronic. Acute cough lasts
for less than three weeks and is most commonly because of
an acute respiratory tract infection. It could also be because of
acute exacerbation of underlying chronic pulmonary disease,
pneumonia, and pulmonary embolism. Cough is referred to as
being subacute if it is present for more than three weeks (three to
eight weeks) or chronic if it persists for more than eight weeks3.
It is interesting to note that patients who seek medical attention
for chronic cough are more often females.4-6 Furthermore, among
subjects with chronic cough, women tend to cough more often
and to have heightened cough reflex sensitivity compared to
men. Women have more sensitive cough reflex than men.5
Cough Reflex Arc
The stimulation of a complex reflex arc is necessary for
each cough. This is set off by the irritation of cough receptors
that exist not only in the epithelium of the upper and lower
respiratory tracts, but also those in the pericardium, esophagus,
diaphragm, and stomach. Receptors sensitive to acid, cold, heat,
capsaicin-like compounds and other chemical irritants trigger
the cough reflex by activating ion channels of the transient
receptor potential vanilloid type 1 (TRPV1) and transient
receptor potential ankyrin type 1 (TRPA1) classes.7-11 Mechanical
cough receptors are stimulated by triggers such as touch or
displacement. The receptors in larynx and tracheobronchial tree
respond to both mechanical and chemical stimuli.12
Impulses from stimulated cough receptors are carried to the
“cough center” in the medulla via the vagus nerve, which is
under some control by higher cortical centers. The finding that
women are more prone to develop chronic cough than men
are explained by the sex-related differences in cough reflex
sensitivity.3,13-15 The efferent signals are carried from the cough
center through the vagus, phrenic, and spinal motor nerves
to expiratory musculature which results in the production of
cough (Figure 1).12
Although there is extensive experimental data on single
agent antitussives and antitussive combinations, there is a
10
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
major paucity of published literature on these combinations in
nonspecific cough.
Treatment of dry cough remains a challenge in some patients
and this article reviews the scope of the current drugs and
combination of Codeine and Chlorpheniramine in the effective
management of dry cough.
Current Drugs Used in Treatment of
Dry Cough
Treatment of cough mainly consists of treating the underlying
cause. A productive cough should not be suppressed except
in special circumstances (eg, when it exhausts the patient or
prevents rest and sleep) and generally not until the cause
has been identified. Suppressing a productive cough is less
advisable because sputum needs to be cleared. Cough remedies
are categorized as antitussives and expectorants. Mucolytics,
proteolytic enzymes, antihistamines, and bronchodilators are
sometimes used.
Antitussives: These drugs may be centrally or peripherally
acting. Centrally acting antitussives inhibit or suppress the cough
reflex by depressing the medullary cough center or associated
higher centers. The most commonly used drugs in this group
are dextromethorphan and codeine.
Dextromethorphan, a congener of the narcotic analgesic
levorphanol, has no significant analgesic or sedative properties,
does not depress respiration in usual doses, and is nonaddictive.
No evidence of tolerance has been found during long-term use.
Codeine, which has antitussive, analgesic, and slight sedative
effects, is especially useful in relieving painful cough. It also
exerts a drying action on the respiratory mucosa that may be
useful (eg, in bronchorrhea) or deleterious (eg, when bronchial
secretions are already viscous). Nausea, vomiting, constipation,
tolerance to antitussive as well as analgesic effects, and physical
dependence can occur, but potential for abuse is low.
Other centrally acting antitussives include chlophedianol,
levopropoxyphene, and noscapine in the nonnarcotic group
and hydrocodone, hydromorphone, methadone, and morphine
in the narcotic group.
Peripherally acting antitussives may act on either the afferent
or the efferent side of the cough reflex. On the afferent side, an
antitussive may reduce the input of stimuli by acting as a mild
analgesic or anesthetic on the respiratory mucosa, by modifying
the output and viscosity of the respiratory tract fluid, or by
relaxing the smooth muscle of the bronchi in the presence of
bronchospasm. On the efferent side, an antitussive may make
secretions easier to cough up by increasing the efficiency of the
cough mechanism. Peripherally acting agents are grouped as
demulcents, local anesthetics, and humidifying aerosols.
Demulcents are useful for coughs originating above the
larynx. They form a protective coating over the irritated
pharyngeal mucosa. They are usually given as syrups or lozenges
and include acacia, licorice, glycerin, honey, and wild cherry
syrups.
Local anesthetics (eg, lidocaine, benzocaine, hexylcaine
hydrochloride, and tetracaine) are used to inhibit the cough
reflex under special circumstances (eg, before bronchoscopy
or bronchography). Benzonatate (100 mg po tid), a congener of
tetracaine, is a local anesthetic; its antitussive effect may be due
to a combination of local anesthesia, depression of pulmonary
stretch receptors, and nonspecific central depression.
Expectorants: These drugs are intended to help expel
bronchial secretions from the respiratory tract by decreasing their
viscosity, thus facilitating removal, and by increasing the amount
of respiratory tract fluid, thus exerting a demulcent action on the
mucosal lining. Most expectorants increase secretions through
reflex irritation of the bronchial mucosa. Some, like the iodides,
also act directly on the bronchial secretory cells and are excreted
into the respiratory tract.
The use of expectorants is highly controversial. No objective
experimental data show that any of the available expectorants
decreases sputum viscosity or eases expectoration. Data may be
lacking partly because of inadequate technology for obtaining
such evidence. Thus, the use and choice of expectorants are often
based on tradition and the widespread clinical impression that
they are effective in some circumstances.
Adequate hydration is the single most important measure
that can be taken to encourage expectoration. If it is unsuccessful,
using an expectorant in addition may produce the desired result.
Guaifenesin (100 to 200 mg po q 2 to 4 h) is the most commonly
used expectorant in OTC cough remedies. It has no serious
adverse effects, but there is no clear evidence of its efficacy.
Many other traditional expectorants (eg, ammonium chloride,
terpin hydrate, creosote, squill) are found in numerous OTC
cough remedies. Their efficacy is doubtful, particularly in the
dosages of most preparations.
Less commonly used drugs: Mucolytics (eg, acetylcysteine)
have free sulfhydryl groups that open mucoprotein disulfide
bonds, reducing the viscosity of mucus. As a rule, their usefulness
is restricted to a few special instances such as liquefying thick,
tenacious, mucopurulent secretions (eg, in chronic bronchitis and
cystic fibrosis). Acetylcysteine is given as a 10 to 20% solution
by nebulization or instillation. In some patients, mucolytics may
aggravate airway obstruction by causing bronchospasm. If this
occurs, these patients may inhale a nebulized sympathomimetic
bronchodilator or take a formulation containing acetylcysteine
(10%) and isoproterenol (0.05%) before taking the mucolytic.
Proteolytic enzymes (eg, pancreatic dornase) are useful only
when grossly purulent sputum is a major problem. They seem
to offer no advantage over mucolytics. Local irritation of the
buccal and pharyngeal mucosa and allergic reactions commonly
follow repeated doses. Dornase alfa, the new highly purified
recombinant human deoxyribonuclease I (rhDNase), seems
likely to become important in the treatment of cystic fibrosis,
although its place has not been defined.
Antihistamines have little or no use in treating cough. Their
drying action on the respiratory mucosa may be helpful in the
early congestive phase of acute coryza but may be deleterious,
especially to patients with a nonproductive cough resulting from
retained viscous airway secretions. They may also be beneficial
in chronic cough due to postnasal drip associated with allergic
sinusitis.
Bronchodilators (eg, ephedrine and theophylline) may be
useful if cough is complicated by bronchospasm. Atropine
is undesirable because it thickens bronchial secretions. The
anticholinergic drug ipratropium bromide can often ameliorate
an irritating type of cough and does not adversely affect mucus
secretions. Inhaled corticosteroids have become a mainstay in
the treatment of cough in asthma.
Management of Cough: Focus on combination of antitussive
preparations
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
Table 1: Possible mechanisms of cough suppression by firstgeneration antihistamines29
Mechanism
Description
Peripheral
Direct
Prevent the production of cough which is an effect of
histamine receptors on sensory afferents
Indirect
Nasal mucus secretion induced by histamine receptors
promotes cough and that induced by cholinergic
mechanisms produce cough by a mechanical action on
pharyngeal or laryngeal mechanoreceptors that elicit
cough
Central
Direct
Block the histamine H1 receptors in the central nervous
system which may directly promote the production of
cough.
May bind to nonhistaminergic receptors in the central
nervous system that control cough excitability.
Indirect
Block the histamine H1 receptors in the central nervous
system and this decrease the nasal mucus secretion.
May bind to nonhistaminergic receptors that regulate
mucus secretion.
Induce sedation that could result in a reduction in cough
excitability.
Single Agents may not be effective, Combination may be
essential for better control:
Many antitussive preparations are available are combinations
of codeine or dextromethorphan with antihistamines,
decongestants, expectorants, and/or antipyretics. 1 In India,
several such cough mixtures containing an anti-histaminic and
an opioid derivative claiming increased efficacy are available.
However, whatever knowledge is available on these cough
mixtures is mostly based on the experience of the practicing
clinicians and there is a paucity of published clinical trials.
Antitussives or more often, referred to as cough suppressants
are used for effective symptomatic relief of dry or non-productive
cough. First generation anti-histamines like chlorpheniramine,
centrally acting opioid derivatives like codeine and anticholinergic drugs are often used alone or in combination.16
Codeine
Amongst the many anti-tussive agents available for the
management of cough, Codeine, is one of the most frequently
used centrally acting cough suppressant and has been widely
regarded as the ‘gold standard’ cough suppressant drug since
a long time. This perception was based on its efficacy in animal
models17-20 as well as several older placebo-controlled clinical
trials on patients with various airway disorders such as chronic
bronchitis or chronic obstructive pulmonary disease.21,22
Codeine and other centrally acting cough suppressants like
pholcodeine and dextromethorphan act directly on the cough
centre in the brain and reduce the discharge of nerve impulses
to the muscles that cause coughing.23 These drugs can cause
sedation and constipation in some patients
Besides their anti-tussive action, opioids like codeine also
exhibit proven analgesic action. In fact, these agents cause cough
suppression at lower doses than that required for analgesia. A
10- or 20-mg oral dose of codeine, produces a demonstrable
antitussive effect, although ineffective for analgesia and higher
doses produce even more cough suppression.24
Of the centrally acting antitussives, codeine and
dextromethorphan are the most commonly used. In adults,
both these drugs have been shown to inhibit fictive cough in
animal models, and suppress artificially induced, disease-related
11
and chronic cough in humans.25,26 There is a linear relationship
between a codeine dosage of 7.5 to 60 mg/d and a decrease in
the frequency of chronic cough.27 Codeine (60 mg) significantly
reduced the cough frequency compared to placebo (p<0.001),
and also produced a greater reduction in cough intensity than
placebo and lower doses of codeine (20 and 30 mg; p<0.001).28
Eddy et al. opine that a multimodal action of codeine, including
antitussive, analgesic and sedative effects is an advantage in
special cases: an analgesic effect could be desirable, when cough
is associated with pain and a sedative action could help if the
patient is apprehensive or if the cough was initiated or enhanced
by central stimuli (nervous cough).29 Codeine has also shown to
be effective in the management of chronic cough caused due to
various etiologies.30
Importantly, the danger of development of dependence
to Codeine at doses used to suppress cough is very small.29
Furthermore, addiction is uncommon in individuals with no
existing vulnerability to addiction.32 Compared to animals,
codeine is less toxic to humans, possibly because it produces
less respiratory depression. Dependence is far less frequent in
humans, compared to that with morphine and also abstinence
syndrome is less intense.33
Chlorpheniramine Maleate (The importance / role of First
generation Anti-histamines in management of cough)
First generation anti-histamines like chlorpheniramine reduce
the cholinergic transmission of nerve impulses in the cough
reflex, hence, reduce the frequency of cough and dry up the
secretions, making them ideal for treating cough concomitant
with rhinorrhea.34 Additionally, sedation, which otherwise is
considered a side-effect of these drugs can be valuable in this
situation, particularly if the cough is disturbing the sleep.25
Table 1 describes the possible mechanisms by which these
antihistamines suppress cough.35
As discussed previously, since cough is an entirely vagusmediated phenomenon 36, the difference in the antitussive effects
of the first- and second-generation antihistamines is explained
by their relative anticholinergic activity. Although both these
groups of drugs are competitive antagonists to histamine
at the H1-receptor site, the first-generation antihistamines
also demonstrate competitive antagonism of acetylcholine at
neuronal and neuromuscular muscarinic receptors. Additionally,
first-generation antihistamines, cross the blood–brain barrier
due to their lipophilicity, whereas the relatively lipophobic
second-generation antihistamines do not.37 This concept is
further supported by recent animal data demonstrating that the
antitussive actions of antihistamines are not directly related to
H1-receptor blockade.38 Of interest is that this study showed an
independence of the antitussive actions of antihistamines and
their sedative effects.
There have been very few clinical trials examining the
antitussive effects of antihistamines. In healthy volunteers, the
first-generation antihistamine, diphenhydramine, inhibited
cough induced by citric acid.39 In contrast to this, the nonsedating, second-generation antihistamine, terfenadine, was
ineffective in suppressing capsaicin-induced cough.40 Another
second-generation agent, loratadine, was also ineffective in
healthy volunteers; however, it did suppress cough induced by
ultrasonically nebulized distilled water in patients with nasal
disease and unexplained chronic cough. 41
Several studies have shown that rhinitis/postnasal drip
syndrome (PNDS) is one of the most common causes of chronic
cough.42-44 First generation antihistamines are known to be
12
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
Table 2 : Patients who achieved the clinical endpoint (improvement of >75%) for various parameters during the study period
CS1 (n=132)
CS2 (N=131)
CS3 (N=104)
Day3
Day7
Day3
Day7
Day3
Day7
36 (27.48)
102 (77.86)
37 (33.94)
109 (100)
Cough Frequency
44 (33.33)
111(84.09)*
85 (64.89)
124 (94.6)
69 (63.3)
105 (96.3)
Frequency of Night Awakenings
85 (64.39)
117 (88.64)$
Playing activity score
64 (48.48)
101 (76.52)
68 (47.71)
96 (75.23)
52 (46.85)
82 (73.87)
Appetite Score
59 (44.71)
97 (73.48)
56 (40.37)
96 (71.56)
44 (39.64)
78 (70.27)
Behavior Score
69 (52.27)
105 (79.5)
73 (55.73)
100 (76.34)
59 (53.15)
91 (81.98)
Global Assessment of Wellbeing
56 (42.42)
70 (53.03)
46 (35.11)
57 (43.51)
38 (34.86)
63 (57.8)
#
Figures in parentheses indicate the percentages; *p<0.05, comparison versus CS-3 for day 7; $p<0.05, comparison versus CS-2 and CS-3 for day 7;
p>0.05, for all other individual comparisons of CS-1 with CS-2/Cs-3 for respective days.
Parameter#
effective in the treatment of cough in patients with nasal disease.45
These drugs inhibit the release of histamine and leukotrienes
produced by eosinophils and mast cells. Chronic cough in
individuals with no asthma has been shown to be associated
with airway inflammation by the presence of eosinophils and
metachromatic cells and epithelial damage.46 First generation
antihistamines are therefore, especially helpful in non-asthmatic
cough.
Recent guidelines published by the American College
of Chest Physicians (ACCP) recommend the use of a firstgeneration antihistamine in combination with a decongestant
for the treatment of chronic cough due to PNDS, considering
the observed ineffectiveness of the newer second-generation,
relatively non-sedating antihistamines in acute cough associated
with the common cold.47
Combination of Codeine and Chlorpheniramine
An Indian study compared pholcodiene plus promethazine
(CS-1) with dextromethorphan plus chlorpheniramine (CS-2) and
codeine plus chlorpheniramine (CS-3 ) in pediatric population 48.
The details of the number and percentage of patients achieving
clinical end-points for the symptoms are summarized in Table
2. A greater percentage of patients in the CS-3 group achieved
the clinical endpoint for cough episodes by day 7 compared to
those in the CS-1 group.
All three cough preparations were comparable for night
awakenings (table-2). The authors concluded from this study
that all the three combinations studied were equi-efficacious in
providing relief of signs and symptoms of cough.
Summary and Conclusions
Cough is one of the most common symptoms encountered in
clinical practice. There are many over-the-counter combination
syrups available for the management of cough. These are the
mainstay of therapy in case of nonspecific cough and may act
as adjuvant in addition to treatment of the specific cause, in case
of cough associated with other conditions.
Opioids and older or first generation antihistamines have
been used in the management of cough since a long time, and
have shown some benefit. Codeine and chlorpheniramine
maleate are archetypal drugs belonging to these two classes
respectively. Their combination may be useful as an antitussive
in the management of nonspecific cough. However, there is a
major paucity of published literature on this combination and
therefore, a large-scale randomized trial on the efficacy and safety
of this combination is warranted.
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