Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00045
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: October 2006
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Bibliographic ID: UF00087345
Volume ID: VID00045
Source Institution: University of Florida
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James Terrell, Pharm.D. Candidate

Cough is the most common reason patients
seek medical attention in the United States.1 Since
coughing may be provoked by a number of condi-
tions such as allergies, the common cold, pneumonia,
heart failure, or pulmonary embolism, proper diagno-
sis and treatment can be perplexing. Complicating
the matter, many of the drugs available for cough,
including the "gold standard" codeine, have failed to
show efficacy in recent trials. This review will sum-
marize the current data available for commonly used
cough remedies and assess their appropriateness for
treating acute cough.
Acute cough refers to any cough, regardless
of etiology, that has persisted for less than 3 weeks.
Chronic cough is defined as cough that lasts longer
than 3 weeks. Current treatment guidelines for
chronic cough differ from those of acute cough and
will not be discussed in great detail.1
Before treating an acute cough, underlying
chronic conditions, such as asthma and GERD,
should be ruled out. Also, it is important to ensure
that the patient does not have a upper respiratory
tract infection, which may warrant antimicrobial
therapy. This is especially true due to the recent in-
crease in adult pertussis (whooping cough) through-
out the U.S. Finally, the clinician should differenti-
ate productive from non-productive cough. Cough
suppressants should be avoided in the former.2

In 2005, a two-year prospective study evalu-
ating 136 children (<18 years old, mean 2.7) with
cough, defined as lasting 1-6 weeks, revealed that in
67% of the cases, an infectious agent was present.
The results of this study (Table 1), indicate that 58%
of cough-associated respiratory infections are caused
by viruses.3 However, the small sample size limits
the reliability of these findings. In 2001, the World
Health Organization (WHO) reported that rhinovirus
is responsible for over 50% of colds in adults and
that cough symptoms abate in 7-9 days.4
Data on frequency and prevalence of cough is
difficult to interpret since many cases go untreated
and/or are not reported. In 1985, it was estimated
that over 2 billion dollars were spent on over the
counter (OTC) cough and cold remedies.4

Physiology of cough
Coughing is a natural defense mechanism
that can be mechanically (increased mucus or bron-
choconstriction) or chemically induced (capsaicin,
histamine, bradykinin, etc). Activation of either of
these pathways sends signals to the nucleus tractus
solitarius (NTS) which activates the cough reflex via
efferent nerve fibers. The cortex can inhibit the NTS
allowing some voluntary control. A local pulmonary
rI.. ..il

PharmaNote Volume 22, Issue 1 October 2006




INDEX FOR VOLUME 21 (OCT. 2005-SEP. 2006)

Volume 22, Issue 1 October 2006


Table 1. Common etiologies of acute cough*3
Percentage (%)
Rhinovirus 32
B. pertussis 17
RSV 11
Rhinovirus + B. pertussis 10
* 136 screened specimens. One or more pathogens were found in 91 (67%)

axon reflex can produce a cough when fibers inner-
vating the lung release neurokinins, activating adja-
cent cough receptors.5

In the United States there are over 1000 prod-
ucts marketed to treat cough.6 The FDA has ap-
proved the following 6 agents for treatment of cough:
dextromethorphan (DM), hydrocodone, codeine, di-
hydrocodeine, hydromorphone, and carbetapentane.
Other drugs used to treat cough include histamine 1
(H1) receptor antagonists and benzonatate.

DM is hypothesized to inhibit cough by bind-
ing to sigma-1 type receptors in the NTS and periph-
ery. Some have suggested that it may also work on
NMDA receptors.5 Both mechanisms are theorized
to suppress the cough reflex without a narcotic effect
seen with opioid receptor stimulation. Dosing for
DM is depicted in Table 2. Important pharmacoki-
netic parameters of DM are listed in Table 3.

Opioids cause direct cough inhibition by
binding to mu receptors in the medulla. At concen-
trations needed to suppress cough, opioids can lead
to dependency, nausea, and respiratory depression.
Of the available opioids, codeine has the lowest inci-
dence of adverse effects and is considered the 'gold
standard' for cough suppression.
Codeine is usually given orally in a suspen-
sion with an onset of action of less than an hour. The
recommended doses are listed in Table 2. Relevant
pharmacokinetic parameters for codeine are provided
in Table 3.
Dose adjustments are recommended for pa-
tients with hepatic impairment or a creatinine clear-
ance less than 50 ml/min. Side effects include
drowsiness, constipation, and itching.

DM and codeine
Centrally acting antitussives, such as codeine
and dextromethorphan, are proven to be an effective
cough suppressant in animal models.7 It is widely
accepted that codeine and DM are effective cough
suppressants. However, recent data in humans have
shown codeine and DM to be ineffective at suppress-
ing cough.8-10 These newer studies tend to have lar-
ger populations and selectively recruited patients
with upper airway disease, the major cause of acute
It's been hypothesized that cough originating
in the larynx (i.e. upper airway pathology) use neural
pathways that are less sensitive to codeine and DM,
whereas cough originating in the tracheobronchial
tree responds well to these drugs.' Furthermore,
cough associated with upper airway disease are actu-
ally "expiration reflexes". Expiration reflexes are
specific to the larynx and are not true coughs in that
they are not preceded by a large inhalation. These
two hypotheses, which have been demonstrated in
animal models, tend to explain why older human tri-
als involving patients with lower airway disease con-
cluded that codeine and DM were effective cough
Human studies often utilize a nebulized
chemical, like capsaicin or citric acid, to invoke a
cough. Antitussive efficacy is then determined by
administering the drug, rechallenging with the cough
stimulant, and measuring the change in cough fre-
quency and/or intensity. Repeated challenges to cit-
ric acid produces less reaction with each exposure,
suggesting that the body adapts to it.1 This adapta-
tion may cause a false change from baseline in cough
frequency and intensity, leading investigators to con-
clude that the intervention is efficacious.
Manap et a110 administered 30 mg of DM, 60
mg of DM, and placebo to their study group. Citric
acid was given every minute for 5 minutes to gener-
ate a cough. This was performed every hour for 12
hours. Results indicated 60 mg of DM significantly
reduced cough response compared to placebo and 30
mg DM was no different than placebo. This experi-
ment was powered to detect a 10% change in cough
frequency. It is unclear whether a 10% change in
cough frequency translates into clinically significant
improvement. It has been reported that a 20%
change is the minimal threshold for clinical improve-
Lee et al9 studied 43 adults aged 18-60 (mean
22.9) with recent URTI (<3 weeks) to detect a 20%

PharmaNote Volume 22, Issue I October 2006

Volume 22, Issue I October 2006


Table 2. Recommended dosing scheme for centrally-acting antitussives


1-3 months old
3-6 months old
7-12 months old
2-6 years old
6-12 years old

> 12 years old

0.5-1.0 mg every 6-8 hours
1-2 mg every 6-8 hours
2-4 mg every 6-8 hours
2.5-7.5 mg every 4-8 hours (syrup)
5-10 mg every 4 hours or
15 mg every 6-8 hours

10-20 mg every 4 hours or
30 mg every 6-8 hours or
60 mg every 12 hours

30 mg
60 mg

120 mg

< 2 years old Not recommended NA
2-6 years old 2-5 mg every 4-6 hours as needed 30 mg
6-12 years old 5-10 mg every 4-6 hours as needed 60 mg

> 12 years old 10-20 mg every 4-6 hours as needed 120 mg

* Maximum of 1.5mg/kg/day; NA = information not available

change from baseline. Patients were given either 30 way disease, the centrally acting antitussives codeine
mg DM or placebo. They found no significant dif- and dextromethorphan provide very little in terms of
ference between the effects of placebo or DM on ei- cough suppression and that any benefit is due to in-
ther 1) cough frequency, expressed as number of creased reflex inhibition imparted by cortical control.
coughs per 10 minutes 2) cough intensity, measured Contrary to the findings in these trials, a re-
by decibel force, or 3) subjective assessment. A ma- cent meta-analysis of cough regimens suggested that
jor advantage of this study is that disease-induced DM is beneficial in acute cough, since two of the
cough was chosen over chemically stimulated cough. three studies indicated significant findings.1 These
Unfortunately, the study was underpowered to detect conflicting results underscore the need for newer,
a 20% difference between groups due to attrition, sufficiently powered, randomized control trials that
Lee's study was designed very similar to an utilize cohorts accurately representing the patient
earlier experiment that challenged the usefulness of population.
codiene in patients with a recent URTI.8 Patients
were given 50 mg of codeine or placebo and their H1 antagonists
cough was assessed. No difference was found be- H1 antagonists like diphenhydramine and
tween the two groups using 1) frequency 2) intensity chlorpheniramine exert their effects peripherally by
or 3) subjective assessment. preventing mast-cell degranulation and decreasing
Trials that found no difference between anti- vascular permeability and bronchoconstriction. By
tussives and placebo did, however, detect a down- decreasing the vascular permeability, less mucus es-
ward trend in cough symptoms suggesting a placebo capes into the airway; thus, decreasing the frequency
effect. The placebo effect can be explained by the of mechanically induced cough. This "drying effect"
patient's cortical control over the cough reflex. A is also beneficial in patients with post-nasal drip syn-
study by Hutchings et al9 showed that patients asked drome, the leading cause of chronic cough. These
to suppress their cough reflex, whether chemically drugs also exhibit anticholinergic and sedative side
induced or disease related (URTI), can almost com- effects.
pletely eliminate it. In acute cough due to upper air- Currently, there are little available data sup-

PharmaNote Volume 22, Issue 1 October 2006


Maximum daily dose

Table 3. Pharmacokinetic parameters for centrally-acting antitussives

Dextromethorphan Codeine
Onset of action 15-30 minutes 30-60 minutes

Duration of action < 6 hours <6 hours

Metabolism Hepatic to dextrorphan* Hepatic to morphine*

Elimination Urine some unchanged Urine 3-16% unchanged

Renal adjustments None CrCl 10-50 ml/min: 75% of normal dose
CrCl <10 ml/min: 50% of normal dose
* Active metabolites

porting the use of an antihistamine as monotherapy
to treat acute cough. The current guidelines suggest
using a first generation antihistamine combined with
a decongestant for cough due to the common cold.13
Studies have confirmed that only a combination with
a decongestant, like pseudoephedrine, reduces cough
frequency.14 Non-sedating antihistamines have
failed to show a similar benefit. 15

Benzonatate (Tessalon Perles) is a chemical
analog of tetracaine, a local anesthetic. Benzonatate
exerts its action by suppressing nerve firing of
stretch receptors in the lung endothelium to the NTS.
Its onset of action is less than 30 minutes and dura-
tion of action may be as long as 8 hours.
The side-effect profile is more extensive than
the other available options and includes: sedation,
headache, nausea, vomiting, chest numbness, ocular
irritation, and nasal congestion. Benzonatate is not
FDA approved for cough and the only evidence of its
efficacy comes from case reports on opioid-resistant
patients with terminal cancer.16

At this point, there is little data to support
treating acute cough. Patients suspected of having
the common cold could be given an antihistamine/
decongestant combination. Patients with a non-
productive acute cough of unconfirmed etiology may
be offered dextromethorphan or codeine with the un-
derstanding that any benefit may be marginal. The
side effect profile of codeine may make it less desir-
able. In addition, many states have enacted laws re-
quiring prescriptions for codeine-containing prod-
ucts, making it more difficult for patients to obtain

them. In most cases, dextromethorphan-containing
products are a safe option to recommend for these
patients. For non-productive cough not due to upper
airway infections, codeine and dextromethorphan
remain first line agents and should be offered.

1. Diagnosis and management of cough: ACCP evi-
dence based clinical practice guidelines. Chest
2006.Available online: http://
www.chestjournal.org/content/vol 129/1_suppl/.
Accessed March 7, 2006.
2. de Jongste JC, Shields MD. Cough 2: Chronic
cough in children. Thorax 2003;58:998-1003.
3. Versteegh FG, et al. Community-acquired patho-
gens associated with prolonged coughing in chil-
dren: a prospective cohort study. Clinical Micro-
biology and Infection 2005;11:801-7.
4. WHO. Cough and cold remedies for the treat-
ment of acute respiratory infections in young
children. Geneva, World Health Organization
5. Reynolds SM, Mackenzie AJ, Spina D and Page
CP. The pharmacology of cough. TRENDS in
Pharmacological Science 2004;25:569-576.
6. Clinical Pharmacology. Available online. http://
cpip.gsm.com. Accessed March 18, 2006.
7. Bolser, Donald C. Current and future centrally
acting antitussives. Resp Phys & Neurobiology
2006. Available online: www.sciencedirect.com.
Accessed March 15, 2006.
8. Freestone C, Eccles R. Assessment of the anti-
tussive efficacy of codeine in cough associated
with common cold. J Pharm Pharmacol 1997;
9. Lee PCL, Jawad MSM, Eccles R. Antitussive

PharmaNote Volume 22, Issue 1 October 2006

Volume 22, Issue I October 2006


Efficacy of Dextromethorphan in Cough Associ-
ated with Acute Upper Respiratory Tract Infec-
tion. J Pharm Pharmacol 2000;52:1137-42.
10. Manap RA, Wright CE, Gregory A, et al. The
antitussive effect of dextromethorphan in relation
to CYP2D6 activity. Br J Clin Pharmacol
11. Rostami-Hodjegan A, Abdul-Manap R, Wright
CE, et al. The placebo response to citric acid-
induced cough: pharmacodynamics and gender
differences. Pulmonary Pharmacology & Thera-
peutics 2001;14:315-9.
12. Hutchings HA, Eccles R, Smith AP, Jawad M.
Voluntary cough suppression as an indication of
symptom severity in upper respiratory tract infec-
tions. Eur Respir J 1993;6:1449-54.
13. Pratter MR, Brightling, CE, Boulet LP, Irwin RS.
An empiric integrative approach to the manage-
ment of cough: ACCP evidence based clinical
practice guidelines. Chest 2006; 29:222S-231S.
14. Arroll B. Non-antibiotic treatments for upper-
respiratory tract infections (common cold). Resp
Med 2005;99:1477-84.
15. Dicpinigaitis PV, Gayle YE. Effect of the sec-
ond-generation antihistamine, fexofenadine, on
cough reflex sensitivity and pulmonary function.
Br J Clin Pharmacol 2003;56:501-4
16. Doona M, Walsh D. Benzonatate for opioid-
resistant cough in advanced cancer. Palliative
Medicine 1997;12:55-8.

Index for Volume 21 (Oct 2005 Sep 2006)

Topic Issue (Page)


Community-associated methicillin-
resistant staphylococcus
aureus (MRSA)

Herbal supplements in hyperlipidemia
Insulin detemir

Aug 2006 (04)
Sep 2006 (06)

Jan 2006 (01)
Sep 2006 (01)
Apr 2006 (01)
Feb 2006 (01)

Jan 2006 (01)
Mar 2006 (04)
May 2006 (01)
Mar 2006 (01)

Levemir Mar 2006 (01)
Linezolid vs. Vancomycin: Treatment Jul 2006 (01)
of skin and soft tissue infections
and hospital-acquired pneumonia
caused by methicillin-resistant
S. aureus (MRSA)
Micafungin Nov 2005 (04)
MycamineTM Nov 2005 (04)

Phosphodiesterase-5 inhibitors for
erectile dysfunction

Statin in ACS

Aug 2006 (01)

Apr 2006 (02)
Dec 2005 (01)
Oct 2005 (02)
Jun 2006 (01)
Jun 2006 (01)
Sep 2006 (06)
Jan 2006 (06)
Aug 2006 (04)
Jan 2006 (05)
Oct 2005 (01)

Nov 2005 (01)
Dec 2005 (01)
Jul 2006 (01)
Sep 2006 (01)


Phara~oe Vlum 22 Isse 1Octber200

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor

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Volume 22, Issue I October 2006

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