Review
Monthly Focus: Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis
1. Background
2. The normal cough reflex
3. The enhanced cough reflex
4. Specific antitussive treatments
5. Nonspecific antitussives
6. Potential novel classes of
nonspecific antitussives
7. Expert opinion
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10.1517/13543784.14.1.19 © 2005 Ashley Publications Ltd ISSN 1354-3784
Drugs to suppress cough
K F Chung
National Heart & Lung Institute, Imperial College & Royal Brompton Hospital, London, SW3, UK
Cough is an important defensive reflex of the airway and also a common
symptom of respiratory disease. Cough after common respiratory virus
infection is transient but is more persistent when associated with conditions
such as asthma, rhinosinusitis, gastro-oesophageal reflux, chronic obstruc-
tive pulmonary disease and lung cancer. Persistent cough may be due to
peripheral and/or central sensitisation of cough reflexes initiated by cough
receptors, rapidly adapting receptors or nociceptors. Treatment directed at
associated conditions such as asthma (with anti-inflammatories) and gastro-
oesophageal reflux (with proton-pump inhibitors) improve cough. There
remains a need to use drugs that suppress the neural activity of cough
(termed nonspecific), as treatments directed at the clinical cause(s) of the
underlying cough (termed specific) may not be effective. The most effective
indirect antitussives are opioids such as morphine, codeine or pholcodeine,
but they produce side effects such as drowsiness, nausea, constipation and
physical dependence. Opioids such as κ- and δ-receptor agonists, non-opio-
ids such as nociceptin, neurokinin and bradykinin receptor antagonists, can-
nabinoids, vanilloid receptor-1 antagonists, blockers of Na+-dependent
channels, and large conductance Ca2+-dependent K+-channel activators of
afferent nerves may represent novel antitussives.
Keywords: antitussive, cough, cough receptor, opioids, cough reflex
Expert Opin. Investig. Drugs (2005) 14(1):19-27
1. Background
Cough is a protective reflex, an essential part of the defence of the respiratory tract,
but can also become a prominent symptom of many respiratory diseases. Persist-
ence of cough needs to be investigated in order to exclude serious diseases. Cough
caused by common respiratory viruses is usually transient, lasting for a few days,
but for which over-the-counter cough mixtures are commonly used. Chronic
cough is experienced by ≤ 16% of the population, partly accounted for by chronic
smoking [1]. Cough is one of the most common complaints that general practition-
ers or respiratory specialists are confronted with. Many pulmonary and non-pul-
monary conditions can cause cough, and the physician must go through a
diagnostic work-up to find the cause of the cough. After exclusion of serious ill-
nesses such as cancer, conditions such as asthma, chronic obstructive pulmonary
disease (COPD), bronchiectasis, gastro-oesophageal reflux or rhinosinusitis may be
found and the patient managed accordingly with treatment of the specific cause(s)
with specific antitussives [2]. Sometimes, a cause may not be found, or treating the
associated cause may not bring the cough under control. Persistent cough, although
not life threatening, can cause general debility, weakness and social embarrassment,
all of which contribute to a deterioration in quality of life [3]. Nonspecific antitus-
sives that solely inhibit cough caused by any disease can be used but those that are
currently available are not very efficacious.
19
Drugs to suppress cough
2. The normal cough reflex
Two types of mechanically sensitive airway afferent nerves have
been defined, namely rapidly adapting or slowly adapting
receptors (RAR and SAR). Chemically sensitive C-fibres (noci-
ceptors) also respond to chemical irritants such as capsaicin.
RARs and nociceptors have been implicated in the mediation
of cough [4-6] and are predominately present in the larynx, tra-
chea and carina. SARs have a permissive effect on cough. Pep-
tide neurotransmitters are often associated with capsaicin-
sensitive afferent C-fibres in the airways and stimulation of
C-fibres initiates local axonal reflexes mediated by the release
of neuropeptides such as neurokinin A and substance P, which
may also induce cough indirectly by causing oedema, mucus
secretion and airway smooth muscle contraction.
A cough receptor that responds to punctuate mechanical
and acid stimuli with cough and is distinct from RARs and
nociceptors has been characterised in the guinea-pig [7]. It has
been postulated that this cough receptor may mediate the pri-
mary defensive cough response, whereas cough evoked by
chemical irritation or by muscle constriction may involve
RARs and nociceptors through their subsequent interaction
with sensory information from the primary cough receptor in
the CNS.
C-fibres, RARs or other cough receptors project to differ-
ent subnuclei in the nucleus tractus solitarius in the brain
stem through vagal primary afferent nerves, and these net-
works of neurons mediating cough and breathing constitute
the cough center. Second-order neurons project to other
nuclei associated with the regulation of breathing. Integra-
tion of the various inputs occur centrally. SAR afferent input
may have a facilitatory effect on the induction of cough [8].
Interaction of RAR with C-fibre activity in the brain stem
may be needed to initiate cough, as supported by the overlap
of C-fibre and RAR termination sites in the nucleus tractus
solitarius [9]. Centrally acting antitussives have effects at the
level of the nucleus tractus solitarius by modifying neuronal
activity and neurotransmitter actions but may also act at
other sites. Other parts of the brain may interact with the
cough nuclei and cortical control is important as cough can
be suppressed by volitional control [10].
The efferent pathway for cough includes actions on laryn-
geal and skeletal respiratory muscles and on airway smooth
muscle and mucus glands in the airways. These are impor-
tant in producing the rapid changes in airflow and cough
sound production, together with bronchoconstriction and
mucus production.
3. The enhanced cough reflex
The cough response is enhanced in patients with persistent
cough, as demonstrated by the increased tussive response of
these patients to inhaled irritants such as capsaicin [11]. This
process of sensitisation may invoke both peripheral and/or
central mechanisms (Figure 1). Central sensitisation may
20 Expert Opin. Investig. Drugs (2005) 14(1)
occur by integration of signals from various sensory nerve
subtypes in the CNS to initiate exaggerated reflexes and sen-
sation [12]. Substance P may represent an important central
mechanism for sensitisation of the cough reflex and its per-
sistence. In a model of allergic inflammation, neuroplastic
changes in the response of vagal primary afferent neurons
are present, such that Aδ mechanosensitive RARs release
substance P, when under normal conditions they do not [13].
Substance P in the nucleus tractus solitarius can increase
bronchopulmonary C-fibre reflex activity [14] and sensitise
other respiratory and airway reflexes [15]. As nociceptor acti-
vation alone is not able to activate brain stem neurons, there
is a neurokinin-dependent reduction in their threshold for
subsequent activation by cough receptors.
Peripheral mechanisms of heightened cough reflex may
also be possible through the release of inflammatory media-
tors such as prostaglandins or bradykinin that could
enhance the response and interactions of the cough receptor
[16,17]. Antitussive drugs may act at peripheral, central or at
both levels.
4. Specific antitussive treatments
In conditions such as asthma, cough-variant asthma or eosi-
nophilic bronchitis, inhaled corticosteroid therapy is often
used with success to control cough [18,19]. Leukotriene receptor
antagonists can also be effective in inhibiting asthma-associ-
ated cough [20]. Sometimes, cough associated with asthma may
not respond to appropriate anti-asthma treatments. Topical
nasal corticosteroids, sometimes with a nasal decongestant,
antibiotics, antihistamines or nasal ipratropium bromide are
used for treating rhinosinusitis, but there have been no con-
trolled studies of these treatments. Older sedating antihista-
mine preparations with anticholinergic properties are thought
to be more effective than the current generation of antihista-
mines [21,22]. Proton pump inhibitors or histamine H2 receptor
antagonists can be effective for gastro-oesophageal reflux,
although double-blind controlled trials have shown small
effects [23,24]. It is possible that other components of the reflux-
ate may be important in the cough as fundoplication repair to
correct reflux has been reported to control cough in patients
initially not responding to treatment with proton-pump inhib-
itors [25]. Cough may often not respond to treatment of the
cause, the associated disease may not be treatable (e.g., lung
cancer) or there is no obvious cause of the cough. Under these
circumstances treatment aimed directly at suppressing cough
(nonspecific antitussives) should be considered.
There is some uncertainty as to whether cough in condi-
tions usually associated with the production of mucus such
as COPD or bronchiectasis should be suppressed as such
suppression may lead to mucus accumulation with an
increased risk of lung infections. Expectorants and muco-
lytic medications such as N-acetylcysteine, carbocisteine,
bromhexine and methylcysteine may improve clearing of
secretions by changing their composition and rheologic
 Chung

PERIPHERAL CENTRAL

Baclofen? Volitional control

Anticholinergic? NK antagonists?
Acid pH inhibitors Local anaesthetic Opioids
(e.g., PPIs) Expectorant CORTEX
mucolytic? Cough receptor
CNS
Mucus
Periciliary fluid nTS

ve
Epithelium Phrenic nerves

er
sn
Airway Blood vessel RAR
Goblet cell Spinal motor nerves

gu
C-fibers Recurrent laryngeal nerves
mucosa

Va
Local axon reflex Respiratory muscles
Oedema Laryngeal muscles
Mucus
Eosinophil Monocyte
Mast cell Submucosal
gland
Neutrophil COUGH

Histamine, prostaglandins, LTD4

Anti-inflammatory:
corticosteroids
leukotriene antagonists Airway smooth muscle
cyclooxygenase inhibitors

Bronchodilator: β2-agonist
Anti-cholinergics

Figure 1. Pathways of cough reflex and sites of action of antitussives, which may act at the level of airway mucosa
(peripheral) or centrally (central) or both.
CNS: Central nervous system; LTD4: Leukotriene D4; NK: Neurokinin; nTS: Nucleus tractus solitarius; PPI: Proton pump inhibitor; RAR: Rapidly adapting receptor.

properties, but these have not been effective in controlling
cough. Direct mucus inhibitors may be helpful. Nonspecific
antitussives may also be needed as there is an enhanced
cough reflex in COPD [26]. For a summary of treatments
and their effects see Figure 1 and Table 1.
5. Nonspecific antitussives
5.1 Narcotic and non-narcotic antitussives
Opioids including morphine, diamorphine and codeine are
effective antitussive agents but at effective doses cause physical
dependence, respiratory depression and gastrointestinal colic.
Codeine is the methylether of morphine and has long been the
standard centrally acting antitussive drug against which the
pharmacological and clinical effects of newer drugs have been
measured. Opioids may not only act at the level of the cough
network in the brain stem but may also inhibit peripheral activa-
tion of cough receptors and on other sites in the CNS. Codeine
is probably the most commonly prescribed antitussive. Codeine
possesses antitussive activity against pathological cough [27,28]
and against induced cough in normal volunteers [29], but appears
to be ineffective against acute cough of the common cold [30].
Morphine and diamorphine should only be used for severe
distressing cough such as that which occurs in terminal lung
cancer. They cause sedation, respiratory depression and consti-
pation. Non-narcotic antitussives include dextromethorphan,
which is a synthetic derivative of morphine with no analgesic
or sedative properties but is as effective as codeine in suppress-
ing acute and chronic cough when given orally [27,31]. One
study shows it to be superior over codeine [31]. A small antitus-
sive efficacy of a single 30-mg dose has been demonstrated
against cough associated with upper respiratory tract infections
[32]. Other non-narcotic preparations include noscapine and
levopropoxyphene, although their antitussive efficacy has not
been proven.
6. Potentialnovel classes of nonspecific
antitussives
6.1 Opioid receptor agonists
Opioid receptor agonists are classified by their activities at the
opioid receptors-µ, -κ and -δ (Box 1). The current com-
pounds, morphine and codeine, are mostly µ-receptor ago-
nists and may possess central as well as peripheral actions.
BW-443C, a µ-opioid receptor agonist and a pentapeptide
polar agonist, by aerosol acts on µ-receptors on sensory recep-
tors in the lung and has peripheral antitussive activity in the
lungs [33]. This, however, has not been demonstrated in
humans [34].
Opioids may also act on κ-opioid receptors for their anti-
tussive effects [35]. A δ-selective receptor agonist (SB-221122)
was shown to inhibit citric acid-induced cough in the

Expert Opin. Investig. Drugs (2005) 14(1) 21

Drugs to suppress cough

Table 1. Treatments for cough. Box 1. Potential new antitussives.

Treating the specific underlying cause(s)
• Opioids, µ-, κ- and δ-receptor agonists
Asthma, cough-variant α-Adrenergic agonist
• Nociceptin (orphanin)
asthma, bronchodilators and inhaled
• Neurokinin receptor antagonists (NK1, NK2 and NK3)
corticosteroids; leukotriene
inhibitors • Bradykinin B2 receptor antagonists
Eosinophilic bronchitis Inhaled corticosteroids • Transient receptor potential vanilloid receptor-1
antagonists
Allergic rhinitis and postnasal Topical nasal steroids and
• Cannabinoids
drip antihistamines
Topical nasal anticholinergics • GABAB
• Large conductance Ca2+ -dependent K+ channel
Gastro-oesophageal reflux Histamine H2 antagonist or • ATP-dependent K+ channels
proton pump inhibitor
• 5-Hydroxytryptamine subtype1A receptor
Therapy with angiotensin- Discontinue and replace with • Frusemide and other diuretics
converting enzyme inhibitor alternative drug such as • Local anaesthetics (voltage-dependent sodium blockers)
angiotensin II receptor
antagonist
Chronic bronchitis/COPD Smoking cessation
Treatments for COPD Capsaicin-induced bronchoconstriction is attenuated by
Bronchiectasis Postural drainage. Treat nociceptin [43], an action possibly due to the inhibition of
infective exacerbation and tachykinin release from sensory C-fibres. Nociceptin admin-
airflow obstruction istered intravenously or via the intracerebroventricular route
Symptomatic treatment (only after consideration of cause suppresses capsaicin- and mechanically induced cough [44,45],
of cough) effects blocked by the NOP1 antagonist J-113397 but not
Acute cough likely to be Simple linctus by an opioid receptor antagonist. This NOP1 antagonist
transient (e.g., upper does not appear to penetrate the blood–brain barrier in the
respiratory viral infection) guinea-pig when administered orally and remains effective as
Persistent cough particularly Opiates (codeine or an inhibitor of capsaicin-induced cough, indicating that it
nocturnal pholcodeine) also acts peripherally [46].
Persistent intractable cough Opiates (morphine or Nociceptin inhibits the airway microvascular leakage
due to terminal incurable diamorphine) induced in guinea-pig airways by intraoesophageal hydro-
disease chloric acid infusion, probably acting at the prejunctional
COPD: Chronic obstructive pulmonary disease. level by inhibiting tachykinin release [47]. Furthermore, the
ability of nociceptin to block capsaicin-induced tachykinin
guinea-pig [36], an effect prevented by a δ-receptor antagonist release and bronchoconstriction has been traced to the activa-
(SB-244525). Paradoxically, an oral selective opioid δ-recep- tion of an inward-rectifier K+ channel [48]. So far there is no
tor antagonist, TRK-851, with 100 – 250 times greater data in humans.
potency in inhibiting cough in rat and guinea-pig than
codeine, is being developed as a potential antitussive [37]. 6.2 Tachykinin receptor antagonists
Levodropropizine, a non-opioid antitussive and derivative Tachykinins are present in capsaicin-sensitive primary affer-
of phenylpiperazino-propane, inhibits vagally induced cough ent nerves and act through the tachykinin receptor subtypes
in the guinea-pig by activating a reflex mediated by capsaicin- NK1R, NK2R, NK3R [49]. In rodents, capsaicin and other irri-
sensitive afferents, and not by a central mechanism of action tants can cause the release of tachykinins from peripheral
[38]. It inhibits C-fibre activity induced by chemical stimuli [39]. nerve endings in the lungs via a local axon reflex. Tachykinins
It has been compared with dextrometorphan in patients with are potent bronchoconstrictors, increase microvascular per-
non-productive cough and shown to have a more favourable meability and have various pro-inflammatory effects. These,
risk–benefit profile [40]. together with a direct effect on myelinated Aδ-fibres, contrib-
ute to the stimulation of cough. Tachykinins may enhance
6.1.1 Nociceptin the responses of RARs and have also been implicated in the
Nociceptin/orphanin is the endogenous peptide ligand for central sensitisation of cough [14].
the orphan opioids like NOP1, which is a G-protein-cou- In the guinea-pig, an NK2 receptor antagonist, SR-48968,
pled seven transmembrane receptor. Nociceptin does not inhibited citric acid-induced cough, while an NK1 receptor
stimulate opioid receptors. NOP1 receptors are widely dis- antagonist was ineffective [50,51]. A study in asthmatic sub-
tributed in the CNS and are also present in airway nerves in jects found no effect of CP-99994 against bronchoconstric-
the guinea-pig [41], where nociceptin has been found to tion and cough induced by hypertonic saline [52]. A non-
inhibit nonadrenergic and noncholinergic responses [42]. peptide NK3 receptor antagonist (SB-235375), with low

22 Expert Opin. Investig. Drugs (2005) 14(1)


penetrance into the CNS, inhibited citric acid-induced
cough and airway hyper-reactivity in the guinea-pig [53,54]
but its development has been suspended. There are some
clinical trials still in progress.
6.3 Bradykinin B2 receptor antagonists
Bradykinin is a short peptide produced by the action of pro-
teases, which induces inflammation and stimulates sensory
nerve endings to induce the release of neuropeptides. Brady-
kinin activates RARs and also causes bronchoconstriction
[55]. It also activates airway C-fibres and can cause coughing
in the guinea-pig and in patients with asthma. The B2 recep-
tor antagonist HOE-140 (icatibant) inhibited citric acid-
induced cough in the guinea-pig [56]. In the guinea-pig, an
inhibitor of angiotensin-converting enzyme, caused sensiti-
sation of the cough reflex, which was inhibited by a B2
receptor antagonist (HOE-140) [57]. A number of B2 recep-
tor antagonists have been developed [58] but these have not
been tested in cough.
6.4 Transient receptor potential vanilloid receptor-1
Capsaicin, the pungent ingredient of chilli peppers, stimu-
lates airway C- and Aδ-fibres, and also causes the release of
neuropeptides in the airways of guinea-pigs and rats, leading
to airway smooth muscle constriction and plasma extravasa-
tion. These lead to an increase in the activity of RARs. Cap-
saicin activates transient receptor potential vanilloid
receptor-1 (TRPV-1) present on subpopulations of primary
afferent neurons [59]. Capsazepine is a receptor antagonist of
TRPV-1 and blocks capsaicin- and citric acid-induced
cough [60]. The TRPV-1 receptor is localised to small-diame-
ter afferent neurons in dorsal root and vagal sensory ganglia
[61] and is stimulated by protons, the endogenous receptor
agonist of TRPV-1, an endogenous eicosanoid, anandamide
and inflammatory mediators such as 12-hydroperoxy-
5,8,10,14-eicosatetraenoic acid and leukotriene B4. TRPV-1
channel activity is strongly modulated by the action of
inflammatory mediators such as prostaglandins and brady-
kinin, through a protein kinase A- or C-mediated receptor
phosphorylation [61,62].
An increase in the expression of TRPV-1 in epithelial air-
way nerves of the airway mucosa of patients with non-asth-
matic chronic cough has been reported. The increase was
correlated with the degree of capsaicin cough responsiveness
[63], supporting a role for TRPV-1 in the enhanced cough
reflex seen in chronic cough. Novel TRPV-1 antagonists
such as iodo-resiniferatoxin (I-RTX) are very potent block-
ers, being 450-fold more potent that capsazepine. I-RTX has
been shown to be effective in inhibiting cough induced by
citric acid and capsaicin in the guinea-pig [64]. Noncompeti-
tive TRPV-1 antagonists consisting of the trimers of
N-alkylglycines are also effective in reducing capsaicin-
induced neurogenic inflammation [65]. Other classes of
TRPV-1 antagonists are rapidly appearing [66] and should be
tested in chronic cough.
Expert Opin. Investig. Drugs (2005) 14(1)
Chung
6.5 Cannabinoids
Interest in the cannabinoids as modulators of cough was first
shown by the demonstration that intravenous
∆9-tetrahydrocannabinol reduced the amplitude of the cough
response induced by the electrical stimulation of the superior
laryngeal nerve or by mechanical stimulation of the tracheal
mucosa in anesthetised cats [67]. However, there is conflicting
data regarding the receptor mediating these effects in cough.
A selective CB2 agonist, JWH-133, reduced citric acid-
induced cough in conscious guinea-pig, an action that is asso-
ciated with the inhibition of sensory nerve depolarisation of
the isolated vagus nerves induced by hypertonic saline, capsai-
cin and prostaglandin E2 [68]. This was suggestive of a periph-
eral mode of action of cannabinioids. However, an
endogenous cannabinoid, anandamide, inhibited cough and
bronchospasm induced by capsaicin in rodents through the
activation of CB1 cannabinoid receptors present on airway
nerves [69]. In another study, CB1 and CB2 antagonists had no
effect on anandamode-induced cough. In mice, the antitus-
sive effects of a cannabinoid agonist against capsaicin-induced
cough were shown to act via the activation of CB1 receptors,
probably ocurring centrally, as this was a µ2-opioid effect [70].
6.6 Ion channel modulators
6.6.1 K+ channels
Several K+ channels are located on vagal sensory neurons. A
benzimidazalone compound, NS-1619, is an opener of a
large-conductance Ca2+-activated channel (BKCa). It inhibits
citric acid-induced cough and the generation of action poten-
tials in the guinea-pig tracheal Aδ- and C-fibres stimulated by
hyperosmolality [71]. These effects were prevented by iberiot-
oxin, a BKCa channel selective blocker. An ATP-sensitive K+
channel opener, pinacidil, also inhibits cough induced by cap-
saicin in the guinea-pig, an effect reversed by the ATP-sensi-
tive K+ channel blocker glibenclamide [72]. Moguistine may
work as an ATP-sensitive K+ channel opener [72].
6.6.2 Chloride channels and diuretics
Isotonic solutions of low chloride concentrations can stimu-
late action potential discharge of a subpopulation of Aδ-fibres
and C-fibres in the guinea-pig [73], and activates afferent fibres
in the dog [74]. Low-concentration chloride solutions induce
cough in man and the diuretic frusemide inhibits cough
induced by low-chloride content solutions but not by capsai-
cin [75]. Frusemide to some extent inhibits airway afferent
action potential discharge and sensitises SARs and desensitises
RARs in rat airways [76]. The mechanism by which frusemide
works is unknown [77].
6.7 GABAB
GABA is an inhibitory neurotransmitter present in the cen-
tral and peripheral nervous system. The development of
selective GABA receptor agonists and antagonists have led
to the discovery of potential antitussive effects of these
compounds. GABAB receptors modulate cholinergic and
23
Drugs to suppress cough

tachykininergic nerves [78]. Capsaicin-induced cough is
inhibited in the conscious guinea-pig by the GABAB recep-
tor agonists, baclofen and 3-aminopropylphosphinic acid,
an effect mediated through the central stimulation of
GABAB receptors [79]. In human volunteers, there was an
inhibitory effect of baclofen on capsaicin-induced cough
[80] but only a small beneficial effect was shown in two
patients with chronic cough [81].
6.8 Local anaesthetics
Afferent nerves need voltage-gated Na+ channels for action
potential conduction from the nerve terminals to the CNS.
Lignocaine and bupivicaine are local anaesthetics by virtue of
their Na+ channel blocking activity, and block the cough
response when delivered to the upper and lower airways by
aerosol [82]. These agents also dampen upper airway protective
reflexes and may occasionally induce bronchoconstriction,
and therefore need to be used with care. Lignocaine inhala-
tion inhibits cough at doses that do not affect reflex broncho-
constriction [83]. Their duration of action is only of the order
of ≤ 30 min. At present, these are usually reserved for the
most severe persistent cough patients [84].
A quartenary ammonium compound, RSD-931, which
inhibits spontaneously and histamine-evoked discharges from
airway RARs but activates pulmonary C-fibres, reduces citric
acid- and capsaicin-induced cough in guinea-pigs and rabbits
[85]. This profile of effect was dissimilar to that of lignocaine,
which was more generally inhibitory.
6.9 5-Hydroxytryptamine
5-Hydroxytryptamine (5-HT) receptors are present in nodose
ganglia and facilitates neural transmission in visceral C-fibre
afferents. Activation of central 5-HT pathways mediate the
antitussive activity of opiates in experiments performed in
mice [86]. Infusion of 5-HT and of 5-hydroxytryptophan
reduced cough responses to chloride-deficient solutions but
had no effect on capsaicin responses [87]. In guinea-pigs, an
agonist at the 5-HT1A receptor, 8-hydroxy-2-(di-n-pro-
pylamino)-tetralin (8-OH-DPAT) showed both excitatory
and inhibitory influences on the cough reflex to capsaicin,
which may be initiated via postsynaptic stimulation of central
serotoninergic neurons and/or co-existing peripheral sites [88].
7. Expert opinion
There is a great need for novel non-specific antitussives that can
inhibit the cough response and the urge to cough directly along
the cough pathways. In the meantime, there will be improve-
ments in the bioavailability of currently available antitussives
based mainly on opioid pharmacology (e.g., slow-release
dextrometorphan). An improved understanding of the cough
pathways and of the mechanisms of sensitisation of cough are
important endeavours because, from these developments,
potential targets for antitussive therapy can be identified with
some degree of confidence. However, many of these potential
antitussives have only been tested at the preclinical stage.
At the preclinical stage, small animals have been used to test
antitussives, but of the small animals only the guinea-pig pro-
duces a cough akin to humans, with a noise similar to a human
cough. Other rodents such as mice and rats do not cough but
produce an expiration reflex, which certain investigators refer
to as cough but is likely to be different. In addition, the use of
anesthetised animals for the study of cough is fraught with
problems and should be avoided. Although the conscious
guinea-pig model is probably the best approach in animals,
other considerations of species variability in cough pathways
and of behavioural physiology must be taken into account.
Nevertheless, this model would be useful for studying cough in
pathologically induced conditions.
The reason why many potential antitussives have so far not
been tested in man is related to the relative uncertainty as to
the process of conducting these clinical trials. Methods of
measuring cough are slowly being established, such as the
measurement of cough reflex sensitivity, recording and meas-
uring cough frequency and strength, and specific quality of
life questionnaires [89,90]. The challenge of the future is to
conduct clinical trials in relevant populations suffering from
chronic cough and to demonstrate clinical efficiency.

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Affiliation
K F Chung MD, DSc, FRCP
National Heart & Lung Institute, Imperial
College & Royal Brompton Hospital, London,
SW3, UK
Tel: +44 207 351 8995; Fax: +44 207 351 8126;
E-mail: f.chung@imperial.ac.uk
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