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Potential Future Therapies for the Management of Cough : ACCP Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Peter V. Dicpinigaitis, MD, FCCP
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Correspondence to: Peter Dicpinigaitis, MD, FCCP, Einstein Division/Montefiore Medical Center, 1825 Eastchester Rd, Bronx, NY 10461; e-mail: pdicpinigaitis@pol.net



Chest. 2006;129(1_suppl):284S-286S. doi:10.1378/chest.129.1_suppl.284S
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Background: When the etiology of a patient’s chronic cough is established, specific antitussive therapy that is aimed at a particular cause of cough is highly effective. Nevertheless, in certain situations, therapy with cough suppressants, which previously were classified as nonspecific antitussive therapy, and which aim at suppressing the cough reflex regardless of the cause of cough, will be necessary.

Methodology: The data for this review were obtained with the aid of a National Library of Medicine (PubMed) search, which was performed in June 2004, of literature published in the English language from 1966 to 2004, using the search terms “cough,” “antitussive,” “pharmacotherapy,” “future therapies, ” and “potential therapies.”

Results/conclusions: Currently available cough-suppressant therapy is severely limited by a dearth of effective agents and/or their unacceptable side effects. Several classes of pharmacologic agents are currently under investigation in an attempt to develop clinically useful cough suppressants.

Multiple prospective studies have shown that antitussive therapy that is aimed at a specific etiology of cough is highly successful.13 Occasionally, therapy with cough suppressants, which were previously referred to as nonspecific antitussive therapy, and were intended to suppress the cough reflex regardless of the inciting factor, is necessary and appropriate. Such circumstances include chronic unexplained cough, which was previously referred to as idiopathic cough; cough due to irreversible causes, such as pulmonary fibrosis and inoperable lung cancer; and severe cough requiring transient relief while specific antitussive therapy takes effect. Unfortunately, the currently available suppressant therapy is limited by a lack of effective agents and/or their unacceptable side effects. Hence, a great need exists for more clinically useful cough-suppressant agents.

Below is a brief overview of several areas of current investigation, mostly in animal models, that may lead to the development of novel antitussive therapies (Table 1 ). The data for this review were obtained with the aid of a National Library of Medicine (PubMed) search, which was performed in June 2004, of the literature published in the English language from 1966 to 2004, using the search terms “cough,” “antitussive,” “pharmacotherapy,” “future therapies,” and “potential therapies.”

The tussive agent capsaicin, which is an extract of red peppers, has achieved common usage in clinical research because it induces cough in a reproducible and dose-dependent manner.45 The target receptor of capsaicin, the type 1 vanilloid (VR1) receptor, was discovered on peripheral pain-sensing neurons,6as well as throughout the CNS.7 The isolation of the VR1 receptor creates the opportunity for the development of potentially useful antagonists.

Agonists of the μ-opioid receptor (such as codeine) suppress cough at the expense of adverse effects that may include sedation, respiratory depression, nausea, constipation, and potential for abuse. A more specifically acting agent that could inhibit cough without such undesirable side effects would offer significant benefit over the currently available narcotic antitussive agents. Selective agonists of the δ-opioid receptor have been developed, and have demonstrated antitussive activity in animals.8

Opioid-like orphan receptors have been identified throughout the mammalian central and peripheral nervous system, including the lung. Nociceptin/orphanin FQ, an endogenous ligand of the opioid-like orphan receptor, has been shown to inhibit mechanically-stimulated9and capsaicin-induced cough10in animal studies. Furthermore, nociceptin/orphanin FQ has been demonstrated to inhibit capsaicin-induced tachykinin release and bronchoconstriction through a mechanism involving inward-rectifier potassium channel activation.11

In human airways, inflammatory cells appear to be the major source of tachykinins, which include various neuropeptide transmitters such as substance P, neurokinin (NK) A, NKB, and calcitonin gene-related peptide.12Animal studies13 have suggested that tachykinins, through stimulation of three receptor subtypes (ie, NK1, NK2, and NK3), induce neurogenic inflammation, bronchial hyperresponsiveness, and cough. Antagonists of the three NK receptor subtypes have been isolated and have demonstrated antitussive activity in animal studies.,1216

The endogenous cannabinoid anandamide has been shown in animal studies17to inhibit capsaicin-induced cough and bronchospasm, while inducing bronchospasm in animals that are devoid of vagal tone. These contrasting effects are both mediated through peripheral cannabinoid type 1 receptors that are located in airway nerves. Subsequent trials18 in guinea pigs demonstrated that anandamide induces cough through the activation of the VR1 receptor. The development of more selective cannabinoid receptor agonists and antagonists may provide clinically useful antitussive agents.

5-Hydroxytryptamine (5-HT) has been demonstrated to suppress experimentally induced cough in healthy volunteers.19The 5-HT receptor antagonist pizotifen was shown to counteract the inhibitory effect of morphine against capsaicin-induced cough, thereby implying a role for 5-HT receptors in the antitussive action, but not sedative action, of opioids.20 A better understanding of the role of 5-HT receptors in the human cough reflex may result in the development of antitussive agents lacking the undesirable characteristics of opioids.

Animal studies have demonstrated that the modulation of potassium channels can inhibit experimentally induced cough. In guinea pigs, for example, the benzimidazolone compound NS1619, which is a large-conductance calcium-activated potassium channel opener, inhibited airway sensory nerve activity and citric acid-induced cough.21The antitussive action of the vasodilator pinacidil and the thiazolidine compound moguisteine were attenuated by glibenclamide, an adenosine triphosphate-sensitive potassium channel antagonist, thereby suggesting a role for adenosine triphosphate-sensitive potassium channels in the mechanism of action of both agents.22 Further elucidation of the role of potassium channels in pathologic cough may yield effective therapeutic agents in the future.

1. For patients with cough, the aforementioned drugs, which are not commercially available in the United States for human use, should be evaluated in the setting of properly performed clinical trials. Quality of evidence, expert opinion; net benefit, intermediate; grade of recommendation, E/B

Abbreviations: 5-HT = 5-hydroxytryptamine; NK = neurokinin; VR1 = type 1 vanilloid receptor

Table Graphic Jump Location
Table 1. Potential Future Antitussive Therapies
Irwin, RS, Curley, FJ, French, CL (1990) Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outline of specific therapy.Am Rev Respir Dis141,640-647
 
Pratter, MR, Bartter, T, Akers, S, et al An algorithmic approach to chronic cough.Ann Intern Med1993;119,977-983
 
McGarvey, LP, Heaney, LG, Lawson, JT, et al Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol.Thorax1998;53,738-743
 
Midgren, B, Hansson, L, Karlsson, J-A, et al Capsaicin-induced cough in humans.Am Rev Respir Dis1992;146,347-351
 
Dicpinigaitis, PV Short- and long-term reproducibility of capsaicin cough challenge testing.Pulm Pharmacol Ther2003;16,61-65
 
Caterina, MJ, Schumacher, MA, Tominaga, M, et al The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature1997;389,816-824
 
Mezey, E, Toth, ZE, Cortright, DN, et al Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human.Proc Natl Acad Sci U S A2000;97,3655-3660
 
Kotzer, CJ, Hay, DW, Dondio, G, et al The antitussive activity of delta-opioid receptor stimulation in guinea pigs.J Pharmacol Exp Ther2000;292,803-809
 
Bolser, DC, McLeod, RL, Tulshian, DB, et al Antitussive action of nociceptin in the cat.Eur J Pharmacol2001;430,107-111
 
McLeod, RL, Parra, LE, Mutter, JC, et al Nociceptin inhibits cough in the guinea-pig by activation of ORL1receptors.Br J Pharmacol2001;132,1175-1178
 
Jia, Y, Wang, X, Aponte, SI, et al Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel.Br J Pharmacol2002;135,764-770
 
Joos, GF, Pauwels, RA Pro-inflammatory effects of substance P: new perspectives for the treatment of airway disease?Trends Pharmacol Sci2000;21,131-133
 
Advenier, C, Lagente, V, Boichot, E The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough.Eur Respir J1997;10,1892-1906
 
Moreaux, B, Nemmar, A, Vincke, G, et al Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs.Eur J Pharmacol2000;408,305-312
 
Hay, DW, Giardina, GA, Griswold, DE, et al Nonpeptide tachykinin receptor antagonists: III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.J Pharmacol Exp Ther2002;300,314-323
 
El-Hashim, AZ, Wyss, D, Lewis, C Effect of a novel NK1 receptor selective antagonist (NKP608) on citric acid-induced cough and airway obstruction.Pulm Pharmacol Ther2004;17,11-18
 
Calignano, A, Katona, I, Desarnaud, F, et al Bidirectional control of airway responsiveness by endogenous cannabinoids.Nature2000;408,96-101
 
Jia, Y, McLeod, RL, Wang, X, et al Anandamide induces cough in conscious guinea-pigs through VR1 receptors.Br J Pharmacol2002;137,831-836
 
Stone, RA, Worsdell, YM, Fuller, RW, et al Effects of 5-hydroxytryptamine and 5-hydroxytryptophan infusion on the human cough reflex.J Appl Physiol1993;74,396-401
 
O’Connell, F Central pathways for cough in man: unanswered questions.Pulm Pharmacol Ther2002;15,295-301
 
Fox, AJ, Barnes, PJ, Venkatesan, P, et al Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.J Clin Invest1997;99,513-519
 
Morita, K, Kamei, J Involvement of ATP-sensitive K(+) channels in the antitussive effect of moguisteine.Eur J Pharmacol2000;395,161-164
 

Figures

Tables

Table Graphic Jump Location
Table 1. Potential Future Antitussive Therapies

References

Irwin, RS, Curley, FJ, French, CL (1990) Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outline of specific therapy.Am Rev Respir Dis141,640-647
 
Pratter, MR, Bartter, T, Akers, S, et al An algorithmic approach to chronic cough.Ann Intern Med1993;119,977-983
 
McGarvey, LP, Heaney, LG, Lawson, JT, et al Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol.Thorax1998;53,738-743
 
Midgren, B, Hansson, L, Karlsson, J-A, et al Capsaicin-induced cough in humans.Am Rev Respir Dis1992;146,347-351
 
Dicpinigaitis, PV Short- and long-term reproducibility of capsaicin cough challenge testing.Pulm Pharmacol Ther2003;16,61-65
 
Caterina, MJ, Schumacher, MA, Tominaga, M, et al The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature1997;389,816-824
 
Mezey, E, Toth, ZE, Cortright, DN, et al Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human.Proc Natl Acad Sci U S A2000;97,3655-3660
 
Kotzer, CJ, Hay, DW, Dondio, G, et al The antitussive activity of delta-opioid receptor stimulation in guinea pigs.J Pharmacol Exp Ther2000;292,803-809
 
Bolser, DC, McLeod, RL, Tulshian, DB, et al Antitussive action of nociceptin in the cat.Eur J Pharmacol2001;430,107-111
 
McLeod, RL, Parra, LE, Mutter, JC, et al Nociceptin inhibits cough in the guinea-pig by activation of ORL1receptors.Br J Pharmacol2001;132,1175-1178
 
Jia, Y, Wang, X, Aponte, SI, et al Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel.Br J Pharmacol2002;135,764-770
 
Joos, GF, Pauwels, RA Pro-inflammatory effects of substance P: new perspectives for the treatment of airway disease?Trends Pharmacol Sci2000;21,131-133
 
Advenier, C, Lagente, V, Boichot, E The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough.Eur Respir J1997;10,1892-1906
 
Moreaux, B, Nemmar, A, Vincke, G, et al Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs.Eur J Pharmacol2000;408,305-312
 
Hay, DW, Giardina, GA, Griswold, DE, et al Nonpeptide tachykinin receptor antagonists: III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.J Pharmacol Exp Ther2002;300,314-323
 
El-Hashim, AZ, Wyss, D, Lewis, C Effect of a novel NK1 receptor selective antagonist (NKP608) on citric acid-induced cough and airway obstruction.Pulm Pharmacol Ther2004;17,11-18
 
Calignano, A, Katona, I, Desarnaud, F, et al Bidirectional control of airway responsiveness by endogenous cannabinoids.Nature2000;408,96-101
 
Jia, Y, McLeod, RL, Wang, X, et al Anandamide induces cough in conscious guinea-pigs through VR1 receptors.Br J Pharmacol2002;137,831-836
 
Stone, RA, Worsdell, YM, Fuller, RW, et al Effects of 5-hydroxytryptamine and 5-hydroxytryptophan infusion on the human cough reflex.J Appl Physiol1993;74,396-401
 
O’Connell, F Central pathways for cough in man: unanswered questions.Pulm Pharmacol Ther2002;15,295-301
 
Fox, AJ, Barnes, PJ, Venkatesan, P, et al Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.J Clin Invest1997;99,513-519
 
Morita, K, Kamei, J Involvement of ATP-sensitive K(+) channels in the antitussive effect of moguisteine.Eur J Pharmacol2000;395,161-164
 
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