Skip to main content

Advertisement

SpringerLink
Log in

Importance of Placebo Effect in Cough Clinical Trials

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Eccles R, Morris S, Jawad M (1992) Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther 17:175–180

    CAS  PubMed  Google Scholar 

  2. Eccles R (1996) Codeine, cough and upper respiratory infection. Pulm Pharmacol Ther 9:293–297

    Article  CAS  Google Scholar 

  3. Freestone C, Eccles R (1997) Assessment of the antitussive efficacy of codeine in cough associated with common cold. J Pharm Pharmacol 49:1045–1049

    CAS  PubMed  Google Scholar 

  4. Bolser DC, Davenport PW (2007) Codeine and cough: an ineffective gold standard. Curr Opin Allergy Clin Immunol 7:32–36

    Article  CAS  PubMed  Google Scholar 

  5. Oken BS (2008) Placebo effects: clinical aspects and neurobiology. Brain 131:2812–2823

    Article  PubMed  Google Scholar 

  6. Moerman D (2002) Deconstructing the placebo effect and finding the meaning response. Ann Intern Med 136:471–476

    PubMed  Google Scholar 

  7. Stewart-Williams S, Podd J (2004) The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull 130:324–340

    Article  PubMed  Google Scholar 

  8. Benedetti F (2008) Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol 48:33–60

    Article  CAS  PubMed  Google Scholar 

  9. Cannon W (1929) Bodily changes in pain hunger, fear, rage: an account of recent research into the function of emotional excitement. Appleton-Century-Crofts, New York

    Google Scholar 

  10. Eccles R (2002) The powerful placebo in cough studies. Pulm Pharmacol Ther 15:303–308

    Article  CAS  PubMed  Google Scholar 

  11. McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873–904

    Article  PubMed  Google Scholar 

  12. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS (2005) Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 25:7754–7762

    Article  CAS  PubMed  Google Scholar 

  13. Wager TD, Scott DJ, Zubieta JK (2007) Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci USA 104:11056–11061

    Article  CAS  PubMed  Google Scholar 

  14. Benedetti F (1996) The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64:535–543

    Article  CAS  PubMed  Google Scholar 

  15. Amanzio M, Benedetti F (1999) Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 19:484–494

    CAS  PubMed  Google Scholar 

  16. Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev 6:545–552

    Article  CAS  Google Scholar 

  17. Rostami-Hodjegan A, Abdul-Manap R, Wright CE, Tucker GT, Morice AH (2001) The placebo response to citric acid-induced cough: pharmacodynamics and gender differences. Pulm Pharmacol Ther 14:315–319

    Article  CAS  PubMed  Google Scholar 

  18. Lee PC, Jawad MS, Hull JD, West WH, Shaw K, Eccles R (2005) The antitussive effect of placebo treatment on cough associated with acute upper respiratory infection. Psychosom Med 67:314–317

    Article  PubMed  Google Scholar 

  19. Moulton C, Pennycook AG (1994) Relation between Glasgow coma score and cough reflex. Lancet 343:1261–1262

    Article  CAS  PubMed  Google Scholar 

  20. Hutchings HA, Eccles R, Smith AP, Jawad M (1993) Voluntary cough suppression as an indication of symptom severity in upper respiratory tract infections. Eur Respir J 6:1449–1454

    CAS  PubMed  Google Scholar 

  21. Choudry NB, Harrison AJ, Fuller RW (1992) Inhibition of gustatory rhinorrhea by intranasal ipratropium bromide. Eur J Clin Pharmacol 42:561–562

    Article  CAS  PubMed  Google Scholar 

  22. Eccles R (2006) Mechanisms of the placebo effect of sweet cough syrups. Respir Physiol Neurobiol 152:340–348

    Article  PubMed  Google Scholar 

  23. Jain R, Mukherjee K, Singh R (2004) Influence of sweet tasting solutions on opioid withdrawal. Brain Res Bull 64:319–322

    Article  CAS  PubMed  Google Scholar 

  24. Pecina S, Smith KS, Berridge KC (2006) Hedonic hot spots in the brain. Neuroscientist 12:500–511

    Article  PubMed  Google Scholar 

  25. Lewkowski MD, Young SN, Ghosh S, Ditto B (2008) Effects of opioid blockade on the modulation of pain and mood by sweet taste and blood pressure in young adults. Pain 135:75–81

    Article  CAS  PubMed  Google Scholar 

  26. McKemy DD (2005) How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation. Mol Pain 1:16

    Article  PubMed  Google Scholar 

  27. Voets T, Owsianik G, Nilius B (2007). TRPM8. Handb Exp Pharmacol (179):329–344

  28. Bodding M, Wissenbach U, Flockerzi V (2007) Characterisation of TRPM8 as a pharmacophore receptor. Cell Calcium 42(6):618–628

    Article  PubMed  Google Scholar 

  29. Laude EA, Morice AH, Grattan TJ (1994) The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs. Pulm Pharmacol 7:179–184

    Article  CAS  PubMed  Google Scholar 

  30. Morice AH, Marshall AE, Higgins KS, Grattan TJ (1994) Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 49:1024–1026

    Article  CAS  PubMed  Google Scholar 

  31. Ernst E, Resch KL (1995) Concept of true and perceived placebo effects. BMJ 311:551–553

    CAS  PubMed  Google Scholar 

  32. Kienle G, Kiene H (1996) Placebo effect and placebo concept: a critical methodological and conceptual analysis of reports on the magnitude of the placebo effect. Altern Ther Health Med 2:39–54

    CAS  PubMed  Google Scholar 

  33. Hutchings HA, Morris S, Eccles R, Jawad M (1993) Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers. Respir Med 87:379–382

    Article  CAS  PubMed  Google Scholar 

  34. Lee P, Cotterill-Jones C, Eccles R (2002) Voluntary control of cough. Pulm Pharmacol Ther 15:317–320

    Article  CAS  PubMed  Google Scholar 

  35. Evans D (2003) Placebo. The belief effect. Harper Collins, London

    Google Scholar 

  36. Moerman D (2002) Meaning, medicine and the ‘Placebo effect’. Cambridge University Press, Cambridge

    Google Scholar 

  37. Benedetti F, Amanzio M (1997) The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 52:109–125

    Article  CAS  PubMed  Google Scholar 

  38. Hutchings HA, Eccles R (1994) The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects. Eur Respir J 7:715–719

    Article  CAS  PubMed  Google Scholar 

  39. Simonyan K, Saad ZS, Loucks TM, Poletto CJ, Ludlow CL (2007) Functional neuroanatomy of human voluntary cough and sniff production. Neuroimage 37:401–409

    Article  PubMed  Google Scholar 

  40. Fava M, Evins AE, Dorer DJ, Schoenfeld DA (2003) The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom 72:115–127

    Article  PubMed  Google Scholar 

  41. Eccles R, Loose I, Jawad M, Nyman L (2003) Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. Pain Med 4:118–124

    Article  PubMed  Google Scholar 

  42. Eccles R, Jawad MS, Jawad SS, Angello JT, Druce HM (2005) Efficacy and safety of single and multiple doses of pseudoephedrine in the treatment of nasal congestion associated with common cold. Am J Rhinol 19:25–31

    PubMed  Google Scholar 

  43. Eccles R, Eriksson M, Garreffa S, Chen SC (2008) The nasal decongestant effect of xylometazoline in the common cold. Am J Rhinol 22:491–496

    Article  PubMed  Google Scholar 

  44. Eccles R, Jawad M, Jawad S, Ridge D, North M, Jones E, Burnett I (2006) Efficacy of a paracetamol-pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection. Curr Med Res Opin 22:2411–2418

    Article  CAS  PubMed  Google Scholar 

  45. Miller FG, Wendler D, Swartzman LC (2005) Deception in research on the placebo effect. PLoS Med 2:e262

    Article  PubMed  Google Scholar 

  46. Waring DR (2008) The antidepressant debate and the balanced placebo trial design: an ethical analysis. Int J Law Psychiatry 31:453–462

    Article  PubMed  Google Scholar 

  47. Clayden JR, Bell JW, Pollard P (1974) Menopausal flushing: double-blind trial of a non-hormonal medication. Br Med J 1:409–412

    Article  CAS  PubMed  Google Scholar 

  48. Swartzman LC, Burkell J (1998) Expectations and the placebo effect in clinical drug trials: why we should not turn a blind eye to unblinding, and other cautionary notes. Clin Pharmacol Ther 64:1–7

    Article  CAS  PubMed  Google Scholar 

  49. Thomson R (1982) Side effects and placebo amplification. Br J Psychiatry 140:64–68

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Common Cold Centre, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, Wales, UK

    Ron Eccles

Authors
  1. Ron Eccles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ron Eccles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eccles, R. Importance of Placebo Effect in Cough Clinical Trials. Lung 188 (Suppl 1), 53–61 (2010). https://doi.org/10.1007/s00408-009-9173-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-009-9173-3

Keywords

Search

Navigation