Environmental and occupational respiratory disorders
Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease

https://doi.org/10.1016/j.jaci.2005.09.055Get rights and content

Background

Codeine is the standard antitussive treatment to which novel agents are compared. Little is known about the objective effect of any treatments on cough in chronic obstructive pulmonary disease (COPD).

Objective

To quantify the effect of codeine on objective cough frequency (quantified as time spent coughing: cough seconds, cs/h), citric acid cough threshold, and subjective measures in a double-blind, placebo-controlled crossover study in COPD.

Methods

We studied 21 patients with physician-diagnosed, stable disease who complained of cough (76.9% male; mean age, 67.7 years; mean predicted FEV1, 53.4%; median smoking history, 43.5 pack-years). Each subject performed a cough challenge (single breath, citric acid), 10-hour daytime ambulatory and overnight cough recordings, subjective cough scores, and visual analog scales at baseline and on 2 study days, 1 week apart. Codeine phosphate 60 mg or matched placebo were given, in random order, at the start of each cough recording (0 and 12 hours).

Results

Median time spent coughing at baseline was 8.27 cs/h (interquartile range [IQR], 5.94-11.67); after placebo treatment, 7.22 cs/h (IQR 4.42-10.40); and after codeine treatment, 6.41 cs/h (IQR 3.86-9.10). Codeine treatment had a significant effect on time spent coughing compared with baseline (P = .02) but not compared with placebo (P = .52). There were no significant differences in cough challenge thresholds (log concentration of tussive agent causing 2 coughs or log concentration of tussive agent causing 5 coughs) or subjective cough measures for codeine compared with placebo.

Conclusion

In this study, codeine was no more effective than placebo in patients with COPD complaining of cough.

Clinical implications

Codeine is the antitussive agent to which we compare new treatments; however, in a group of stable patients with COPD, it had no effect on cough frequency over placebo.

Section snippets

Subjects

Patients with stable COPD (FEV1 30-75% predicted) who complained of cough (subjective cough score of 2 or more; Table I) were invited for screening. Patients with exacerbations in the last month, previous acute hypercapnic ventilatory failure, or low transcutaneous oxygen saturation (<92%) were excluded. Current smokers and patients who reported a history of gastroesophageal reflux disease, postnasal drip, and asthma were ineligible. The study was approved by the Local Research Ethics

Results

Twenty-six patients were screened, 21 patients met the inclusion criteria and were enrolled in the randomized study, and 19 patients completed the study. Fourteen were male subjects, and subjects had a mean age of 68.0 ± 6.86 years (Table II). One patient did not complete both treatment days because of an episode of gastroenteritis, and 1 patient had an exacerbation related to paint fumes and was excluded. Complete data on 19 subjects are presented (Table III) and were analyzed. Two subjects

Discussion

This is the first double-blind, randomized, placebo-controlled study to use a range of outcomes, including ambulatory cough monitoring, to assess the efficacy of an antitussive agent in COPD. It shows that codeine has no additional antitussive effect above that of placebo in patients with stable COPD who complained of cough. However, both codeine and placebo showed substantial reductions in time spent coughing during the day compared with baseline, underlining the necessity for appropriately

References (31)

  • C.T. French et al.

    Evaluation of a cough-specific quality-of-life questionnaire

    Chest

    (2002)
  • R. Eccles

    The powerful placebo in cough studies?

    Pulm Pharmacol Ther

    (2002)
  • L. Pavesi et al.

    Application and validation of a computerized cough acquisition system for objective monitoring of acute cough: a meta-analysis

    Chest

    (2001)
  • S. Rennard et al.

    Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey

    Eur Respir J

    (2002)
  • S.S. Birring et al.

    Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ)

    Thorax

    (2003)
  • M.N. Yaman et al.

    A cross-sectional comparison of two cough specific health related quality of life questionnaires

    Thorax

    (2003)
  • M.J. Doherty et al.

    Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease

    Thorax

    (2000)
  • J.A. Smith et al.

    Measurements of cough in chronic obstructive pulmonary disease

    Thorax

    (2003)
  • H. Matthys et al.

    Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough

    J Int Med Res

    (1983)
  • H. Sevelius et al.

    Dose response to codeine in patients with chronic cough

    Clin Pharmacol Ther

    (1971)
  • C.R. Woolf et al.

    Objective assessment of cough suppressants under clinical conditions using a tape recorder system

    Thorax

    (1964)
  • H. Sevelius et al.

    Objective assessment of antitussive agents in patients with chronic cough

    J New Drugs

    (1966)
  • M. Aylward et al.

    Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects

    Eur J Respir Dis

    (1984)
  • I.D. Cox et al.

    An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose-response curve to citric acid

    Br J Clin Pharmacol

    (1984)
  • J.P. Dilworth et al.

    Cough threshold after upper abdominal surgery

    Thorax

    (1990)
  • Cited by (133)

    • Management of chronic refractory cough in adults

      2020, European Journal of Internal Medicine
    • A systematic review of methods of citric acid cough reflex testing

      2019, Pulmonary Pharmacology and Therapeutics
    View all citing articles on Scopus

    Supported by an educational grant from GlaxoSmithKline Ltd.

    Disclosure of potential conflict of interest: The authors have declared they have no conflict of interest.

    View full text