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Three Part Question

In [ED patients with acute cough] is [codeine better than other antitussives] in regards to [improvement in severity or frequency of the cough]?

Clinical Scenario

A 26 year old otherwise healthy male presents to the emergency department with a dry cough that has been present for 5 days. He has tried over-the-counter medications in an attempt to improve his cough symptoms without success. He would like to know if codeine would be better.

Search Strategy

Medline 1950-04/10 using OVID interface, Cochrane Library (2010), PubMed clinical queries.
[(exp cough/ or cough.mp) AND (exp codeine/)]. LIMIT to human AND English.

Search Outcome

83 papers were found of which 4 were relevant to the three part question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Freestone, C. et al Oct 1997 Wales, UK	A recruited sample of 82 otherwise healthy patients with a cough from an acute upper respiratory tract infection were studied on two separate days. Patients were either given 50mg of codeine or matched placebo. On day one cough measurements were made both before and 90 minutes after treatment, this was repeated 2-5 days later. Cough measurements were made by subjective scores of severity, a cough sound-pressure level (CSPL) measured by a sound meter and cough frequency by an ink-pen microphone recorder while sitting in a quiet room watching a video.	Prospective blinded clinical trial	Day 1 t-test for CSPL 90 minutes after treatment	Mean Placebo 76.10 dBA. Codeine 76.55dBA. P=0.8165; 95%CI (-3.4-4.3)	This study could have some bias in that the subjects are not fully blinded to the study. They are aware that cough is being recorded since the CSPL sound meter was attached directly to their neck in an unnatural environment. Also, the dose of codeine was higher than the recommended adult OTC single dose.
			Day 1 t-test for cough frequency 90 minutes after treatment	Mean placebo 12.71 and codeine 13.23. P=0.8871; 95%CI (-6.8-7.9)
			Day 1 U-test for subjective score 90 minutes after treatment	Median placebo 1.0 and codeine 1.0. tied P value=0.8020
			Day 1 to 2 paired t test for CSPL	Mean on Day 1 82.59dBA and Day 2 75.14dBA. P<0.0001 (95% CI 5.4-9.6)
			Day 1 to 2 paired t test for cough frequency	Mean on Day 1 25.57 and Day 2 11.46. P<0.0001 (95% CI 10.2-18.0)
			Day 1 to 2 non parametric matched-pairs signed-rank sum test for subjective scores	Median on Day 1 2.0 and Day 2 1.0. tied P value <0.0001
Taylor, JA. et al. May 1993 USA	49 children from 18 months to 12 years of age in private pediatric practices with cough less than 14 days randomly received either codeine (10mg/5ml), dextromethorphan (15mg/5ml) or placebo at bedtime for 3 consecutive nights. All patients receiving codeine or dextromethorphan also received guaifenesin (100mg/5ml). Patients from 18 months to 5 years received 2.5ml and those from 6-12 years age received 5ml. A parent questionnaire was then completed with questions including cough frequency, loss of sleep and posttussive emesis. This was then generated into a cough score from 0 to 4 and a cough symptoms score from 0 to 9 from each study day.	Randomized controlled trial	Regression analysis between codeine and placebo	p=0.70	The size of the study may have been to small to detect smaller but statistically significant differences in reduction of symptoms. The outcome measures, being based on a subjective parent questionnaire are also somewhat weak. There is no objective measure to this study. It is also possible that the doses of medication were inadequate to produce an effect, especially since dosing was lumped into two large categories based on age rather than weight. It is also possible that children with mild reactive airway disease were inadvertently included in this study since the main measure of disease was night cough.
			Regression analysis between DM and placebo	p=0.41
			All group cough score from Day 1 to Day 3	coefficient=0.87; p<0.0002
Croughan-Minihane, MS. et al. Mar-Apr 1993 USA	97 adult patients presenting to their family physician with uncomplicated respiratory infection were randomized to receive either guaifenesin (100mg/5ml), guaifenesin plus codeine(100mg/15mg/5ml) or guaifenesin plus dextromethorphan(100mg/30mg/5ml). They were to take 10mL four times a day. They were followed by telephone interviews at specific intervals on days 2,4 and 10 to assess cough frequency, severity of cough, loss of sleep, subjective benefit, loss of work/school days, treatment adherence and side effects.	Randomized Clinical Trial	Chi square analysis for ability to keep up with daily activities	Day 2 p=0.62 and day 10 p=0.50	Did not reach their calculated sample size for sufficient power. They also had interval losses to follow up with different patients on different days that could have altered the results.
			Chi square analysis for awakened from sleep	Day 2 p=0.97, Day 4 p=0.69, Day 10 p=0.93
			Chi square analysis for having trouble getting to sleep	Day 2 p=0.56, Day 4 p=0.88, Day 10 p=0.87
			Chi square analysis for absence from school/work	Day 2 p=0.29, Day 4 p=0.94, Day 10 p=0.69
			Chi square analysis for frequent bouts of coughing	Day 2 p=0.42, Day 4 p=0.25, Day 10 p=0.62
			Chi square analysis for subjective improvement in cough	Day 2 p=0.84, Day 4 p=0.29, Day 10 p=0.20
Eccles, R. et al. June 1992 Wales, UK	91 adult subjects with a non-productive cough lasting 6-96 hours and no underlying history of lung disease were randomized to receive either 30mg/10ml of codeine or 10ml of placebo. They then participated in a 3 hour laboratory phase in which cough counts by microphone and subjective cough severity measurements were made. This was followed by a 4 day home phase where a diary scoring cough severity and 13 other symptoms was kept.	Randomized Controlled Trial	Lab phase frequency of cough	No statistically significant difference in mean cough frequency between the two groups at any time.	The laboratory phase of this study could be considered an unnatural environment.
			Lab phase visual analogue score (VAS) for cough severity	At no time from pretreatment to end of treatment period was there a significant difference between the mean scores
			Home phase cough symptom analysis	At no time was there significant difference (P>0.1 for all tests) between the codeine and placebo group

Comment(s)

Many prior studies looking at the effects of cough and codeine have been conducted. However, few have been randomized control trials in the setting of a non-induced acute cough. These studies all tend to show a reduction in cough symptoms over time in all groups with no statistically significant difference between codeine and other groups. These studies overall suggest the need to re-evaluate the use of codeine in the acute cough setting.

Clinical Bottom Line

Codeine has not been shown to provide improvement in severity of cough symptoms in the acute setting when compared to other antitussives or placebo.

References

1. Freestone, C. et al. Assessment of the antitussive efficacy of codeine in cough associated with common cold. Journal of Pharmacy & Pharmacology Oct 1997; 49(10): 1045-9
2. Taylor JA. et al. Efficacy of cough suppressants in children. Journal of Pediatrics May 1993; 122(5 Pt 1):799-802
3. Croughan-Minihane, MS. et al. Clincial trial examining effectiveness of three cough syrups Journal of the American Board of Family Practice Mar-Apr 1993; 6(2): 109-15
4. Eccles, R. et al. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection Journal of Clinical Pharmacy and Therapeutics June 1992; 17(3): 175-80