Assessment of antitussive efficacy of dextromethorphan in smoking related cough: objective vs. subjective measures

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dextromethorphan is widely used as a cough suppressant in over the counter medications.• Its efficacy in altering cough reflex sensitivity has been shown in healthy volunteers. In contrast evidence for an effect on clinically important cough is poor. WHAT THIS STUDY ADDS• A significant decrease in evoked cough was seen with dextromethorphan compared with placebo. However, both placebo and active treatment improved subjective data to a similar degree.• We doubt the validity of currently used objective tests in the investigation of antitussives. AIMSUsing an established model of smokers cough we measured the antitussive effects of dextromethorphan compared with placebo. METHODSThe study was a randomized, double-blind placebo controlled, crossover comparison of 22 mg 0.8 ml -1 dextromethorphan delivered pregastrically with matched placebo. Objective and subjective measurements of cough were recorded. Subjective measures included a daily diary record of cough symptoms and the Leicester quality of life questionnaire. Cough frequency was recorded using a manual cough counter. The objective measure of cough reflex sensitivity was the citric acid, dose-response cough challenge. RESULTSDextromethorphan was significantly associated with an increase in the concentration of citric acid eliciting an average of two coughs/inhalation (C2) when compared with placebo, 1 h post dose by 0.49 mM (95% CI 0.05, 0.45, geometric mean 3.09) compared with placebo 0.24 mM (geometric mean 1.74) P < 0.05 and at 2 h 0.57 mM (95% CI 0.01, 0.43, geometric mean 3.75) compared with placebo 0.34 mM (geometric mean 2.19) P < 0.05). There was a highly significant improvement in the subjective data when compared with baseline. However, there was no significant difference between placebo and active treatment. No correlation was seen between cough sensitivity to citric acid and recorded cough counts or symptoms. When both subjective and objective data were compared with screening data there was evidence of a marked 'placebo' effect. CONCLUSIONSThe objective measure of cough sensitivity demonstrates dextromethorphan effectively diminishes the cough reflex sensitivity. However, subjective measures do not support this. Other studies support these findings, which may represent a profound sensitivity of the cough reflex to higher influences.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…It still heavily relies on codeine and its derivatives such as dextromethorphan. This is a problem because there is little evidence that codeine derivates can provide any clinical benefit in cough relief over placebo in patients with chronic cough (Ramsay et al, 2008), yet they have significant adverse effects (ranging from itch to hallucinations) as well as a well documented abuse potential (www.nhtsa.gov/people/injury/research/ job185drugs/dextromethorphan.htm).…”

Antitussive Drugs—Past, Present, and Future

“…It has been shown to bind to a series of receptors, including the N-methyl-D-aspartate (NMDA) glutamate receptors (Netzer et al, 1993, Chou et al, 1999, s-1 receptors (Chou et al, 1999), nicotinic (Glick et al, 2001), and serotonergic receptors (Meoni et al, 1997). This complex activity is believed to suppress cough by altering the threshold for cough initiation primarily via its effects as an NMDA antagonist at the level of antagonizing glutamate receptors in the nTS in the CNS (Ramsay et al, 2008).…”

“…Finally, Ramsay et al (2008) reported a placebocontrolled randomized, double-blind crossover study in subjects with smoking-related cough.…”

Is opiate action in cough due to sedation?

“…Ideally, these various modalities of assessment should be combined to form a composite of response since each modality assesses a different facet of cough [Morjaria et al 2013]. In the first study, there was significant improvements in subjective cough assessment but this was not replicated objectively undermining the importance of the CAA-induced cough challenge model in the assessment of cough [Doherty et al 2000;Ramsay et al 2008]. Sedation was assessed via prompted patient self reporting rather than specific metrics since these have only been applied to patients in the intensive care setting [Ramsay et al 1974;Sessler et al 2002].…”