Theobromine inhibits sensory nerve activation and cough

Abstract

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Effects on Peripheral and Central Blood Pressure of Cocoa With Natural or High-Dose Theobromine

“…Theobromine has been shown to exert an inhibitory effect on parasympathetic activity 26 and is a selective antagonist of the A1 adenosine receptor 27 : these mechanisms could explain the increase in HR without changes in CO or SVR in the TEC group. The increases in HR and PWV observed in the present study result in a forward wave that is larger in amplitude but more concave in shape (please see the online Data Supplement).…”

Antitussive Drugs—Past, Present, and Future

“…More recently, theobromine (Fig. 20) has been demonstrated to inhibit sensory nerve activation and cough in humans (Usmani et al, 2005), and a large multicenter trial is ongoing evaluating the effects of theobromine on chronic cough clinically (Clancy et al, 2013). Theophylline has recently been demonstrated to inhibit the cough reflex via an effect on BK K + channels (Dubuis et al, 2014).…”

Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial

“…It has a rapid onset, long duration of activity (>4 hours), is substantially more effective than caffeine in inhibiting cough induced by citric acid in the guinea-pig model, and it is at least as effective as theophylline and doxophylline (4). Theobromine has also been shown to suppress capsaicin-induced cough in humans with no AEs, and is considered a novel and promising treatment which may pave the way for a new class of antitussive drugs (4).…”

“…Sufferers consume 75 million doses of over-the-counter antitussive medication annually, totalling £98.7 million in the UK in 2014 (2,3). Codeine and dextromethorphan are the most commonly prescribed opioid-derived antitussives but their use is limited by unpredictable efficacy and unacceptable adverse events (AEs), such as somnolence, dizziness, nausea and constipation (4)(5)(6)(7).…”

“…It has a long history of clinical use and has been suggested as a promising therapy for the treatment of persistent cough (4,(10)(11)(12). BC1036 is a nonopioid, non-narcotic, theobromine treatment and its main mechanisms of action are inhibition of phosphodiesterases and blockade of adenosine receptors.…”