The Efficacy of a NOP1 Agonist (SCH486757) in Subacute Cough

Abstract

Currently, opiates are widely used as antitussives but have substantial side effects. Recently, it has been proposed that NOP1 receptor agonists may be useful as a novel approach to cough suppression. Therefore, we compared the effect of NOP1 receptor agonist SCH486757 with matched placebo and codeine in a multicentre, double-blind, parallel-group study in patients with subacute cough. The primary outcome was change in cough severity scores, with the key secondary outcome change in objective daytime cough counts. We studied 91 subjects with subacute cough [59 (65%) female, median age = 41(range = 18-64) years, and median cough duration = 33 (range = 16-99) days]. Subjects were randomised to receive either SCH486757 100 mg, codeine 30 mg, or matched placebo twice daily for 5 days. Cough severity was scored throughout using a diary card and objective cough frequency recorded for 8 h at baseline and on the first and last treatment days. There were no significant differences in changes in average cough severity scores from baseline to treatment between SCH486757 and placebo [mean change = -0.57 (-30.1%) vs. mean change = -0.49 (-19.7%); P = 0.56] or between codeine and placebo [mean change = -0.72 (-33.2%); P = 0.07 compared to placebo). Changes in objective cough counts also showed no differences between the three treatment groups. There were some hints of possible limited antitussive efficacy with SCH486757. Unfortunately, the maximum clinical dose is limited by its tendency to produce somnolence. If the therapeutic ratio of NOP1 agonists could be improved, these drugs may still prove to contain effective antitussives.

How best to measure cough clinically

“…The VitaloJAK has been validated, and been used in patients with acute cough, chronic cough and COPD. It has also been used to evaluate antitussive therapy in clinical trials [30,31].…”

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…This was the first small-molecule NOP agonist to enter human clinical testing. 57 This compound and a close analog 14 (SCH225288, Figure 1) 117 are high affinity NOP full agonists, and were extensively characterized in experimental models of cough (guinea pig capsaicin-induced cough, and cat mechanical-induced cough) and shown to be more potent than commonly used antitussives codeine and dextromethorphan. 116,117 Indeed, the natural peptide N/OFQ, given intravenously, has also been shown to inhibit cough in experimental models at doses that do not affect general activity in the animal.…”

New concepts in the management of chronic cough

“…In a randomised controlled trial in patients with a post viral subacute cough, the NOP1 agonist was not superior to placebo or codeine. 45 Indirect antitussive drugs include those that suppress the cough reflex indirectly such as drugs with anti-inflammatory activity. The leukotriene antagonist, Zafirlukast, has been shown to reduce cough hypersensitivity and is recommended for treatment of cough variant asthma.…”