Cough Responses to Tussive Agents in Health and Disease

Coughing is a distressing symptom which has a major impact on quality of life. It has been estimated that cough costs the UK economy £1 billion each year. Currently there are no effective anti-tussive agents to treat subjects with cough. Although drugs such as morphine may have some anti-tussive effect, side effects unacceptable.

Currently our understanding of the mechanisms which lead to coughing in different diseases is poor. Many mechanistic studies rely on testing the sensitivity of the cough reflex by inhalation of capsaicin (chilli-pepper extract) or citric acid. These challenges do not differentiate well between health and disease or between different disease states. Other agents such as prostaglandins and bradykinin are known to stimulate a coughing but responses to these agents have rarely been used as a measure of cough reflex sensitivity and not been compared to standard challenges.

It is clear that patients with common airway diseases such as COPD and asthma cough significantly more than healthy subjects. Moreover subjects presenting with chronic cough have cough rates an order of magnitude higher than most patients with airway disease. These differences are poorly represented by the differences in current cough challenge tests.

The investigators hypothesize that patterns of cough responses to different tussive agent may better differentiate between health and different disease states. These patterns may also suggest the different mechanisms leading to cough in different diseases.

Inclusion criteria

• General

• Adult subjects aged 18 years and over
• Meet criteria for subject groups as outlined below

(1) Healthy volunteers

• Non-smokers
• No history of respiratory disease

(2) Healthy smokers

• Current smokers with smoking history of ≥10 pack years
• Spirometry within normal limits i.e. FEV1>80% predicted and FEV1/FVC ratio >75% predicted

(3) Asthma

• Physician diagnosis of asthma
• Airways hyperresponsiveness to methacholine; PC20<16mg/ml (within last 2 years)
• Non-smokers or ex-smoker with smoking history of ≤10 pack years

(4) COPD

• Physician diagnosis of COPD
• Ex-smokers with smoking history of ≥20 pack years
• Spirometry demonstrating airflow obstruction i.e. FEV1/FVC ratio <70%

(5) Chronic Cough

• History of a dry cough for >8 weeks
• Normal CXR
• Non-smokers or ex-smoker with smoking history of ≤10 pack years

Exclusion criteria

• 1) Symptoms of upper respiratory tract infection within the last 6 weeks 2) Participation in another clinical trial of an investigational drug within the last 4 weeks 3) Use of medication likely to alter cough reflex sensitivity i.e. ACE inhibitors, codeine phosphate, morphine sulphate, 4) Patients with severe respiratory disease i.e. FEV1 < 1 litre, 5) Significant medical co-morbidities likely to affect ability to participate in the trial or affect cough reflex sensitivity e.g. diabetes, stroke, Parkinson's disease, multiple sclerosis etc.