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1. Methods were devised and evaluated for inducing breathlessness by submaximal graded exercise in healthy subjects while objective measurements of cardiorespiratory function were made. Breathlessness was assessed with serial visual analogue scales (VAS), but with various measures to enhance repeatability. 2. A high level of reproducibility was obtained in spite of the subjective nature of the assessment. Individual responses were described by the relationship between breathlessness and ventilation. The sensitivity of the method was demonstrated by the use of inspiratory resistances which disturbed this relationship and caused greater breathlessness for a given level of ventilation. 3. These methods were applied to six healthy subjects to analyse the effects of acute doses of diazepam and promethazine on breathlessness induced by graded exercise or by rebreathing carbon dioxide in a double-blind study. 4. During exercise, diazepam and promethazine did not reduce breathlessness, although there was a minor trend with promethazine. During exposure to elevated levels of carbon dioxide, diazepam and promethazine had no effect on breathlessness. Diazepam and promethazine produced similar levels of sedation, but neither drug had significant effects on the ventilatory response to carbon dioxide. These preliminary findings contrast with those reported for chronic diazepam in 'pink puffers'. 5. Raised levels of carbon dioxide caused greater breathlessness in relation to ventilation than did exercise.

1 In six healthy subjects, respiration and the sensation of breathlessness were assessed during submaximal exercise and the subsequent recovery. The overall responses were expressed by the relationship of breathlessness to minute volume. 2 Because of the high subjective component in the assessments, validation of the method in these particular subjects was an integral part of the study. The relationship of breathlessness to ventilation during identical periods of exercise was highly reproducible and sensitivity was demonstrated by an alteration in this relationship in the presence of an inspiratory resistance. 3 Codeine at a dose of 60 mg by mouth was compared with placebo, each treatment being given on two occasions. The study was conducted in a double-blind fashion with randomisation of the order of treatments.4 Codeine at this dose allowed higher levels of carbon dioxide to be tolerated during breath-holding; oxygen uptakes at rest and during exercise were unaffected. Ventilation and breathlessness at the end of exercise were each slightly but significantly reduced by codeine but the relationship between breathlessness and ventilation was not changed. Codeine did not prevent detection of an inspiratory resistance.

Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and to determine the contributions from promethazine's major pharmacological actions. Twelve healthy subjects participated in a double‐blind, within‐subject comparison of promethazine and placebo each given acutely by mouth. Breathlessness was assessed with visual analogue scales during a progressive exercise test and was related to minute ventilation. Promethazine had no significant effect on breathlessness nor on the relationship between breathlessness and ventilation. The role of histamine‐antagonism was investigated in a subgroup of the subjects by administration of mebhydrolin. No effect on breathlessness was detected. In contrast, the standard phenothiazine, chlorpromazine, caused a marked and statistically significant reduction in breathlessness without affecting ventilation and without causing detectable sedation. This unexpected finding merits further study in patients and is discussed with reference to the role of chlorpromazine as a constituent of Brompton's Mixture.

A recent meeting of the European Society for Clinical Respiratory Physiology, held in Antwerp, focused on the mechanisms and management of respiratory symptoms. Dyspnoea received particular attention and this review is based on a talk presented at that meeting.The clinical problem posed by dyspnoea, or breathlessness, is of considerable magnitude. Precise data on its prevalence a re lacking but it is the most common symptom in patients with cardiorespiratory disease. Many chronic diseases are associated with dyspnoea, notably cardiac failure and chronic obstructive pulmonary disease. Extrapolation from the epidemiological survey of the Respiratory Diseas~ Study Group of the RCGP [I) would suggest that. m the UK alone, approximately 750,000 patients with chronic bronchitis experience dyspnoea induced by walking on level ground.A therapeutic agent which reduces the sensation of dyspnoea would be expected to improve the quality of life for the patient by delaying the restrictions on Hfestyle imposed by breathlessness and by mitigating a symptom which causes distress and induces anxiety. This would be no substitute for specific therapy directed at the underlying disease process, but could be of value when the patholot:,ry is not reversible. Close analogies exist with the use of analgesics to treat pain.Discovery of drugs to reduce dyspnoea is difficult because the pathophysiological mechanisms are still in dispute. In addition, animal models are limited in the study of sensations. In this laboratory known pharmacological agents were used in studies on man to discover the possible mechanisms of dyspnoea.No progress could be made until methods were available for assessing breathlessness. Precision was necessary in these assessments and there had to be knowledge of the reliability and limitations of the method in view of its subjective nature. Over about ten years, experience has been gained ~hich provi?es opportunities to optimize future experunentaJ des1gn and to appreciate when credibility has been over-