The effect of codeine on the Urge-to-Cough response to inhaled capsaicin

Abstract

We have shown previously in normal subjects that a sensory measure, the Urge-to-Cough rating, increases at concentrations of inhaled capsaicin that are lower than those necessary to elicit reflex cough. This finding suggests that the Urge-to-Cough may represent an index of the cough response. Research on cough in the human has most often employed challenge with inhaled capsaicin to induce reflex cough. Current measures of cough sensitivity in the human provide no information regarding the intensity of cough. The influence of codeine on cough perceptual sensitivity and the relationship to cough intensity with capsaicin-induced cough in normal subjects has not been evaluated. This study determined the effect of codeine on capsaicin-induced cough perceptual sensitivity and motor response in normal subjects in a double-blind, placebo-controlled, crossover study. This approach investigated the relevance of cough sensitivity, intensity, and sensory modalities in the assessment of cough suppression in humans. This study consisted of three experimental trials: administration of placebo, 30 mg codeine and 60 mg codeine. The study was double-blinded. The order of the three trials was randomized. Respiratory motor pattern was recorded with EMGs from the rectus abdominis, lateral abdominal muscles and eighth intercostal space. The subjects leaned into a fume hood to inspire deeply for 2 s once through a mouthpiece connected to the nebulizer. A modified Borg scale was used to estimate their Urge-to-Cough. The experimental trial consisted of eight test solutions of 0-200 microM capsaicin. Each solution was presented three times in a randomized block order for a total of 24 presentations. The lowest capsaicin concentration to elicit a cough was determined. The lowest capsaicin concentration to elicit an Urge-to-Cough greater than zero was identified. The Urge-to-Cough sensitivity was determined from the log-log slope. For placebo, the Urge-to-Cough was zero with inhalation of the vehicle and no coughs were observed. The threshold capsaicin concentration for subjects to report an Urge-to-Cough was 15.6 microM (+/-2.6 SEM). The capsaicin concentration threshold for eliciting a cough was significantly greater, 39.3 microM (+/-5.6 SEM). As the capsaicin concentration increased, the magnitude estimation of the Urge to-Cough increased. The slope of the log-log relationship for the Urge-to-Cough was 0.94 (+/-0.07 SEM). As the capsaicin concentration increased, the number and intensity of the coughs increased. The administration of 30 and 60 mg codeine had no significant effect on the threshold capsaicin concentration for the Urge-to-Cough. There was also no significant codeine effect on the slope of the log-log Urge-to-Cough relationship. Thirty and sixty milligram codeine had no significant effect on the relationship between the capsaicin concentration and the number and intensity of the coughs. The results of this study demonstrate that the threshold for a subject to perceive an Urge-to-Cough was less than the capsaicin concentration that elicits the cough motor response. There was a direct relationship between the sensory intensity (magnitude estimation of the Urge-to-Cough) and the cough number and intensity. Thus, as the sense of an Urge-to-Cough increased the cough motor response increased. Neither the 30 nor 60 mg codeine affected the perceptual or motor sensitivity to capsaicin-induced cough. These results showed that the initial threshold for responding to capsaicin-induced cough is the perception of an Urge-to-Cough, followed by a motor cough response if the capsaicin is increased above the perceptual threshold. As the capsaicin concentration increases, both the perceptual need to cough and the cough motor response increase. The response of subjects to inhalation of capsaicin consisted of both a sensory component leading to perception of an Urge-to-Cough and motor cough behavior.

Fig. 1

Airflow and expiratory muscle EMG pattern in response to a capsaicin-elicited cough. (a) The airflow pattern of the capsaicin-elicited cough. The dose of capsaicin was 100 μM inhaled for about 2 s. The cough response was associated with two inspirations and six expulsive events. The first inspiration had four expulsive events before the subsequent second inspiration. The second inspiration was followed by two expulsive events. The cough reacceleration, CR, definition of the cough resulted in a CR4 for the first cough response and CR2 for the second cough response. (b) The corresponding EMG activity for the airflow pattern in (a). The top three traces are the raw EMG signal for intercostal space 8, rectus abdominis and lateral abdominal wall surface recordings. The bottom three traces are the moving time average (50 ms time constant) of the full wave rectified of the 3 EMG recordings.

Fig. 2

Dependent cough variables as measured from the airflow pattern of a cough, CR1. The vertical lines on the airflow trace mark the time points for phase delineation. The hatched area under the expiratory airflow indicates the area of the plateau phase.

Fig. 3

Relationship between the Urge-to-Cough magnitude estimation and the capsaicin concentration. The group means and standard deviations of the magnitude estimations are plotted against the corresponding capsaicin concentrations on a log–log scale. The diamond symbols represent the mean magnitude estimation for placebo treatment, the square symbols represent the mean magnitude estimation for 30 mg codeine treatment and the triangle symbols represent the mean magnitude estimation for 60 mg codeine treatment. There were no significant treatment effects.

Fig. 4

Relationship between the total cough number with auditory counting and the capsaicin concentration. The group means and standard deviations of the cough numbers are plotted against the corresponding capsaicin concentrations on a linear scale. The diamond symbols represent the mean cough numbers for placebo treatment, the square symbols represent the mean cough numbers for 30 mg codeine treatment and the triangle symbols represent the mean cough numbers for 60 mg codeine treatment. There were no significant treatment effects.

Fig. 5

Relationship between the summed integrated EMG area and the capsaicin concentration. The integrated areas of each expulsive event were summed for all the expulsive events at each capsaicin concentration. Panel (a) is the relationship for intercostals space 8 measurements, (b) is for rectus abdominis measurements and (c) is for lateral abdominal wall measurements. The group means and standard deviations of the summed integrated areas are plotted against the corresponding capsaicin concentration. The gray bars represent the mean summed integrated area for placebo treatment, the black bars represent the mean summed integrated area for 30 mg codeine treatment and the open bars represent the mean summed integrated area for 60 mg codeine treatment. There were no significant treatment effects.

Fig. 6

(a) The relationship between the group mean Urge-to-Cough magnitude estimation and total cough number. As the capsaicin concentration increased, the Urge-to-Cough magnitude estimation and corresponding total number of coughs increased. (b) The relationship between the group mean Urge-to-Cough magnitude estimation and summed integrated area of the lateral abdominal EMG activity. As the capsaicin concentration increased, the Urge-to-Cough magnitude estimation and corresponding summed integrated EMG increased. Only the lateral abdominal EMG response is presented, however, an identical relationship was found for intercostals space 8 and rectus abdominis EMG activity.

Fig. 7

Threshold for eliciting a motor cough and perceptual sense of an Urge-to-Cough. The group mean and standard deviation for the minimum capsaicin concentration to elicit a motor cough is represented by the stippled bars. The group mean and standard deviation for the minimum capsaicin concentration to elicit a Borg perceptual score greater than zero for the Urge-to-Cough is represented by the cross hatched bars. The cough motor perceptual Urge-to-Cough responses for placebo, 30 mg codeine and 60 mg codeine treatments are indicated. There were no significant treatment effects.