Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure.
OBJECTIVE
We sought to test the hypothesis that suppression of chemosensitivity (respiratory response to arterial blood gases) with dihydrocodeine may improve dyspnea and exercise tolerance in patients with chronic heart failure.


BACKGROUND
Exertional dyspnea is a common limiting symptom in patients with chronic heart failure. The mechanisms underlying this symptom are not fully understood but may be related to increased ventilation caused, in part, by the augmentation of chemosensitivity. Suppression of chemosensitivity with mild opiates may thus improve this symptom as well as exercise tolerance.


METHODS
Twelve men with chronic heart failure (mean [+/-SE] age 65.5 +/- 1.5 years, range 58 to 75; left ventricular ejection fraction 21.3 +/- 3.0%, range 8 to 39) received placebo or dihydrocodeine (1 mg/kg body weight) on two separate days in a randomized, double-blind design. One hour later, hypoxic and hypercapnic chemosensitivities were assessed using the transient inhalations of pure nitrogen and the rebreathing of 7% carbon dioxide in 93% oxygen, followed by treadmill cardiopulmonary exercise testing. The symptoms of dyspnea and fatigue during the exercise test were assessed using a modified Borg scale from 0 to 10.


RESULTS
There was a significant fall in hypoxic and hypercapnic chemosensitivities with dihydrocodeine administration compared with placebo (0.447 +/- 0.096 vs. 0.746 +/- 0.104 liter/min per percent arterial oxygen saturation, p = 0.005; 2,480 +/- 0.234 vs. 2.966 +/- 0.283 liter/min per mm Hg, p = 0.01, respectively). Exercise duration was prolonged from 455 +/- 27 s on placebo to 512 +/- 27 s (p = 0.001) with dihydrocodeine, and peak oxygen consumption increased from 18.0 +/- 0.6 to 19.7 +/- 0.6 ml/kg per min (p = 0.002). The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to carbon dioxide output, decreased from 34.19 +/- 2.35 to 30.85 +/- 1.91 (p = 0.01). With dihydrocodeine administration, the change in the modified Borg score for dyspnea was -0.80 (p = 0.003) at 6 min and -0.33 (p = 0.52) at peak exercise, whereas that for fatigue did not change significantly. Arterial oxygen saturation was maintained during exercise despite dihydrocodeine administration (99.3% at rest vs. 98.9% at peak exercise, p = 0.21).


CONCLUSIONS
Augmented chemosensitivity is important in the pathophysiology of chronic heart failure. Its suppression with dihydrocodeine was associated with a reduction of exercise ventilation, an improvement in exercise tolerance and a decrease in breathlessness. Pharmacologic modulation of chemosensitivity may benefit patients with chronic heart failure and merits further investigation.
Chua
T P
TP
Department of Cardiac Medicine, Royal Brompton Hospital, London, England, United Kingdom.
Harrington
D
D
Ponikowski
P
P
Webb-Peploe
K
K
Poole-Wilson
P A
PA
Coats
A J
AJ
D000368:Aged; D002628:Chemoreceptor Cells / Q000187:drug effects* / Q000503:physiopathology; D003061:Codeine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004311:Double-Blind Method; D004417:Dyspnea / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects*; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D006935:Hypercapnia / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology; D008297:Male; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
C014481:dihydrocodeine; D003061:Codeine