Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea

Abernethy et al report that four days of treatment with slow release
morphine led to a significant reduction in breathlessness in their
patients, most of whom had COPD(1). They suggest that their findings are
generalisable but we believe that caution should be exercised before the
results of a short term study are used as evidence that morphine is
effective and well tolerated in the long term treatment of breathlessness
in patients with COPD.

Abernethy and colleagues cite a recent systematic review as further
evidence that opioids are effective for the treatment of breathlessness(2)
but most of the studies included in the review were single dose studies.
There were only three studies where subjects took opioids regularly for
two or more weeks and we do not believe that these studies support the
wider use of opioids in COPD. In one of these studies we treated 16
patients with severe COPD using a double-blind, randomised, placebo
controlled, crossover design. Slow release morphine was titrated up to
10mg b.d. and then continued for another four weeks. Despite a small, non
-significant improvement in the dyspnoea subscale of the Chronic
Respiratory Disease Questionnaire (CRQ) with morphine there was no
difference in the overall CRQ scores. The score for the mastery subscale
of the CRQ was significantly worse with morphine as was the six minute
walk distance and almost all of the subjects experienced adverse effects
including constipation, nausea and sedation. Nine patients elected to
continue morphine after the study but only 4 were still taking it three
months later. In another study of patients with COPD, Eiser et al(3)
studied 14 subjects and compared 2.5mg of diamorphine, 5 mg of diamorphine
and placebo six hourly for 2 weeks. The VAS scores for dyspnoea was
slightly worse with diamorphine although the difference was not
statistically significant. Several subjects were troubled by constipation
and nausea. In the third study, Woodcock et al treated 16 subjects with
30mg of dihydrocodeine t.i.d. for 2 weeks and 60mg t.i..d. for 2 weeks(4).
Five of the 16 subjects did not complete the study because of nausea and
vomiting. In the remaining 11 subjects there was a small but significant
reduction in breathlessness with 30mg of dihydrocodeine but no benefit at
all was seen with the 60mg.

Until further studies are undertaken the widespread use of morphine
for the long term treatment of dyspnoea in patients with COPD cannot be
recommended.

1.Abernethy AP, Currow DC, Frith P, Fazekas PS, McHugh A, Bui C.
Randomised, double-blind, placebo controlled crossover trial of sustained
release morphine for the management of refractory dyspnoea. BMJ 2003; 357:
523-528.

2.Poole PJ, Veale AG, Black PN. The effect of sustained-release
morphine on breathlessness and quality of life in severe chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 175: 1877-
1880.

3.Eiser N, Denman WT, West C, Luce P. Oral diamorphine: lack of
effect on dyspnoea and exercise tolerance in the "pink puffer"syndrome.
Eur Respir J 1991; 4: 926-931

4.Woodcock AA, Johnson MA, Geddes DM. Breathlessness, alcohol and
opiates. N Engl J Med 1982; 306: 1363-4.

Peter Black
Associate-Professor

Phillippa Poole
Associate-Professor

Department of Medicine
University of Auckland
Private Bag 92019
Auckland, New Zealand

Competing interests:  
None declared