Oral, sustained release morphine can provide added relief to patients who have intractable breathlessness despite maximal treatment of the underlying causes of dyspnoea. In this adequately powered, randomised controlled trial, morphine provided a 7-10 mm improvement in the visual analogue scale for dyspnoea—results with both clinical and statistical significance. These results were corroborated by participants' reports of much better sleep during the morphine period. Sensitivity analysis showed that morphine still provided clinical benefit to the study population even if the modelled participants who withdrew experienced 25% worsening of their dyspnoea. Further, the results showed the same magnitude of improvement as seen in the pooled results of other trials (8 mm on the visual analogue scale).9
The results of this study are applicable to many outpatient settings in general practice, palliative care, and respiratory care. The study population of elderly, poorly functioning people predominantly with chronic obstructive pulmonary disease represents patients we encounter often, for whom few symptomatic options are available. The criteria used to identify participants were simple and as broad as possible. Patients needed only to be suffering from the symptom of refractory breathlessness. We specifically avoided invasive procedures such as measuring arterial blood gases or pulmonary function to identify eligible candidates as this would not be generalisable or ethical for many outpatient and palliative care settings.
Oral, long acting morphine was chosen for its convenience and continuous action. The sustained release morphine product used can be given once daily; evidence for its efficacy as a 24 hour medication was provided by the dramatic improvements in the evening dyspnoea scores. A small background dose of opioid may be better tolerated than the peaks and troughs of immediate release formulations.19
Although the results are significant and generalisable, clinicians should prescribe morphine for the control of dyspnoea with care. This was not a safety study, and it was not powered to detect significant side effects. The data imply that side effects were minimal. Neither respiratory depression nor severe sedation was identified. All participants who withdrew because of morphine encountered vomiting or sedation, which may be transient or treatable. Constipation was the only notable and common side effect. Review of the daily constipation scores showed that the constipation started to improve by the fourth day of the morphine period; early intervention could have an impact. An important consideration is that most patients who would be considering this treatment do not have any other options and are otherwise severely distressed and limited by their breathlessness. Hence, although the risk of constipation and other side effects is real, this may be an appropriate treatment for many patients, provided that the patient and doctor monitor for clinical benefit and side effects together.
The study design has several limitations. Firstly, there was no washout (no treatment) period. shows the persistence of the side effects of morphine into the early part of the placebo period. We recognised these risks a priori. The challenge was to develop a short protocol that would be acceptable and ethical for a group of very ill patients who did not have any other medical options. Although a parallel trial would have addressed this concern, it would have doubled numbers in a clinical population for which others have had difficulty recruiting. Instead we elected a crossover trial with an analysis plan that concentrated on the end of the treatment period only.14
We planned that sequence and period analyses would precede any analysis of treatment; fortunately, neither sequence nor period effects were identified.
Secondly, there was no blinding for constipation. To accommodate this, the only investigator aware of the constipation was the study nurse (AM), who was not involved in the analysis. Thirdly, the morphine dose chosen was 20 mg daily. Some clinicians may regard this as a relatively high dose in patients who had not been treated with opioids before. As the study was being designed it was the lowest once daily, sustained release formulation available. Subsequent dose ranging studies are needed.
Fourthly, the reduced evening dyspnoea scores and improved sleep may have been related to changes made by the participant, such as increased use of oxygen during the day or continuous positive airway pressure at night. Such potential confounders should have been equally distributed between the groups through randomisation. Finally, the clinical significance of a 7-10 mm change in the visual analogue scale may be questioned. We are not aware of any studies that correlate direct clinical meaning with specific changes of distance in the dyspnoea scale. None the less, in a population of patients in whom pharmacological treatment is not an option, the opportunity for a 5-10% improvement in a disabling symptom is welcome.
This study shows that rigorous randomised controlled trials can be performed in this population. Key factors were a short study period, simple bedside evaluation, collaboration across disciplines, one identified recruitment nurse, once daily dosing, and an evolving clinical culture that seeks evidence based approaches to care. Future directions include an effectiveness study that is adequately powered to evaluate safety. Such a study may well show that, with close monitoring, patients could continue taking opioids while tolerance develops to the nausea and sedation. Dose ranging studies in opioid tolerant and naive participants are also planned.
What is already known on this topic
Pooled data in a meta-analysis of eight small underpowered randomised trials support the clinical use of oral or parenteral opioids including morphine to manage refractory breathlessness
Clinical guidelines for the management of intractable dyspnoea in the palliative care and respiratory settings are contradictory owing to inadequate primary evidence supporting the efficacy and safety of morphine in this setting
What this study adds
This is the first adequately powered randomised controlled trial that showed the superiority of oral morphine for relief of the sensation of breathlessness.
This study was completed before the meta-analysis was published; it confirms the main findings of the meta-analysis with results of the same magnitude
The morphine administered in this study was an oral, once daily, sustained release formulation.
Side effects were minimal and no evidence of respiratory depression was found. Constipation was treated expectantly