Regular, low-dose, sustained-release oral morphine for chronic breathlessness – Building the evidence

Author: Diana Ferreira

Ferreira, Diana, 2022 Regular, low-dose, sustained-release oral morphine for chronic breathlessness – Building the evidence, Flinders University, College of Medicine and Public Health

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Chronic breathlessness is a devastating syndrome affecting a large proportion of people with chronic diseases. Despite receiving multiple disease-targeting and non-pharmacological treatments for chronic breathlessness, many people do not achieve adequate symptom control. Opioids are the only recommended pharmacological treatment to reduce breathlessness in these circumstances. In particular, regular, low-dose, sustained-release morphine reduces chronic breathlessness, with an acceptable safety profile. However, interindividual response to this medication is variable and questions remain about its safety in the broader context of daily life. This multi-method research project includes six discrete sub-studies focused on aspects related with the safety and effectiveness of regular, low-dose, sustained-release morphine for chronic breathlessness.

Sub-study 1 qualitatively explores patients’ and carers’ experiences with severe chronic breathlessness associated with chronic obstructive pulmonary disease (COPD) and their perceptions of regular, low-dose, sustained-release morphine. Results revealed dyads manage chronic breathlessness together to achieve maximal function for both. Functional improvement is the major driver for wanting to continue long-term treatment. Driving emerged as an important activity, contributing to increase dyad’s physical and social space. Based on their perceptions, breathlessness at rest impairs driving, while sustained-release morphine does not.

Sub-study 2 is a systematic review of the impact of therapeutic opioid-agonists on driving-related skills. Included studies suggest that stable doses of therapeutic opioid agonists do not seem to impact driving-related skills of people with chronic conditions. No studies evaluated regular, low-dose, sustained-release morphine.

Sub-studies 3 to 5 were quantitative, hypothesis-generating, prospective sub-studies embedded in a randomised controlled trial (RCT) of regular, low-dose, sustained-release morphine for COPD-associated severe chronic breathlessness. Sub-study 3 explores this medication impact on simulated driving. A signal for worsening driving-simulator performance was registered after 48 hours of morphine therapy, which dissipated after one week on stable doses. Sub-study 4 explored genetic differences contributing to explain interindividual variability in response to morphine. Results suggest specific genotypes may influence both breathlessness intensity and response to this medication. Sub-study 5 explores whether sustained-release morphine modulates hypothalamic–pituitary–adrenal (HPA) axis activity. Results suggest that age, performance status, perceived sleep quality and breathlessness intensity may influence the degree of HPA dysfunction associated with chronic breathlessness; people deriving more “net benefit” with sustained-release morphine may also improve HPA axis function.

Sub-study 6 is a crossover RCT of regular, low-dose, sustained-release morphine for a different aetiology of chronic breathlessness – pulmonary arterial hypertension (PAH). Although this study did not recruit to target, it suggests this medication may not reduce chronic breathlessness in people with PAH and may generate more harms.

Hypotheses generated by this research project contribute to inform future research in this field and provide important insights to improve clinical practice. From a safety perspective, this work highlights the need to exercise caution when providing driving advice to people with chronic breathlessness, particularly when initiating regular, low-dose, sustained-release morphine. From an effectiveness perspective, this work suggests that genetic factors and disease aetiology may contribute to influence response to morphine. HPA axis modulation may be one of the mechanisms by which people derive benefit from this medication.

Keywords: chronic breathlessness, sustained-release morphine, palliative care, chronic obstructive pulmonary disease

Subject: Palliative Care thesis

Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: Prof David Currow