Discussion
Patients’ choice to continue the study medication seems to be motivated by the experienced net effect (weighing benefits and harms). Benefits included breathlessness improvement, increased mobility and positive side effects such as improved sleep at night; constipation was the only harm reported. Caregivers’ and patients’ experiences are similar, although caregivers tend to focus more on observable benefits which made a difference in their own lives. Caregivers are critical in helping manage regular, low-dose, sustained-release morphine harms and seem to contribute to the likelihood of continuing this medication in the long term. Participants’ experiences seem to vary according to morphine doses. Generally, people taking placebo or sustained-release morphine 8 mg were less likely to report benefits or harms. People taking 16 mg and 24 mg were more likely to experience benefits, but also side effects (beneficial or harmful). The only participant taking sustained-release morphine 32 mg experienced only harms.
The concept of net effect when beneficial has been used to explain people’s choices of sustained-release morphine versus placebo for chronic breathlessness.21 24 This study saw net effect, with positive, negative or neutral outcomes which, in turn, drive decisions to continue or cease the study medication. From the participants’ perspective, although symptomatic improvement was essential, better function was the main driver of perceived benefit. This aligns with previous work describing the importance of independence and mobility for patients with COPD who become increasingly more restricted as the disease progresses.3 35 Up until now, intensity of breathlessness measured with unidimensional breathlessness scales has been used as the preferred outcome of measure in RCTs of opioids for chronic breathlessness. Findings from this study suggest that primary outcome measures focused on function may be more relevant for this population. This hypothesis is further supported by a previous RCT of people with COPD and chronic breathlessness in which regular, low-dose, sustained-release oral morphine has been shown to significantly improve health status using the COPD assessment test, especially when assessing walking upstairs or hills.36 As a result, it is important to select primary outcome measures evaluating function in future studies evaluating opioids for chronic breathlessness.
For caregivers, observable gains in function are also critical not only because they see their loved ones become more independent, but also because their own living space increases.4 In some cases, caregivers provide unique perspectives on the benefits and downsides of therapy, that the patient alone is unable to provide. Since chronic breathlessness infiltrates the lives of both patients and caregivers, it is important to include caregivers’ perspectives in the assessment or reassessment of any new therapy, in order to get a full picture of its effects.37
This study brings a new lens on side effects caused by regular, low-dose, sustained-release morphine. First, while some side effects were experienced as harmful, others were perceived as helpful. Importantly, clinicians’ and patients’ perceptions are not always aligned, particularly in symptom evaluation.38 39 This study highlights that side effects typically perceived as harmful by clinicians may contribute to treatment success in some cases. Second, sedation and nausea were not reported in this study. These are frequent opioid side effects particularly during therapy initiation and upward titration. The use of very small doses of sustained-release morphine (8 mg) and controlled upward titration (maximum 16 mg weekly) may have contributed to these findings. However, constipation was common in this study and one of the few side effects contributing to discontinuing therapy. In line with previous findings, managing constipation might be critical to influence adherence to therapy in people taking regular, low-dose, sustained-release oral morphine for chronic breathlessness.21 Sustained-release morphine 8 mg caused few side effects but was also unlikely to improve breathlessness. With such small doses, the amount of morphine binding to µ-opioid receptors may be insufficient to trigger any clinical effect.40 Slow upward titration allows the development of tolerance to morphine, which can reduce side effects experienced after abrupt introduction of higher doses.40
This qualitative study shows that most people are unaware of the use of sustained-release morphine for chronic breathlessness. This may represent a practical advantage in the clinical setting given that patients may be intrigued about its potential effects and less focused on opioid-related concerns (eg, addiction).41 Additionally, for people who do express concerns, information about the low doses used for chronic breathlessness may be sufficient to reassure them. In any case, support from treating clinicians seems to be critical before initiating the study medication.42 43 However, after experiencing net benefit, some participants may want to continue taking morphine even when they face clinicians’ resistance. This requires clinicians to be well informed and prepared to deal with such challenges. Overall, caregivers were less concerned about side effects and more willing to try a new medication that could improve breathlessness. This is not surprising as caregivers are often severely distressed by patients’ breathlessness and their functional decline.44 It is likely they are receptive to any treatment aiming to reduce patients’ suffering.
Overwhelmingly, participants reported that regular, low-dose, sustained-release morphine was easy to take and therefore not an obstacle to therapy continuation. Sustained-release formulations are often well tolerated because they require less frequent administrations and do not require interruptions to sleep when compared with immediate-release morphine (taken approximately every 4 hours).45 For people who experienced benefit, getting a prescription of sustained-release morphine after the study was difficult and frustrating. This was partially attributed to a lack of a formal indication and registration for chronic breathlessness at that time. However, clinicians are often resistant to prescribe morphine in people with COPD due to fear of respiratory depression and overall concerns related with opioid safety.46 47 Such fears may still persist after sustained-release morphine approval, and may require interventions aiming to inform and support clinicians. Moreover, despite supportive international guidelines,15 16 regular, low-dose, sustained-release morphine is still not registered for chronic breathlessness outside Australia. Thus, accessing this treatment it is still a challenge for many patients with disabling breathlessness and their clinicians.
This study also highlighted the role of caregivers, who are often the only source of support for these patients, having a crucial role in helping to manage the side effects of sustained-release morphine therapy. This is in line with previous work describing the role of carers in the process of adaptation to breathlessness, requiring extreme flexibility and rapid adjustment to the unpredictable challenges imposed by breathlessness.48 Given the caregiver’s role in facilitating coping with constipation and the proportion of patients with a caregiver willing to continue morphine after the trial, this work also suggests that the caregiver may be a key player in patients’ adherence to treatment with regular, low-dose, sustained-release morphine. The relevance of caregivers in facilitating patients’ adherence to therapy was highlighted before,22 suggesting that the caregiver may not only be a care recipient but also a potential co-worker with clinicians.49
This was the first study focusing on people’s experiences with the current recommended formulation and doses of sustained-release morphine for chronic breathlessness.20 People had recently started the medication, and some had chosen to discontinue it. This provided a range of experiences (positive and negative) which were not captured before.23 Participants and researchers were blinded, which reduced bias while selecting and interviewing participants. One limitation of this study is that interviews were conducted by a non-native English speaker (DF). Any misunderstandings between interviewer and interviewees were mitigated by interview and transcription checking performed by a native English-speaker researcher (AH). The qualitative design limits generalisability of the findings. However, data checking/analysis involved researchers with different backgrounds, reducing the risk of bias. All participants had agreed to be part of the trial, which could have led to selection bias of people who were willing to accept morphine. All participants completed at least 3 weeks on the BEAMS Trial. Perceptions from this group may not reflect the views of all people with COPD and chronic breathlessness.
This study has important implications for future research and clinical practice. The concept of ‘net effect’ highlights key factors influencing the decision to continue therapy with regular, low-dose, sustained-release morphine and may be useful to understand people’s choice to continue other therapies for chronic breathlessness. Considering that caregivers are instrumental in alleviating harms associated with regular, low-dose, sustained-release oral morphine, it is essential to investigate caregivers’ needs in this context and understand how patient and caregiver can better cooperate in the management of this medication. It is also imperative to understand how to facilitate coping with therapy for patients who do not have a caregiver. In clinical practice, discussing the potential role of regular, low-dose, sustained-release oral morphine to reduce chronic breathlessness and highlighting the small doses required for this indication may increase patients’ and carers’ acceptance of this medication in clinical practice. For patients taking regular, low-dose, sustained-release oral morphine, carers are active agents in ameliorating the impact of harms associated with therapy. Informing and preparing carers for potential harms of regular, low-dose, sustained-release oral morphine may reduce their anxiety and empower them to better respond to such situations.