Predictable adverse events such as respiratory depression highlight the need for caution when prescribing morphine for refractory breathlessness

From the authors:

“A scientist's aim in a discussion with his colleagues is not to persuade, but to clarify” [1]. We therefore thank D.C. Currow and co-workers for both their comments and the opportunity to continue the discussion regarding the risks and benefits of using opioids to treat refractory chronic breathlessness. The purpose of our recent case report [2] is not to persuade clinicians to prescribe or not prescribe opioids for the off-licence indication of refractory breathlessness, but to highlight and clarify risks of prescribing opioids in this clinical setting and when practising real life medicine, which is so different from the carefully controlled and managed environment of clinical trials.

We readily acknowledge that respiratory depression is a predictable and unremarkable outcome from a significant opioid overdose. Indeed, many physicians cite the risk of respiratory depression as one of their main concerns when considering prescribing opioids for refractory breathlessness [3–7], therefore this event, as rightly noted, is not a new danger. However, the purpose of case reports is to provide detailed and accurate information about individual patients, which is lost and cannot be reported in larger clinical trials. This detailed description of a clinician's experience is essential and allows for discussion as the evidence from clinical trials is translated into the practice of real world medicine.

Therefore, to clarify further this particular case report aimed to discuss not predictable adverse events from an opioid overdose, but: 1) the risks of first initiating opioids for severe breathlessness to patients with acute exacerbations of chronic obstructive pulmonary disease (COPD), as to date these patients have been excluded from all clinical trials investigating the role of opioids for refractory breathlessness; 2) the risks of inadvertent patient dosing errors occurring in COPD patients who are often older, frail, socially isolated and have multiple medical issues; and 3) the need for patient education regarding dosing and adverse events, as well as close supervision and early outpatient review, with ongoing follow-up to monitor treatment response, compliance, side-effects and possible risks [2].

As discussed in our case report, there is currently no evidence to support a regimen that uses both extended release and immediate release morphine preparations together for treating refractory breathlessness [2]. However, it should be noted that the current evidence base for using opioids to treat refractory breathlessness is very limited [8]. Nonetheless, this particular dosing regimen was recommended by the specialist palliative care team to the patient in the case report, because the patient appeared to be actively dying from respiratory failure and had severe and extremely distressing breathlessness at rest (not just on exertion). The case patient required both types of morphine preparation to achieve adequate symptom palliation. Therefore, it is unclear how the comments of D.C. Currow and co-workers regarding the pharmocokinetics of immediate release morphine and its role in managing exertion induced breathlessness bear any relevance to this case report.

Additionally, focusing on the morphine regimen prescribed to the case patient distracts from the fundamental issue, which was that opioid induced respiratory depression occurred after an inadvertent patient dosing error. Such errors may occur with either tablet or liquid medications, therefore the patient could potentially have accidentally overdosed on either an extended release or immediate release morphine preparation. Potential options to prevent patient dosing errors include ceasing morphine prescription on hospital discharge or prescribing daily, extended release morphine administered from a pharmacist-prepared, scheduled, medication dosette box.

We completely agree with D.C. Currow and co-workers that responsible prescribing of opioids inherently includes adequate monitoring and supervision, and indeed we discussed this issue within the case report [2]. There is no doubt that when patients are discharged home with a new prescription of morphine for breathlessness, they should ideally be seen by the prescribing clinician or team within 1–2 weeks of discharge. However, access to urgent outpatient review is often challenging due to high service demands and the ability of each health system to meet those needs. Similarly, for geographically vast countries like Australia, patients may have to travel long distances (requiring a drive of several hours) to attend a hospital outpatient appointment. This poses a significant burden on a patient with severe respiratory disease, who is recovering from an exacerbation and who may be reluctant to return within a few days and wait (potentially hours) to be reviewed. As our aim must be to offer high quality, safe, patient focused care, these issues highlight the absolute need for clinicians to work closely and communicate well with community general practitioners to ensure local, follow-up, supervision and support is immediately available in addition to hospital follow up.

The limited current evidence base suggests that morphine has a small, but important, short term role as an off-licence treatment for chronic refractory breathlessness in stable outpatients [8]. However, our case report highlights that translating limited evidence into wider clinical practice is not straightforward. While we need further clinical trials to better understand optimal morphine dosing and regimen, long term utility and safety, and effect on quality of life, we also need long term, cohort data describing real world experience using opioids in patients with chronic respiratory disease and refractory breathlessness. Finally, as clinicians we must continue to discuss and share our clinical experiences so that we can identify risks, find solutions and prevent avoidable adverse events.