Neither transdermal fentanyl nor oral, sustained-release morphine appear to improve persistent breathlessness in patients with COPD, according to a recent Dutch study.
The study, published in the European Respiratory Journal [link here], found no positive effect of either opioid compared to placebo across outcome measures including dyspnea score, sleep quality, health status, mastery, anxiety or capillary blood gas parameters.
“These findings contribute to a growing body of evidence questioning the use of long acting opioids for persistent dyspnea in real life,” the study said.
“We advocate a focus on a multimodal approach including non-pharmacological interventions as a more promising avenue to investigate for alleviating dyspnea in this patient population.”
The cross-over RCT comprised 58 patients with stable COPD and perceived dyspnoea despite optimal standard therapy. Patients had a mean age of 69 years, were 54% female, and had a baseline FEV1 of 33% predicted and median mMRC score of 4.
Participants were randomised to order of receiving transdermal fentanyl plus oral placebo, oral sustained-release morphine plus placebo patch, or placebo tablets plus placebo patch during three treatment periods of 11 days, separated by 3-day washout periods.
Thirteen patients discontinued the study due to exacerbations and seven due to adverse events.
The study found no statistically significant differences between fentanyl compared to placebo nor morphine compared to placebo with respect to the primary endpoint of mean daily dyspnea score.
As well, there were no significant differences in secondary outcomes such as health status as measured by Clinical COPD Questionnaire, mastery measured by Chronic Respiratory Questionnaire-Mastery domain, anxiety measured by Hospital Anxiety and Depression scale-Anxiety, and capillary carbon dioxide tension.
“We believe the fact that there was no change in health status is an important signal, since treating persistent dyspnea is a form of palliative care aimed to improve someone’s health,” the study said.
Regarding side effects, five participants experienced vomiting during the morphine treatment period compared to none on fentanyl or placebo.
However there were no significant differences between treatment groups with respect to other GI effects of obstipation and nausea, or other effects such as drowsiness and dizziness.
The investigators said they believed their study was the first to investigate fentanyl for persistent dyspnea.
Regarding the evidence on oral morphine, they said there have been inconsistent findings to date which may be related to the research setting, drug formulation, and treatment duration.
They said dyspnea was a complex symptom for which a one-dimensional treatment may be unlikely to succeed.
“This assumption is supported by the fact that trials investigating other medication such as mirtazapine, sertraline and benzodiazepines have found no beneficial effect for breathlessness in advanced cancer and COPD,” they said.
“Fortunately, treatment options comprise more than medication, and in recent years there have been publications about non-pharmacological interventions demonstrating positive results.”
The study noted the participants had stable COPD despite optimal management and the results cannot be translated to the end-of-life setting or acute dyspnea during an exacerbation.
Expert comment: need for nuance
Palliative medicine specialist Professor David Currow, Strategic Professor of the Flinders Ageing Alliance, told the limbic that chronic breathlessness was both prevalent and disabling.
“For people who experience this for long periods of time – this isn’t for days or weeks which I think is the impression of lots of people, it’s for years or decades – it is so disabling. We estimate in Australia that’s at least one in 300 people who can’t leave the house because they’re breathless; it may even be higher than that. That’s a very, very conservative estimate.”
Professor Currow, a co-author of the ERS clinical practice guideline on palliative care for people with COPD or ILD [link here], said one of the challenges was the lack of international consensus on which outcomes to measure for the symptomatic reduction of chronic breathlessness.
“Is it worse breathlessness or is it average? Is it some level of improved function – the ability to get to the letterbox and back rather than just to the front door – which to you or to me seems trivial, but to someone who’s been housebound, it’s a whole new world,” he said.
“We need to put some science behind what is going to be our best measure.”
He said the two opioids tested in the study have shown benefit for exertional breathlessness in the laboratory.
“So there’s no doubt that if you give people morphine or fentanyl before exercise to healthy volunteers in the laboratory, their experience is going to be different,” he said.
Commenting on the Dutch study, he said 76% of participants chose an opioid over placebo as their blinded preferred treatment.
“I don’t think we should underestimate how important that is. I think the most important take-home message is that we’ve got to stop saying, ‘Do opioids work in breathlessness?’ and we actually have to start talking, as we did in pain 50 years ago, about opioid-responsive breathlessness and opioid non-responsive breathlessness.”
“And their call for a multi-dimensional approach is absolutely sound. Everyone who treats breathlessness would strongly support that there isn’t a silver bullet for this. You need really good reversal of any underlying factors, you need great non-pharmacological interventions, and in some people, an informed, time-limited trial of regular low-dose sustained-release morphine is appropriate,” he said.
“We’re not saying ‘We’re going to put you on this forever’; we’re saying ‘We will trial it and see if you get genuine benefit’.”
Regarding future research, Professor Currow said we need “a more nuanced and sophisticated approach” to identify the people who do benefit, the people who don’t benefit, and the people who only experience harm.
“We’ve done our first genotyping study, and I’m keen to expand that dramatically. It’s really interesting that we’ve got genetic variation in baseline breathlessness before any intervention, depending on pathways that are associated with endorphins.”
Professor Currow said Australia remains the only country which has low-dose morphine available for the management of chronic breathlessness.