Objectives We aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular, low-dose, sustained-release oral morphine for chronic breathlessness and (2) clinical characteristics associated with TEAE.
Methods Safety analysis of trial data. Adults with chronic breathlessness (modified Medical Research Council breathlessness score ≥2) due to heart or lung disease, or cancer, not on regular opioids were eligible. Symptoms associated with opioids (TEAE of special interest) were systematically sought using Common Terminology Criteria for Adverse Events (CTCAE) grading. Other harms could be reported at any time. The relationship between characteristics and presence of ≥1 TEAE of special interest was explored using univariable logistic regression analyses.
Results 1449/5624 (26%) Adverse Events from 279 participants were TEAE of which 150/1449 (10%) were severe (CTCAE grades 3–5). 1086/5624 (75%) were events of special interest of which 41/1086 (4%) were severe. Compared with placebo, morphine was not associated with more TEAE or severe TEAE of special interest (TEAE: OR 0.53, 95% CI 0.21 to 1.38, p=0.20; severe TEAE: OR 0.96, 95% CI 0.27 to 3.41, p=0.95) nor with CTCAE severity grade (χ2=4.39, p=0.50). Among the 26/150 (17%) with severe TEAEs, study withdrawal was more common in the morphine arm (18/26 (69%) morphine arm; 8/26 (30%) placebo arm). None of the severe TEAEs was a respiratory harm.
Conclusions Severe morphine-associated toxicity was uncommon and not associated with study arm. Clinical consequences were minor and self-limiting.
Trial registration number ACTRN126000806268.
- chronic breathlessness
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Contributors Concept and design: MJJ and DC. Protocol authors: MJJ, DC, CF and IS. Data analysis: CF and IS. Data interpretation: all; revisions of manuscript for intellectual content and approved final version: all.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests DC has received an unrestricted research grant from Mundipharma, is an unpaid member of an advisory board for Helsinn Pharmaceuticals and has consulted Mayne Pharma and received intellectual property payments from them. MJJ has received consulting institutional payments from Mayne Pharma. No other authors have any conflicting interests with the content of this manuscript.
Patient consent for publication Not required.
Ethics approval Ethics approval was obtained by all participating sites.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Requests to access data can be made to Prof. David Currow ( ). Requests will be considered on a case-by-case basis and managed according to the Palliative Care Clinical Studies Collaboration processes and procedures.