| 1. |
- Currow, David, et al.
(author)
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A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-Arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness : Breathlessness, Exertion and Morphine Sulfate (BEAMS) study protocol
- 2017
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In: BMJ Open. - : BMJ. - 2044-6055. ; 7:7
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Journal article (peer-reviewed)abstract
- Introduction Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended-release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-Arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. Methods and analysis The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics and dissemination Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. Trial registration number NCT02720822; Pre-results.
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| 2. |
- Currow, David, et al.
(author)
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Regular, sustained-release morphine for chronic breathlessness : A multicentre, double-blind, randomised, placebo-controlled trial
- 2020
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In: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 75:1, s. 50-56
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Journal article (peer-reviewed)abstract
- Introduction Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness. Methods Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, â € as needed', immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0-100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst, best and average breathlessness; unpleasantness of breathlessness now, fatigue; quality of life; function; and harms. Results Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference -0.15 mm (95% CI -4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation. Conclusion No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine. Trial registration number ACTRN12609000806268.
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| 3. |
- Ferreira, Diana H., et al.
(author)
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Controlled-Release Oxycodone vs. Placebo in the Treatment of Chronic Breathlessness—A Multisite Randomized Placebo Controlled Trial
- 2020
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In: Journal of Pain and Symptom Management. - : Elsevier BV. - 0885-3924. ; 59:3, s. 581-589
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Journal article (peer-reviewed)abstract
- Context: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated. Objectives: Does oxycodone reduce chronic breathlessness compared with placebo? Methods: A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0–100 mm visual analogue scale) comparing arms Days 5–7. Secondary end points were average and worst breathlessness, quality of life, function, and harms. Results: Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001). Conclusion: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness.
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