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Department of Internal Medicine, Hospital de Egas Moniz—CHLO, Lisbon, PortugalDepartment of Medical Oncology, Portuguese Institute of Oncology (IPO) of Lisbon Francisco Gentil EPE, Lisbon, Portugal
Address correspondence to: José P. Silva, MD, Department of Internal Medicine, Hospital de Egas Moniz—CHLO, Department of Medical Oncology, Portuguese Institute of Oncology (IPO) Lisboa Francisco Gentil EPE, Lisbon, Portugal.
Department of Internal Medicine, Hospital de Egas Moniz—CHLO, Lisbon, PortugalDepartment of Medical Oncology, Portuguese Institute of Oncology (IPO) of Lisbon Francisco Gentil EPE, Lisbon, Portugal
Discipline, Palliative and Supportive Services, Flinders University, Bedford Park, South Australia, AustraliaDepartment of Medicine, Duke University Medical Centre, Durham, North Carolina, USA
Patients' preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy.
Objectives
The aim of this secondary analysis was to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference.
Methods
Data were pooled from three randomized, double-blind, crossover, placebo-controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference.
Results
Sixty-five participants provided sufficient data (60 men; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78–0.93; P < 0.001). There was also an inverse association between morphine preference and sedation (odds ratio = 0.77, 95% confidence interval 0.60–0.99; P < 0.05). An inverse association was also seen between nausea and morphine preference in the univariate model only (P < 0.05). No association was seen between morphine preference and breathlessness intensity, either at baseline or change from baseline.
Conclusion
Participants preferred morphine over placebo for the relief of chronic refractory breathlessness. Morphine offers clinically important improvement, but net benefit can be easily outweighed by side effects, reducing net benefits. Side effects require aggressive management to allow more patients to realize benefits.
Persistent breathlessness despite optimal medical therapy and a person's own adaptation (refractory breathlessness) is prevalent in people with advanced disease.
Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review.
A secondary pooled analysis of three randomized, double-blind, crossover studies revealed that younger age and higher baseline breathlessness were predictors of greater likelihood of response to opioid therapy, whereas functional status and etiology were not.
Furthermore, analysis of this pooled data set found that a difference of only 9 mm on a 0–100 mm Visual Analogue Scale was sufficient for a participant to prefer one treatment arm over another.
Patient preferences for an intervention are derived from the net benefit—that is, patients' perceived balance of benefits and side effects. A better understanding of preferences may allow insight to improve individually tailored prescribing for refractory breathlessness. Factors not yet identified could also influence the net clinical effects in patients' perceived response, impacting on choice and ongoing compliance.
The aim of this study was to explore blinded patient preferences for morphine or placebo for chronic refractory breathlessness from data pooled from the only three double-blind, crossover, randomized controlled trials performed in this setting
were included in these studies. Inclusion criteria in this pooled analysis included completion of the crossover trial and availability of blinded patient preference for the arm of the study that they felt provided better benefit for breathlessness. In the study by Oxberry et al.,
patients were randomized to morphine, oxycodone, or placebo. To optimize comparability in the analysis, patients whose blinded preference relied on oxycodone were excluded (n = 9). Almost all participants had heart failure (HF) (n = 36) or chronic obstructive pulmonary disease (COPD) (n = 29). Two patients had other etiologies (restrictive lung disease (n = 1) and cancer (n = 1)) and also were excluded, leaving 65 participants (Fig. 1). Data were already anonymized. Ethics confirmed that permission was not required for analysis of pooled, anonymized data, where appropriate written informed consent had been obtained for each participant.
Fig. 1Diagram concerning the selection of patients for this study.
Measurements of breathlessness before and after four days of morphine (20 mg/day or 10 mg/day if creatinine > 200 μmol/L [n = 2]) and placebo were collected, seeking to define the effect of morphine on refractory breathlessness. The studies' methods are described in detail elsewhere, including the rationale for combining measures of breathlessness intensity and performance status.
Participants had chronic refractory breathlessness. Baseline participant characteristics collected by all included studies were age, gender, disease etiology, breathlessness intensity, and functional status.
Scale Measurements
Numerical Rating Scale scores were converted to Visual Analogue Scale scores as patient-reported data have similar distributions,
and thus, NRS scores were represented as equivalent 0/100 in the pooled data. For functional status, New York Heart Association Functional Classification was converted to Karnofsky Performance Status,
For toxicity, qualitative outcomes were used because of heterogeneity in the scales used.
Statistical Analysis
Analysis of variance or Kruskal-Wallis tests compared differences between groups for covariates that were normally and nonnormally distributed, respectively. Chi-square tests compared proportions for categorical variables between groups. The primary outcome, morphine preference, is trichotomous: morphine preference, preference for placebo, or no preference. Multivariable ordinal logistic regression assessed associations between morphine preference and age, ECOG PS, disease etiology (HF vs. COPD), baseline breathlessness, improvement in breathlessness, nausea, sedation, and constipation. Improvement in these four symptoms was defined as the change in each attribute over the morphine study period minus the change in each attribute over the placebo period. The proportional odds assumption was examined (using Stata's brant command), and no evidence of model violation was found (P = 0.66). Results are presented with 95% CI, and a P-value of less than 0.05 (two sided) is considered statistically significant. All analyses were performed with Stata 13.1 (StataCorp LP, College Station, TX).
Results
Baseline data from each study are presented in Table 1. Changes in breathlessness achieved in each study are described in Table 2. The combined data set yielded a population with a mean (SD) age of 71.6 (9.8) years of whom 60 were male (Table 1). Disease etiology for breathlessness was HF (55%) and COPD (45%). The median ECOG PS was 2 (ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), and the median (interquartile range) baseline breathlessness was 48 mm (30–60) indicating moderately intense breathlessness.
Table 1Characteristics of the 65 Participants Who Provided Data on Opioid or Placebo Preference for Chronic Refractory Breathlessness
Data from 28 participants were excluded or missing (Fig. 1), with 11 participants not completing the crossover, and missing blinded preference data in six participants. A relative predominance of the excluded subjects was female, but otherwise, clinical and demographic characteristics were similar between the two groups.
Preference
Twenty-eight participants (43.1%) preferred morphine, 21 (32.3%) placebo, and 16 (24.6%) had no preference. For the patients who stated a preference, median breathlessness improvement is presented in Fig. 2.
Fig. 2Variation in median breathlessness intensity (baseline and conclusion) with placebo and morphine. VAS = Visual Analogue Scale.
On multivariable analysis, there was a strong association between morphine preference and younger age (odds ratio [OR] = 0.85, 95% CI 0.78–0.93; P < 0.001) (Table 3). There was also an inverse association between morphine preference and sedation (OR = 0.77, 95% CI 0.60–0.99; P < 0.05). An inverse association was seen between nausea and morphine preference in the univariate model only (P < 0.05). No association was seen between morphine preference and breathlessness intensity, either at baseline or change from baseline.
Table 3Associations Between Morphine Preference and Variables From Pooled Data of Three Randomized, Double-Blind, Placebo-Controlled Crossover Studies of Morphine for Refractory Breathlessness
Fifty-five percent of the patients with HF preferred morphine compared to 28% of people with COPD although this was not statistically significant (OR = 0.50, 95% CI 0.07–3.38; P = 0.48). Only one study provided information on sleep quality.
None of the patients whose sleep quality improved on morphine showed a preference for this drug, and so, this was not included in regression modeling.
Analysis was conducted exploring three adverse effects on morphine preference. There was no multivariate association between blinded patient preference and nausea (P = 0.25), although in the univariate analysis those experiencing nausea were less likely to prefer morphine (P = 0.049). No association between constipation and blinded patient preference was evident (Table 3).
Discussion
This secondary analysis showed that younger age is an important factor in opioid preference for the relief of refractory breathlessness when compared with placebo. Additionally, there is an inverse relationship between the side effects of sedation and nausea, and morphine preference, which suggests that these side effects can easily outweigh any benefits obtained.
Younger Age
Younger age is correlated with patient preference. One observation in this data set that may help to explain this difference is that there was a lower frequency of nausea in younger participants (13% under 70 and 26% over 70 years old). A subgroup analysis to determine the predictors of preference among younger participants was not conducted because there were insufficient participants to conduct a thorough statistical analysis. Additionally, it is possible that an opioid-related reduction of sympathetic drive may be more effective in younger people, which may relate to some dimensions commonly associated with breathlessness.
Future studies could explore this subgroup in more detail.
Disease Etiology
The proportion of participants who preferred morphine was notably higher in HF than COPD. Extensive work has been conducted on the role of opioids in the relief of breathlessness. Central opioid receptor pathways seem to be etiology independent
In this set of data, baseline breathlessness intensity did not correlate with blinded patient preference. This finding was unexpected because previous work has shown that higher values of baseline breathlessness were predictors of response to opioid therapy.
Nevertheless, morphine reduces but does not eliminate breathlessness, and the presence of undesirable side effects seems to have a clear impact on patients' choice, outweighing any clinical benefit obtained.
Other measures such as the affective component of breathlessness
(the unpleasantness of breathlessness) may help to explain why more people, although still blinded, chose morphine than the other options. None of these studies included an affective measure.
Functional Status
No correlation was found between baseline functional status and blinded patients' preference. The studies did not measure physical functioning, either for activities of daily living or physical activity, during or at the end of participation. Patients may continue to exert themselves to the same level of breathlessness so that they may feel that their breathlessness has not changed while on morphine although they are more active. Intensity of breathlessness may ultimately improve but only over time as skeletal muscles and sympathetic activity respond to improved conditioning.
Therefore, it is likely that these studies have not captured all the patient-relevant benefits.
Adverse Effects
There were inverse relationships between blinded morphine preference and, separately, sedation and nausea. Constipation did not seem to play a significant role in morphine preference. On the whole, patients' preference for morphine seems to be hindered by the occurrence of side effects, at times possibly overshadowing any direct effect on the relief of breathlessness.
Previous studies have analyzed patient preference in several fields of medicine with conclusive evidence that medication efficacy and even symptom control are sometimes secondary when compared to medication-induced side effects.
Some studies also reached the conclusion that lack of sedation or nausea is particularly important when preferring or adhering to one therapy over another.
Excessive daytime sleepiness and adherence to antihypertensive medications among Blacks: analysis of the counseling African Americans to control hypertension (CAATCH) trial.
This highlights that side effects should be carefully addressed and aggressively handled, which ultimately might improve the rates of a perceived net clinical benefit, best expressed by patients' blinded preference and, ultimately, long-term compliance with medications.
These data derived from three short-term studies with a crossover design. As it is known, unwanted side effects are most strongly noted in the first days of morphine treatment and often preventive medication is required. In these studies, drugs like antiemetics or laxatives were not regularly used. As such, the first four days of therapy may not be representative of longer term therapy.
Quality of Sleep
Previous studies have shown improvement in quality of sleep in other clinical contexts, at the appropriate morphine dosages.
but participants in this study who reported decreased breathlessness while taking morphine were also likely to report improved sleep quality with morphine (P = 0.039).
Despite an improvement in sleep quality in the morphine arm, this was not a factor in determining morphine preference.
Strengths of the Study
To our knowledge, this was the first study evaluating blinded patient preference for morphine in the setting of chronic refractory breathlessness, although previous analysis of this pooled data set has investigated the clinical improvement in breathlessness intensity required for patients to choose one treatment arm over another irrespective of final choice.
This parameter has been largely underevaluated although there is evidence to show that patient preference and lack of adverse effects is often associated with compliance
This was a post hoc (secondary) analysis conducted on three studies. Two of these studies were adequately powered and one was a pilot. This was an exploratory, hypothesis-generating study. The main aim thus was to provide a basis for future research.
The study conducted by Oxberry et al. had three arms (morphine, oxycodone, and placebo). The patients who preferred oxycodone were excluded from the analysis. Apart from making the data more comparable, as previously stated, there is significant controversy about the role different opioids play in the relief of breathlessness.
Further adequately powered studies are necessary to shed light into this topic.
Measuring breathlessness constitutes a challenge. The most commonly used measurement scales in both clinical practice and research rely solely on unidimensional measurement of breathlessness intensity. Given the multidimensional nature of this symptom, it is easy to miss important benefits obtained with morphine treatment. In addition, a similar issue applies to unidimensional measurements of other symptoms such as nausea and sedation, such as the measurement used in these studies. This unidimensional assessment of side effects might also miss important features that may significantly influence patients' preference.
Furthermore, to analyze breathlessness scores, functional status, and adverse effects, it was necessary to achieve common outcome measures, converting different scales. This could have had an impact in the obtained results.
Sample
The studies analyzed contained a predominance of male subjects. The relative proportion of female subjects who did not complete the crossover was higher than their male counterparts. The opioid trial period was four days and it could be that were adverse events such as nausea and sedation treated more aggressively as opioids were initiated; there could have been more completions, especially as these symptoms often completely resolve soon after opioids are initiated. Longer term data are needed to answer this question. In terms of etiology, the analysis is limited to participants with COPD and HF.
Clinical Implications
This study analyzed blinded participants' preferences rather than the stated primary outcome. In fact, there was no significant direct association between change in breathlessness intensity and blinded morphine preference. This highlights the need to consider patients' perceived net benefit when initiating a therapy including whether level of function improves. The occurrence of side effects should be actively monitored and aggressively treated. Routine inquiry about other important patient-relevant outcomes such as perceived breathlessness unpleasantness and exercise tolerance may help assess whether opioids have provided net clinical benefit.
Unanswered Questions and Future Directions
Adequately powered randomized, double-blind studies should be performed to address the issues concerning predictors of preference. In addition, predictors of side effects and the ways to prevent them should be addressed because they seem to be key factors influencing blinded patients' preference. This work also outlines the need to include other measures of breathlessness, such as the affective component associated and an objective measure of physical activity and function. This could explain the apparent lack of correlation between morphine preference and clinical response. Given the age-related asymmetries of clinical response and preference for opioid therapy, subgroup analysis of younger and older patients should be considered in future studies. These data included three short-term studies. Longer term studies using morphine may help to determine if side effects have the same impact on patients' preference.
Conclusions
In this study, participants preferred morphine over placebo for the relief of chronic refractory breathlessness. Morphine offers clinically important improvement but net benefit is easily outweighed by side effects, reducing overall preference. Side effects require aggressive management to allow more patients to realize benefits. Single, unidimensional measures of breathlessness may miss key benefits of therapy.
Disclosures and Acknowledgments
Dr. Currow has received inventor payments and worked as a consultant to Mayne Pharma; received an unrestricted research grant from Mundipharma; been an unpaid member of an advisory board for Helsinn Pharmaceuticals. Dr. Johnson has worked as a consultant to Mayne Pharma. Dr. Abernethy has research funding from the National Institute of Nursing Research, National Cancer Institute, Agency for Healthcare Research and Quality, DARA, GlaxoSmithKline, Celgene, Helsinn, Dendreon, Kanglaite, Bristol-Myers Squibb, and Pfizer; these funds are all distributed to Duke University Medical Center to support research including salary support for Dr. Abernethy. Pending industry-funded projects include: Galena and Insys. She has had consulting agreements with or received honoraria (>$5000 annually) from Bristol Myers Squibb and ACORN Research. Dr. Abernethy has corporate leadership responsibility in athenahealth (health information technology [IT] company; Director), Advoset (an education company; Owner), and Orange Leaf Associates LLC (an IT development company; Owner). All other authors declare no conflicts of interest.
The authors thank Ms. Debbie Marriott for her ready assistance and for her expertise in article formatting and submission.
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Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review.
Excessive daytime sleepiness and adherence to antihypertensive medications among Blacks: analysis of the counseling African Americans to control hypertension (CAATCH) trial.
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