A randomized, double-blind, crossover, dose ranging study to determine the optimal dose of oral opioid to treat breakthrough pain for patients with advanced cancer already established on regular opioids.

BACKGROUND: Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release opioid is usually a proportion of the total daily dose. METHODS: This multi-site, double blind, randomized trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.) RESULTS: Eighty-five people were randomized in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 min with approximately one-third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 min. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 min. CONCLUSIONS: This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm. SIGNIFICANCE: Despite the widespread use of immediate release morphine solution for breakthrough cancer pain, the ideal dose derived from background dose has not been determined in an adequately powered randomized, double-blind, crossover, dose ranging study. This study tested three dose levels in people with advanced cancer. Given no differences in time to onset, level of analgesia achieved, nor side effects, the lowest dose tested (1/12th of the daily dose) should be used.

Isolating peripheral effects of endogenous opioids in modulating exertional breathlessness in people with moderate or severe COPD: a randomised controlled trial.

QUESTION ADDRESSED BY THE STUDY: Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been tested. MATERIALS PARTICIPANTS AND METHODS: This was a double-blind, randomised, three-arm, cross-over trial in outpatients with spirometry-verified moderate to severe chronic obstructive pulmonary disease. Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30 min after intravenous injection of either methylnaltrexone 0.3 mg·kg-1 (blocking peripheral opioid receptors only) or naloxone 0.1 mg·kg-1 (blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0-10 numerical rating scale) and oxygen consumption (V'O2 ) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test. RESULTS: 17 participants completed the trial: median (range) 66 (55-82) years; 15 males; mean±sd forced expiratory volume (FEV1) 53.8±17.6% predicted; FEV1/forced vital capacity ratio 0.55±15.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and V'O2 ) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue. ANSWER TO THE QUESTION: Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).

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.

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.

Academic detailing of general practitioners by a respiratory physician for diagnosis and management of refractory breathlessness: a randomised pilot study.

BACKGROUND: Academic detailing (AD; also known as educational visiting) facilitates the translation of evidence into practice and has been widely adopted internationally to facilitate practice change. The potential of AD linked to a specific patient and delivered by a specialist physician to general practitioners has not been evaluated. This pilot study assessed the feasibility and acceptability of AD on the knowledge and confidence of GPs caring for people with advanced cancer who had breathlessness at the end of life. METHODS: In this randomised controlled pilot, 35 patient/GP dyads were randomised to AD or usual care. Key messages included: ensuring reversible causes were optimally treated; non-pharmacological and pharmacological treatments were considered; and oxygen considered for hypoxaemic patients. RESULTS: Acceptability: The majority of GPs randomised to AD agreed to participate, reporting benefits to practice. The majority of GPs in the control group requested a copy of academic detailing written materials at study completion. Feasibility: AD visits to GPs' offices could be timetabled reasonably easily, with 24 detailing visits occurring. Self-reported knowledge and beliefs: Ninety two percent of GPs reported the topics covered in the AD sessions were useful, with 83% reporting an increase in knowledge and confidence. AD sessions resulted in 58% of GPs reporting a change in their approach to the management of breathlessness. By contrast, 81% of the usual care group reported low confidence in the management and knowledge of breathlessness. CONCLUSION: AD was acceptable and feasible to participating GPs. This pilot supports proceeding to a fully powered study.

The longitudinal pattern of response when morphine is used to treat chronic refractory dyspnea.

BACKGROUND: While evidence supports using sustained release morphine for chronic refractory breathlessness, little is known about the longitudinal pattern of breathlessness intensity as people achieve symptomatic benefit. The aim of this study is to describe this pattern. METHODS: This secondary analysis used breathlessness intensity scores (100 mm visual analogue scale (VAS)) from a prospective, dose increment study of once daily (morning) sustained release morphine for chronic refractory breathlessness. Participants who achieved <10% improvement over their own baseline at one week (10 mg) were titrated to 20 mg and if no response, another week later to 30 mg for one week. Time was standardized at the first day of the week in which participants responded generating twice daily data one week either side of symptomatic benefit. Analysis used random effect mixed modeling. RESULTS: Of the 83 participants, 17/52 responders required >10 mg: 13 participants (20 mg) and 4 (30 mg), contributing 634 VAS observations. In the week leading to a response, average VAS scores worsened by 0.3 mm/day (p=0.16); the average improvement in the first 24 hours of response was 10.9 mm (7.0 to 14.7; p<0.0001), with continued improvement of 2.2 mm/day (p<0.001) for six more days. CONCLUSION: When treating chronic refractory breathlessness with once daily sustained release morphine, titrate to effect, since inadequate dose may generate no response; and following an initial response, further dose increases should not occur for at least one week. Whether further benefit would be derived beyond day six on the dose to which people respond, and what net effect a further dose increase would have are questions yet to be answered.

The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam.

BACKGROUND: Breathlessness at rest or on minimal exertion despite optimal treatment of underlying cause(s) is distressing and prevalent. Opioids can reduce the intensity of chronic refractory breathlessness and an anxiolytic may be of benefit. This pilot aimed to determine the safety and feasibility of conducting a phase III study on the intensity of breathlessness by adding regular benzodiazepine to low-dose opioid. METHODS: This is a single site, open label phase II study of the addition of regular clonazepam 0.5 mg nocte orally to Kapanol(R) 10 mg (sustained release morphine sulphate) orally mane together with docusate/sennosides in people with modified Medical Research Council Scale ≥2. Breathlessness intensity on day four was the efficacy outcome. Participants could extend for another 10 days if they achieved >15% reduction over their own baseline breathlessness intensity. RESULTS: Eleven people had trial medication (eight males, median age 78 years (68 to 89); all had COPD; median Karnofsky 70 (50 to 80); six were on long-term home oxygen. Ten people completed day four. One person withdrew because of unsteadiness on day four. Five participants reached the 15% reduction, but only three went on to the extension study, all completing without toxicity. CONCLUSION: This study was safe, feasible and there appears to be a group who derive benefits comparable to titrated opioids. Given the widespread use of benzodiazepines for the symptomatic treatment of chronic refractory breathlessness and its poor evidence base, there is justification for a definitive phase III study.

Key characteristics of palliative care studies reported in the specialized literature.

CONTEXT: Although research activity in palliative care is rapidly increasing, the composition of published studies--in terms of significant research characteristics--has not yet been well described. OBJECTIVES: To describe the topics of and funding for palliative care studies reported in the three hospice and palliative care journals with the highest impact factors (Journal of Pain and Symptom Management, Palliative Medicine, and Journal of Palliative Medicine). METHODS: This was a substudy of a larger bibliographic study. The targeted journals were searched for 2007 using a previously validated Ovid MEDLINE filter for palliative care. All empirical palliative care studies were included. Articles were classified according to topics (palliative care patient, caregiver/family, health professional, service provision, tool development, healthy volunteer, medication compatibility, community), study type (intervention, nonintervention), country of origin, and funding source (pharmaceutical company, other funder, unfunded). RESULTS: Of 409 citations identified, the search yielded 189 eligible articles. Most articles were descriptive/observational. Approximately half were unfunded. Caregivers, healthy volunteers, and health service research were the least frequent topics for research. Only five randomized controlled trials were reported. CONCLUSION: Although there is a broad range of research undertaken in palliative care, few studies generate high-level evidence, with data showing a relative lack of funding for hospice and palliative care studies.

Refining a checklist for reporting patient populations and service characteristics in hospice and palliative care research.

CONTEXT: In specialist hospice and palliative care services, variations occur in diagnoses and prognoses of subpopulations referred, service configuration, and the health systems delivering care. These three levels of variation limit the ability to generalize study findings. OBJECTIVES: This article reports on coding one year of palliative care research using a previously developed checklist. The aims were to 1) quantify current reporting of factors related to generalizability in specialist palliative care research; 2) review and potentially refine the checklist in light of the first aim; 3) demonstrate the feasibility of collecting these data; and 4) set out simple processes to aid researchers in reporting, and clinicians in applying, new research evidence in hospice and palliative care. METHODS: A previously published checklist (five domains, 14 core subdomains, and 24 noncore subdomains) was used to code all research articles (n=189) published in 2007 in the three leading palliative care research journals. RESULTS: The most frequently reported subdomains were patient age, gender, and diagnosis; model of service delivery; and patient performance status. Data in subdomains, including time from referral to death, socioeconomic indices, and ethnicity, were rarely reported; none reported whole-of-service or whole-of-population data. In total, 2646 (189×14) core subdomains could have been reported. Data were provided in 28% (746/2646). CONCLUSION: Checklists such as the Consolidated Standards of Reporting Trials evaluate study design, focusing mainly on internal validity. The proposed checklist deals with specific content of hospice and palliative care, focusing on external validity.

The disparity between patient and nurse symptom rating in a hospice population.

BACKGROUND: Meticulous assessment, monitoring, and treatment of symptoms are key components of palliative care. The Symptom Assessment Scale (SAS) is a 0-10 numerical rating scale (NRS) used for self-report of sleep, appetite, nausea, bowels, breathing, fatigue, and pain. Ideally, symptom rating should be by self-report; however, the ratings are often completed by nurses. The aim of this study was to examine the relationship between simultaneous symptom ratings of patients and nurses in an Australian inpatient palliative care unit. METHODS: All inpatients and their treating nurse (blinded to the patient's report) scored the SAS weekly. Nurse symptom rating was considered accurate if the score for an individual symptom differed by ≤1. The relationship for each dyad was examined by comparing absolute values, mean differences, and Pearson correlations. RESULTS: Sixty-four pairs of symptom ratings were obtained from 29 patients (mean 65 years, male 55%, malignancy 90%, mean Karnofsky 50). The absolute differences were closest for nausea, bowels, and breathing domains, and worst for appetite. Mean differences and Pearson correlations did not adequately reflect the disparity between patient and nurse symptom rating, and nurses systematically underreported symptoms. The total difference for the seven items ranged from nurses overreporting the patients' symptoms by 39 points to underreporting by 31 out of a possible 70 points. DISCUSSION: Proxy symptom assessment only modestly correlates with patient symptom rating, can significantly misrepresent the patient's actual symptom burden, and should only be used when the patient is absolutely unable to contribute his or her own view.

Can assessing caregiver needs and activating community networks improve caregiver-defined outcomes? A single-blind, quasi-experimental pilot study: community facilitator pilot.

BACKGROUND: Although the unit of care in palliative care is defined as the patient and their family, there are few rigorous studies on how to improve support for family and friends as they take on the role of caregiver for someone at the end of life. AIM: Separate to patient evaluation and care, this pilot study aimed to define the feasibility and possible outcome measures to evaluate routine assessments and supports specifically for caregivers. DESIGN: In a quasi-experimental design, two communities were included: one received standard specialist palliative care support and one additionally was allocated to a community network facilitator who assessed caregivers' needs and helped mobilize the caregiver's own support network or initiated contact with other community supports in three planned visits. Data were collected at baseline, 4 and 8 weeks using three caregiver assessment tools. Within group comparisons were made using Wilcoxon signed rank test and between group using the Mann-Whitney U-test. PARTICIPANTS: Sixty-six caregivers participated. RESULTS: At 8 weeks, participants in the intervention arm showed significant within-group improvement in caregiver fatigue, sufficient support from others, decreased resentment in the role, greater confidence in asking for assistance and were better able to find resources and support. No between-group changes were seen in this pilot study. CONCLUSIONS: There were objective measures of improved support within the intervention group over time for caregivers through the active engagement of the community network facilitator. This pilot supports the case for an adequately powered study.

Adverse events in hospice and palliative care: a pilot study to determine feasibility of collection and baseline rates.

BACKGROUND: Continuous quality improvement is fundamental in all health care, including hospice and palliative care. Identifying and systematically reducing symptomatic adverse events is limited in hospice and palliative care because these events are mostly attributed to disease progression. OBJECTIVES: The aim of this study was to assess the feasibility of symptomatic adverse events in hospice and palliative care and assessing their incidence. METHODS: A retrospective, consecutive cohort of notes from a specialist palliative care inpatient service was surveyed by a clinical nurse consultant for symptomatic adverse events: falls, confusion, decreased consciousness, hypo- and hyperglycaemia, urinary retention, and hypotension. Demographic and clinical factors were explored for people at higher risk. RESULTS: Data were available on the most recent admissions of 65 people, generating >900 inpatient days. Fifty people (78%) had events precipitating admission, of whom 31 (62%) had at least one further event during admission. Eleven of 15 people who were admitted without an event experienced at least one during their admissions. Only 4 did not have an adverse event. During their stay, there were 0.13 (standard deviation [SD] = 0.19) events per patient per day. No drug-drug or drug-host events were noted. No clinical or demographic factors predicted groups at higher risk. CONCLUSIONS: This pilot highlights the feasibility of collecting, and ubiquity of, symptomatic adverse events, and forms a baseline against which future interventions to decrease the frequency or intensity can be measured. Given the frailty of hospice and palliative patients, any adverse event is likely to accelerate irreversibly their systemic decline.