Debra Rowett

Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Toxicity of Subcutaneous Ketamine in the Management of Cancer Pain

PURPOSE The anesthetic ketamine is widely used for pain related to cancer, but the evidence to support its use in this setting is weak. This study aimed to determine whether ketamine is more effective than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of chronic uncontrolled cancer pain. Ketamine would be considered of net benefit if it provided clinically relevant improvement in pain with limited breakthrough analgesia and acceptable toxicity. PATIENTS AND METHODS In this multisite, dose-escalation, double-blind, randomized, placebo-controlled phase III trial, ketamine or placebo was delivered subcutaneously over 3 to 5 days. RESULTS In all, 185 participants were included in the primary analysis. There was no significant difference between the proportion of positive outcomes (0.04; 95% CI, -0.10 to 0.18; P = .55) in the placebo and intervention arms (response rates, 27% [25 of 92] and 31% [29 of 93]). Pain type (nociceptive v neuropathic) was not a predictor of response. There was almost twice the incidence of adverse events worse than baseline in the ketamine group after day 1 (incidence rate ratio, 1.95; 95% CI, 1.46 to 2.61; P < .001) and throughout the study. Those receiving ketamine were more likely to experience a more severe grade of adverse event per day (odds ratio, 1.09; 95% CI, 1.00 to 1.18; P = .039). The number of patients needed to treat for one additional patient to have a positive outcome from ketamine was 25 (95% CI, six to ∞). The number needed to harm, because of toxicity-related withdrawal, was six (95% CI, four to 13). CONCLUSION Ketamine does not have net clinical benefit when used as an adjunct to opioids and standard coanalgesics in cancer pain.

Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.

Importance Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care. Objective To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care. Design, Setting, and Participants A double-blind, parallel-arm, dose-titrated randomized clinical trial was conducted at 11 Australian inpatient hospice or hospital palliative care services between August 13, 2008, and April 2, 2014, among participants with life-limiting illness, delirium, and a delirium symptoms score (sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items) of 1 or more. Interventions Age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution were administered every 12 hours for 72 hours, based on symptoms of delirium. Patients also received supportive care, individualized treatment of delirium precipitants, and subcutaneous midazolam hydrochloride as required for severe distress or safety. Main Outcome and Measures Improvement in mean group difference of delirium symptom score (severity range, 0-6) between baseline and day 3. Five a priori secondary outcomes: delirium severity, midazolam use, extrapyramidal effects, sedation, and survival. Results Two hundred forty-seven participants (mean [SD] age, 74.9 [9.8] years; 85 women [34.4%]; 218 with cancer [88.3%]) were included in intention-to-treat analysis (82 receiving risperidone, 81 receiving haloperidol, and 84 receiving placebo). In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09-0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06-0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09-1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17-1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20-2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91-1.84; P = .14). Conclusions and Relevance In patients receiving palliative care, individualized management of delirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added. Trial Registration anzctr.org.au Identifier: ACTRN12607000562471.

Delivery Strategies to Optimize Resource Utilization and Performance Status for Patients With Advanced Life-Limiting Illness: Results From the “Palliative Care Trial” [ISRCTN 81117481]

CONTEXT Evidence-based approaches are needed to improve the delivery of specialized palliative care. OBJECTIVES The aim of this trial was to improve on current models of service provision. METHODS This 2×2×2 factorial cluster randomized controlled trial was conducted at an Australian community-based palliative care service, allowing three simultaneous comparative effectiveness studies. Participating patients were newly referred adults, experiencing pain, and who were expected to live >48 hours. Patients enrolled with their general practitioners (GPs) and were randomized three times: 1) individualized interdisciplinary case conference including their GP vs. control, 2) educational outreach visiting for GPs about pain management vs. control, and 3) structured educational visiting for patients/caregivers about pain management vs. control. The control condition was current palliative care. Outcomes included Australia-modified Karnofsky Performance Status (AKPS) and pain from 60 days after randomization and hospitalizations. RESULTS There were 461 participants: mean age 71 years, 50% male, 91% with cancer, median survival 179 days, and median baseline AKPS 60. Only 47% of individuals randomized to the case conferencing intervention received it; based on a priori-defined analyses, 32% of participants were included in final analyses. Case conferencing reduced hospitalizations by 26% (least squares means hospitalizations per patient: case conference 1.26 [SE 0.10] vs. control 1.70 [SE 0.13], P=0.0069) and better maintained performance status (AKPS case conferences 57.3 [SE 1.5] vs. control 51.7 [SE 2.3], P=0.0368). Among patients with declining function (AKPS <70), case conferencing and patient/caregiver education better maintained performance status (AKPS case conferences 55.0 [SE 2.1] vs. control 46.5 [SE 2.9], P=0.0143; patient/caregiver education 54.7 [SE 2.8] vs. control 46.8 [SE 2.1], P=0.0206). Pain was unchanged. GP education did not change outcomes. CONCLUSION A single case conference added to current specialized community-based palliative care reduced hospitalizations and better maintained performance status. Comparatively, patient/caregiver education was less effective; GP education was not effective.

Aggregating single patient (n-of-1) trials in populations where recruitment and retention was difficult: the case of palliative care.

Randomized controlled trials (RCTs) are the gold standard for evaluating new interventions. Different RCT designs apply depending on the patient population, clinical setting, and intervention being evaluated. A design that may help to generate evidence in some clinical areas where recruitment is a challenge is aggregated n-of-1 trials. N-of-1 trials are randomized, double-blind, and multiple crossover comparisons of an intervention and a control treatment. Methodologically robust n-of-1 trials provide an objective means of testing the effectiveness of treatments within individual participants. Aggregation of multiple cycle identically conducted n-of-1 trials yield a population estimate of effect, which potentially commensurate with that derived from other RCT designs. Trial participants contribute data for both intervention and control treatments creating matched data sets while using generally smaller sample sizes than conventional RCT trials. Careful choice of symptoms and medications are required for n-of-1 trials to be feasible. A validated and reliable outcome measure sensitive to change is still required. This article reviews the utility and limitations of aggregated n-of-1 trials to gather evidence in populations where conducting formal RCTs is difficult because of the low prevalence of the underlying condition or the clinical condition making recruitment and retention difficult. The article examines a proposed palliative care trial as a test case.

Self-management and peer support among people with arthritis on a hospital joint replacement waiting list: a randomised controlled trial

INTRODUCTION To evaluate the efficacy of a self-management support program including a 6 week self-management course, individualised phone support and goal setting in osteoarthritis patients on a waiting list for arthroplasty surgery. METHOD Randomised controlled trial of 152 public hospital outpatients awaiting hip or knee replacement surgery who were not classified as requiring urgent surgery. Participants were randomised to a self-management program or to usual care. The primary outcome was change in the Health Education Intervention Questionnaire (HeiQ) from randomisation to 6 month follow-up. Quality of life and depressive symptoms were also measured. Changes in pain and function were assessed using the Western Ontario and McMaster Universities (WOMAC) Arthritis Index. RESULTS At 6 month follow-up, health-directed behaviour was significantly greater in the intervention [mean 4.29, 95% confidence interval (CI) 3.99-4.58] than the control (mean 3.81, 95% CI 3.52-4.09; P=0.017). There was also a significant effect on skill and technique acquisition for the intervention (mean 4.37, 95% CI 4.19-4.55) in comparison to control (mean 4.11, 95% CI 3.93-4.29; P=0.036). There was no significant effect of the intervention on the remaining HeiQ subscales, WOMAC pain or disability, quality of life or depressive symptoms. DISCUSSION The arthritis self-management program improved health-directed behaviours, skill acquisition and stiffness in patients on a joint replacement waiting list, although the observed effects were of modest size (Cohens d between 0.36 and 0.42). There was no significant effect on pain, function or quality of life in the short term. Self-management programs can assist in maintaining health behaviours (particularly walking) in this patient group. Further research is needed to assess their impact on quality of life and over longer periods.

An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice

BACKGROUND Medication registration currently requires evidence of safety and efficacy from adequately powered phase 3 studies. Pharmacovigilance (phase 4 studies, postmarketing data, adverse drug reaction reporting) provide data on more widespread and longer term use. Historically, voluntary reporting systems for pharmacovigilance have had low reporting rates, relying on ad hoc reporting and retrospective chart reviews, or prospective registries have often been limited to specific drugs or clinical conditions. Furthermore, these data are often irrelevant in hospice and palliative care due to the timeliness of which such data become available and the unique characteristics of our population and prescribing: compounding comorbidities, progressive organ failure, accumulation of symptom-specific medications, tendency to attribute toxicity to disease progression, use of old, off-patent medications, and incorporation of evolving evidence. There is a need for prospective, systematic pharmacovigilance in hospice and palliative care. METHOD Here we describe an international, Web-based, 128-bit secure initiative to collect pharmacovigilance data documenting net clinical benefit and safety of common medications. The intention is for a diverse and large group of clinical units to record data prospectively on a small deidentified consecutive cohort of patients started on the medication of interest. A new medication would be studied every 3 months. Three key time points (different for each medication) will be assessed for each patient, collecting easily codefiable data at baseline, a point at which clinical benefit should be experienced, and a point at which short- to medium-term toxicities may occur. Toxicities can additionally be recorded at any time they occur. Data collection will take a maximum of 10 minutes per patient. CONCLUSION The intention is to create an efficient, relevant system to improve hospice and palliative care with maximally generalizable results.

Planning phase III multi-site clinical trials in palliative care: the role of consecutive cohort audits to identify potential participant populations

Goals of workMultiple sites enable more successful completion of adequately powered phase III studies in palliative care. Audits of the frequency and distribution of the symptoms of interest can better inform research planning by determining realistic recruitment goals for each site. The proposed studies are to improve the evidence-base for registration and subsidy applications for frequently encountered symptoms where current pharmacological interventions are being used ‘off-licence’.MethodsSix services participated in a standardised, retrospective, consecutive cohort audit of five symptoms of their inpatient populations to inform the design of double blind randomised controlled phase III studies to which each site would recruit simultaneously. The audit covered all deaths in a 3-month period for people who were referred to a specialist palliative care service who had at least one inpatient admission between referral and death, regardless of when the person was referred to the service. The audits were based around inclusion and exclusion criteria for the proposed studies.Main resultsOf the 468 people whose medical records were reviewed, potential study participant rates varied by symptom having accounted for general and specific inclusion and exclusion criteria: pain 17.7%; delirium 5.8%; anorexia 5.1%; bowel obstruction 2.8% and cholestatic itch 0%. For those people with a symptom of interest, it was noted at the beginning of the inpatient admission more than half the time. Of all inpatients, fewer than one third would be eligible to participate in at least one study.ConclusionsThese data provide a baseline estimate of potential people to approach about clinical trials in supportive care but do not account for clinician ‘gate-keeping’, lack of interest in participating nor withdrawal from the study once initiated. The data are retrospective and therefore, limited by clinical documentation. The audit directly informed an increase in the number of participating sites.

Pharmacovigilance in Hospice/Palliative Care: Net Effect of Haloperidol for Delirium

INTRODUCTION Prescribing practice in hospice/palliative care is largely extrapolated from other areas of clinical practice, with few studies of net medication effects (benefits and harms) in hospice/palliative care to guide prescribing decisions. Hospice/palliative care patients differ in multiple ways from better studied participant groups, hence the applicability of studies in other participant groups is uncertain. Haloperidol, a butyrophenone derivative and dopamine antagonist, is commonly prescribed for nausea, vomiting, and delirium in hospice/palliative care. Its frequent use in delirium occurs despite little evidence of the effect of antipsychotics on the untreated course of delirium. The aim of this study was to examine the immediate and short-term clinical benefits and harms of haloperidol for delirium in hospice/palliative care patients. METHOD A consecutive cohort of participants from 14 centers across four countries who had haloperidol commenced for delirium were recruited. Data were collected at three time points: baseline, 48 hours (clinical benefits), and day 10 (clinical harms). Investigators were also able to report clinical harms at any time up to 14 days after it was commenced. RESULTS Of the 119 participants included, the average dose was 2.1 mg per 24 hours; 42 of 106 (35.2%) reported benefit at 48 hours. Harm was reported in 14 of 119 (12%) at 10 days, the most frequent being somnolence (n=11) and urinary retention (n=6). Seven participants had their medication ceased due to harms (2 for somnolence and 2 for rigidity). Approximately half (55/119) were still being treated with haloperidol after 10 days. CONCLUSION Overall, 1 in 3 participants gained net clinical benefit at 10 days.

Using National Health Policies to Improve Access to Palliative Care Medications in the Community

Access to affordable priority palliative care medicines needs to be informed by good clinical data from well-conducted clinical trials designed to address efficacy, cost-effectiveness, and safety. Availability of priority palliative care symptom control medicines improves the provision of palliation in the place of patients choice including the community. Within Australia, a National Medicines Policy and a Palliative Care Strategy endorsed by Federal and State and Territory health ministers have facilitated a process to improve the evidence for palliative clinical practice and, through this, improve community availability of key medications for people at the end of life. The initiative, coordinated by a working party under government auspices, has brought together medicine regulators, the pharmaceutical industry, government, policy makers, and clinicians. The brief was to improve availability of key palliative care medications within the current national drug regulatory and funding frameworks. The results to date include: a palliative care section within the Pharmaceutical Benefits Scheme generating the first ever patient-defined section; medicines not previously listed now available; commitment of AU

Changes in utilisation of anticholinergic drugs after initiation of cholinesterase inhibitors

9.46 M for a national multisite collaborative clinical study network to improve the evidence for clinical interventions in the palliative care setting through systematic investigation with rigorous Phase III and IV studies to inform registration and subsidy applications; and establishing a national Communication Network of the Palliative Care Medications Working Group for the health workforce and community to improve the quality use where improved access has been achieved.