Belinda Fazekas

Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea

Abstract Objective To determine the efficacy of oral morphine in relieving the sensation of breathlessness in patients in whom the underlying aetiology is maximally treated. Design Randomised, double blind, placebo controlled crossover study. Setting Four outpatient clinics at a hospital in South Australia. Participants 48 participants who had not previously been treated with opioids (mean age 76, SD 5) with predominantly chronic obstructive pulmonary disease (42, 88%) were randomised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo, or vice versa. Laxatives were provided as needed. Main outcome measures Dyspnoea in the morning and evening as shown on a 100 mm visual analogue scale, quality of sleep, wellbeing, performance on physical exertion, and side effects as measured at the end of the four day treatment period. Results 38 participants completed the study; three withdrew because of definite and two because of possible side effects of morphine (nausea, vomiting, and sedation). Participants reported significantly different dyspnoea scores when treated with morphine: an improvement of 6.6 mm (95% confidence interval 1.6 mm to 11.6 mm) in the morning and of 9.5 mm (3.0 mm to 16.1 mm) in the evening (P = 0.011 and P = 0.006, respectively). During the period in which they were taking morphine participants also reported better sleep (P = 0.039). More participants reported distressing constipation while taking morphine (9 v 1, P = 0.021) in spite of using laxatives. All other side effects were not significantly worse with morphine, although the study was not powered to address side effects. Conclusions Sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in the community setting.

The Australia-modified Karnofsky Performance Status (AKPS) scale: a revised scale for contemporary palliative care clinical practice [ISRCTN81117481]

BackgroundThe Karnofsky Performance Status (KPS) is a gold standard scale. The Thorne-modified KPS (TKPS) focuses on community-based care and has been shown to be more relevant to palliative care settings than the original KPS. The Australia-modified KPS (AKPS) blends KPS and TKPS to accommodate any setting of care.MethodsPerformance status was measured using all three scales for palliative care patients enrolled in a randomized controlled trial in South Australia. Care occurred in a range of settings. Survival was defined from enrollment to death.ResultsRatings were collected at 1600 timepoints for 306 participants. The median score on all scales was 60. KPS and AKPS agreed in 87% of ratings; 79% of disagreements occurred within 1 level on the 11-level scales. KPS and TKPS agreed in 76% of ratings; 85% of disagreements occurred within one level. AKPS and TKPS agreed in 85% of ratings; 87% of disagreements were within one level. Strongest agreement occurred at the highest levels (70–90), with greatest disagreement at lower levels (≤40). Kappa coefficients for agreement were KPS-TKPS 0.71, KPS-AKPS 0.84, and AKPS-TKPS 0.82 (all p < 0.001). Spearman correlations with survival were KPS 0.26, TKPS 0.27 and AKPS 0.26 (all p < 0.001). AKPS was most predictive of survival at the lower range of the scale. All had longitudinal test-retest validity. Face validity was greatest for the AKPS.ConclusionThe AKPS is a useful modification of the KPS that is more appropriate for clinical settings that include multiple venues of care such as palliative care.

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.

Specialist palliative care needs of whole populations: a feasibility study using a novel approach

Background: Defining whether people with life-limiting illnesses (PLLI) who do not access specialized palliative care services (SPCS) have unmet needs is crucial in planning and evaluating palliative care. This study seeks to establish the viability of a whole-of-population method to help characterize SPCS access through proxy report. Methods: Questions were included in a piloted annual face-to-face health survey of 3027 randomly selected South Australians on the need for, uptake rate of, and satisfaction with SPCS in 2000. The survey was representative of the cross-section of South Australians by age, gender, socioeconomic status and region. Results: One in three people surveyed (1069) indicated that someone ’close to them‘ had died of a terminal illness in the preceding five years. Of those who identified that a palliative service had not been used (38%, 403), reasons cited included family/friends provided the care (34%, 136) and the service was not wanted (21%, 86). Respondents with income Í / AU

A Comparison of Subcutaneous Morphine and Fentanyl in Hospice Cancer Patients

60 000 per year were more likely to report that a SPCS had been used (P3/4 / 0.01). People who had cancer as their life-limiting illness were more likely to access SPCS (PB / 0.001). The results generate a model comparing SPCS utilization with client benefit. The survey was acceptable to interviewees. Discussion: Uptake rates of SPCS in this survey are consistent with other South Australian whole population estimates of SPCS utilization. Although there are limitations in this survey approach and the questions asked, this method can be developed to improve our understanding of the characteristics and needs of PLLI and their carers.

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

This study compares subcutaneous (s.c.) morphine and fentanyl with respect to pain control and side effects using a 6-day randomized, double-blind, cross-over design. Results were obtained from 23 patients (12 males and 11 females: mean age of 70.5 years) who could tolerate morphine. Thirteen patients were randomized to receive morphine for the first 3 days followed by fentanyl; 10 received fentanyl first followed by morphine. There were no significant differences in the scores for pain between the two drugs, suggesting that fentanyl is equally efficacious and the conversion ratio of morphine 10 mg: fentanyl 150 micrograms is appropriate. Patients had more frequent bowel movements during days 4-6 while on the fentanyl arm [t-test, df (22), P = 0.015]. Other measures for nausea, delirium, and cognitive function showed no differences between the two drugs. This study highlights the need to further assess the role of various opioids in hospice patients, and emphasizes the requirement for sensitive and simple cognitive tests in this population.

The coverage of cancer patients by designated palliative services: a population-based study, South Australia, 1999

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.

Double-Blind, Placebo-Controlled, Randomized Trial of Octreotide in Malignant Bowel Obstruction

Our aims were to determine the extent of coverage by designated palliative care services of the population of terminally ill cancer patients in South Australia, and to identify the types of patients who receive these services and the types who do not. All designated hospice and palliative care services in South Australia notified to the State Cancer Registry the identifying details of all their patients who died in 1999. This information was cross-referenced with the data for all cancer deaths (n=3086) recorded on the registry for 1999. We found that the level of coverage by designated palliative services of patients who died with cancer in 1999 was 68.2%. This methodology was previously used to show that the level of coverage had increased from 55.8% for cancer deaths in 1990 to 63.1% for those in 1993. Patients who died at home had the largest coverage by palliative services (74.7%), whereas patients who died in nursing homes had the lowest coverage (48.4%). Patients who did not receive care from these palliative services tended to be 80 years of age or older at death, country residents, those with a survival time from diagnosis of three months or less, and those diagnosed with a prostate, breast, or haematological malignancy. Gender, socioeconomic status of residential area, and race were not related to coverage by a designated palliative service, whereas migrants to Australia from the UK, Ireland, and Southern Europe were relatively high users of these services. We conclude that the high level of palliative care coverage observed in this study reflects widespread support for the establishment of designated services. When planning future care, special consideration should be given to the types of patients who most miss out on these services.

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

CONTEXT Does octreotide reduce vomiting in cancer-associated bowel obstruction? OBJECTIVES To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. METHODS Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine [200 mg/24 hours], dexamethasone [8 mg/24 hours], and parenteral hydration [10-20 mL/kg/24 hours]). The primary outcome was patient-reported days free of vomiting at 72 hours. RESULTS In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours (P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19-0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide (P = 0.004), potentially reflecting increased colicky pain. CONCLUSION Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted.

Integration, Coordination and Multidisciplinary Care: What can These Approaches Offer to Australian Primary Health Care?

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.