No abstract

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 PARTICIPANTSA 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 MEASURESImprovement 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 RELEVANCEIn 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.

Delirium is a frequent, multifactorial complication in advanced cancer. Despite its terminal presentation in most patients, delirium is reversible in approximately 50% of episodes. Delirium precipitated by opioids and other psychoactive medications and dehydration is frequently reversible with change of opioid or dose reduction, discontinuation of unnecessary psychoactive medication, or hydration, respectively.

The comparative analysis of analgesic interventions for cancer pain is greatly compromised by the lack of well-validated and clinically acceptable tools, which allow a composite classification of pain and patient population characteristics. Although the Edmonton Staging System (ESS) for cancer pain was developed for this purpose, clinical and research utility has been limited due to problems associated with the assessment of some items, especially in relation to definitions and terminology. To overcome these limitations, we designed a revised ESS (rESS) and conducted a multicenter study to determine its inter-rater reliability and predictive value. In revising the rESS, we hypothesized that patients with less problematic pain features would require a shorter time to achieve stable pain control, require less complicated analgesic regimens, be more responsive to opioid therapy, and use lower opioid doses. The rESS items include mechanism of pain, presence or absence of incidental pain, presence or absence of psychological distress and addictive behavior, and level of cognitive function. Patients with cancer pain who were consecutively admitted to two different hospice centers, an acute care consultation service in a teaching hospital or a tertiary palliative care unit in a second teaching hospital were evaluated for study entry. Two independent palliative care specialists completed the rESS where possible within 24 hours of each other. Patients' pain ratings and opioid consumption were recorded daily until the study endpoint (i.e. achievement of stable pain control, discharge or death). Seven hundred and forty-six patients were eligible for study entry and of these, 619 (83%) had a pain syndrome. Inter-rater reliability estimates ranged from 0.67 (pain mechanism) to 0.95 (presence of addiction). In the univariate Cox regression analysis, younger patients (<60), as well as patients with neuropathic pain, incidental pain, psychological distress, or co-morbid psychological distress and addiction, required a significantly longer time to achieve stable pain control (P<0.05). In the multivariate Cox regression analysis, only age (<60), neuropathic pain and incidental pain were significantly associated with time to reach stable pain control (P