Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care

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.

Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care

“…24,25 The current study provides some insights into the efficacy of intravenous haloperidol. In the control group, a single 2-mg dose of haloperidol alone resulted in a rapid decrease in agitation level; however, its effect was highly variable and nonsustained.…”

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma

“…62 A recently published RCT among patients in PC compared risperidone and haloperidol (maximum dose up to 4mg/d) to placebo and did not find a benefit of pharmacological treatment, but instead resulted in more adverse effects. 63 So far, no non-pharmacological trials on delirium treatment in cancer and/or terminally ill patients exist.…”

Antipsychotic prescription to identify delirium: results from two cohorts

“…The available evidence limits the conclusions of these reviews. With a recent randomized controlled trial demonstrating no benefit and possible harms of antipsychotics in a palliative population,15 the findings of this study are timely and can be used to support clinical efforts.…”

“…The use of antipsychotics to control agitation is particularly important in those with the hyperactive delirium subtype, and in particular when the features of delirium are distressing to caregivers and family. While there is considerable debate about the use of antipsychotics in the prevention of delirium in high-risk patients,13–15 a new prescription for an antipsychotic medication in hospitalized patients may represent an underlying delirium.…”