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Original Investigation
January 2017

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

Author Affiliations
  • 1Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia
  • 2Centre for Cardiovascular and Chronic Care, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia
  • 3South West Sydney Clinical School, University of New South Wales, Liverpool, New South Wales, Australia
  • 4Clinical Trials, Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia
  • 5Division of Palliative Care, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 6Clinical Epidemiology, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
  • 7Division of Palliative Care, Bruyere Research Institute, Bruyere Continuing Care, Ottawa, Ontario, Canada
  • 8School of Medicine, Flinders University, Repatriation General Hospital, Daw Park, South Australia, Australia
  • 9School of Psychiatry, University of New South Wales, Randwick, Australia
  • 10Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia
  • 11Drug and Therapeutics Information Service, Repatriation General Hospital, Daw Park, South Australia, Australia
  • 12Department of Palliative Care, Calvary Health Care Kogarah, Kogarah, New South Wales, Australia
  • 13School of Medicine, University of Notre Dame Australia, Darlinghurst, New South Wales, Australia
  • 14Palliative and Supportive Care, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia
  • 15Department of Palliative Care, Royal Melbourne Hospital, Parkville, Victoria, Australia
  • 16Australian Health Services Research Institute, University of Wollongong, Wollongong, New South Wales, Australia
  • 17Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia
JAMA Intern Med. 2017;177(1):34-42. doi:10.1001/jamainternmed.2016.7491
Key Points

Question  What are the benefits of risperidone or haloperidol in reducing distressing symptoms of delirium in patients receiving palliative care?

Findings  In this randomized clinical trial of 247 participants receiving palliative care, distressing behavioral, communication, and perceptual symptoms of delirium were significantly greater in those treated with antipsychotics (risperidone or haloperidol) than in those receiving placebo.

Meaning  Antipsychotic drugs are not useful to reduce symptoms of delirium associated with distress in patients receiving palliative care.


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.