Risperidone, Haloperidol Not Superior to Placebo in Delirium Patients in Palliative Care

Jessica Swain, Mercer University College of Pharmacy

Delirium is a clinical disorder distinguished by loss of cognitive function, perception, and/or consciousness usually occurring over 1-2 days.  Patients with delirium can be combative or uncooperative, have hallucinations and confusion, and have sleep disturbances.  Risk factors for delirium include: age 65 or older, some degree of cognitive impairment, and severe illness with progression or risk of progression.  Reorientation for the patient, identification of the underlying cause, and comfort measures for the patient are ways to manage delirium. [1]

Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care [2]
Design Multi-site, double-blind, parallel-arm, dose-titrated, placebo-controlled, randomized; N= 247
Objective To determine if risperidone or haloperidol provides additional benefits in reducing target symptoms of delirium associated with distress when compared to placebo
Study Groups Risperidone (n= 82); haloperidol (n= 81); placebo (n= 84)
Methods Participants were assigned to receive oral liquid doses of risperidone, haloperidol, or placebo at diagnosis of delirium for the control of target delirium symptoms.  Delirium symptoms are defined as delirium-induced behavior, communication, and/or perceptual disturbance.  Participants 65 years or younger received 1 mg loading dose, then 0.5 mg maintenance doses were administered every 12 hours.  If needed, doses were titrated by 0.25 mg on day 1 and by 0.5 mg every day thereafter to a maximum of 4 mg/day.  For participants older than 65 years, the loading, initial, and maximum doses were halved.  Placebo solution was titrated similarly using match volumes of solution for each dose level.  Protocol-defined, as-needed subcutaneous midazolam hydrochloride (2.5 mg) was available when participants scored 2 on the Nursing Delirium Screening Scale (NuDESC) item for inappropriate behavior or illusions and hallucinations, and were deemed to require immediate intervention for safety or distress.   Participants were observed every 8 hours by trained nurses for delirium symptoms using items 2 (inappropriate behavior), 3 (inappropriate communication), and 4 (illusions and hallucinations) from the NuDESC (score range 0-6) and Memorial Delirium Assessment Scale (MDAS) score was assessed daily (score range 0-30).  
Duration August 13, 2008 to April 2, 2014
Primary Outcome Measure Change in NuDESC from baseline to day three, daily MDAS score, and daily midazolam use
Baseline Characteristics
Risperidone Haloperidol Placebo
Mean NuDESC 2.54 2.6 2.54
Female, n (%) 25 (31) 33 (41) 27 (32)
Mean age, years 74.5 76.5 73.8
Age <65 years, n (%) 18 (22) 8 (10) 17 (20)
Median MDAS score 15.1 14.6 13.7
Cancer diagnosis, n (%) 76 (93) 67 (83) 75 (89)
Risperidone Haloperidol Placebo
Change in NuDESC score +0.66 +0.68 0

Risperidone vs. placebo MDAS score mean difference per day: 0.96 (95% CI, 0.16-1.77; p< 0.001)  

Haloperidol vs. placebo MDAS score mean difference per day: 0.75 (95% CI, -0.03-1.51; p< 0.06)

Risperidone + Haloperidol Placebo p-value
Midazolam use day one, % of treatment arm 34.7 17.3 0.007
Midazolam use day two, (%) 33.1 16.8 0.01
Midazolam use day three, (%) 29.6 13.6 0.02
Adverse Events Common Adverse Events: not disclosed
Serious Adverse Events: death (placebo- 10%; haloperidol- 11%; risperidone- 19%)
Percentage that Discontinued due to Adverse Events: not disclosed
Study Author Conclusions Antipsychotic drugs should not be added to manage delirium symptoms that are known to be associated with distress in patients receiving palliative care.

Delirium evaluations can be subjective; if the same nurse does not perform all evaluations results can vary nurse to nurse.  Midazolam use was compared in placebo versus haloperidol and risperidone combined; however, for a clearer analysis the comparison should have occurred between all three groups individually and been a percent of the total population instead of the treatment group.  A higher percentage of patients in the risperidone group died versus the placebo group; although, this could have been due to the risperidone group having a higher percentage of patients with cancer diagnosis.  The primary outcome looked at change in MDAS score at 72 hours, but resolution of delirium symptoms can take up to 5 to 7 days.  The medication doses used in this study were based off of previous studies that evaluated reduction of delirium scores after 7 days of treatment.  



[1] Young J, Murthy L, Westby M, Akunne A, O’mahony R. Diagnosis, prevention, and management of delirium: summary of NICE guidance. BMJ. 2010;341:c3704

[2] Agar MR, Lawlor PG, Quinn S, et al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA Intern Med. 2017;177(1):34-42.


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