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Risperidol and haloperidol were found to be worse at managing symptoms of delirium associated with distress in patients in palliative care compared non-pharmacologic approaches alone. The findings suggest doctors should look to alternative management strategies for managing such patients.
Two commonly prescribed antipsychotic medications, risperidone (Risperdal) and haloperidol (Haldol), were found ineffective for treating behavioral, communication, and perceptual symptoms of delirium for patients in palliative care, according to the results of a randomized controlled trial published online on December 5 in JAMA Internal Medicine.
The two drugs performed no better than placebo, and they worsened both distress-related delirium symptoms and patient survival.
Previous randomized controlled trials, which found that antipsychotics may improve delirium severity, had major limitations, such as a lack of placebo control or inadequate statistical powering, the study authors wrote. The findings from the current trial, which included placebo controls, confirmed that antipsychotics should not play a role in the management of these patients.
“Antipsychotic drugs should not be added to manage specific symptoms of delirium that are known to be associated with distress in patients receiving palliative care who have mild to moderately severe delirium,” wrote the study authors, led by Meera R. Agar, PhD, a palliative medicine physician at the University of Technology Sydney in Australia.
Alternative management strategies, including screening for delirium, managing precipitants, and providing individualized support through nursing care, should be maintained, they said, and further studies should examine how to better tailor and implement these strategies in palliative care and hospice settings.
For their analysis, researchers enrolled 247 patients at 11 inpatient hospice or hospital palliative care centers in Australia between August 2008 and April 2014. All patients had been admitted with a life-limiting illness and had been diagnosed with delirium associated with distress.
The researchers randomized 82 patients to receive risperidone, 81 to receive haloperidol, and 84 to receive placebo. Age-adjusted titrated oral doses were administered every 12 hours for 72 hours based on delirium symptoms, for a total of six doses. All patients were provided with supportive care and individualized treatment of delirium precipitants. They were also given subcutaneous midazolam hydrochloride as required in cases of severe distress or safety issues.
At 72 hours, the group given risperidone had significantly higher delirium symptoms compared to participants in the placebo arm (p=0.02). Those given haloperidol also showed higher distress associated with delirium compared to those on placebo (p=0.009). And patients in both active arms of the study had more extrapyramidal effects, including acute dyskinesias and dystonic reactions, tardive dyskinesia, and parkinsonism (risperodone, p=0.03; haloperidol, p=0.01) than those on placebo.
Patients in the haloperidol arm had significantly greater sedation on the Richmond Agitation Sedation scale compared to those in the placebo arm (p=0.52), though there were no significant differences between patients in the risperidone arm and those on placebo.
Overall, patients in the placebo group had a better rate of overall survival than those receiving haloperidol (hazard ratio, 1.73; p=0.003); the difference in survival was not significant among those on placebo vs risperidone (HR, 1.29; p=0.14).
The researchers noted several limitations to their study: Only oral solutions were used, so the study excluded people with dysphagia; fewer patients were under 65 years old in the haloperidol group; and study did not employ head-to-head comparisons of haloperidol versus risperidone.
In an accompanying editorial, Donavan T. Maust, MD, and Helen C. Kales, MD, both geriatric physicians at the University of Michigan department of psychiatry, wrote that a lack of incentives to change practice, and the ease of writing a prescription as a quick fix, are largely to blame for health care providers' resistance to adopt nonpharmacologic approaches to delirium treatment, despite the fact that “nearly every expert group” already promotes such strategies as first-line treatment for delirium.
These strategies, they wrote, “lack an industry behind them to promote and profit from their implementation in real-world practice.”
In order for practice to change, “physicians need training and resources so that they are equipped to provide environmental or biopsychosocial interventions in place of a prescription,” they concluded.
Christopher M. Filley, MD, FAAN, professor and chief of neurology at the University of Colorado at Denver Medical Center, agreed that misplaced incentives play a role in the overuse of antipsychotic medications in spite of a lack of evidence.
“In many cases, the desire to offer prompt relief from distress has been combined with a perceived need for assuring the safety of the patient and caregivers,” he told Neurology Today in an interview. “This is a problem in our health care system, as the use of non-pharmacologic treatment is often more time-consuming than the prescribing of medication, and it is not well reimbursed.”
However, Dr. Filley added, “The fact that antipsychotic drugs may actually worsen delirium and increase mortality is sobering. This study has the potential to introduce considerable hesitancy in prescribing antipsychotic drugs for people with delirium. An emphasis on the principles of palliative care” – which by definition means providing comfort to patients in distress – “may assist in altering practice patterns.”
“Early recognition of delirious patients can be improved by enhanced medical and neurologic training emphasizing the importance of the problem, including the potential for reversibility in up to half of affected patients,” Dr. Filley said.
David S. Knopman, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN, said antipsychotics are already drugs of last resort for most neurologists, and the findings merely add to an existing list of reasons not to use them – and to look toward non-pharmacologic approaches.
“I think most neurologists would never use these particular antipsychotics under any circumstances,” Dr. Knopman said. “These are drugs that have been around for a long time, and they are known from clinical trials to have a terribly unfavorable side effect profile – parkinsonism, difficulty swallowing, gait and balance disturbances, tardive dyskinesia – all of which can be life-threatening in acute situations.”
Jason Karlawish, MD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, agreed, stressing that “hospitals and nursing homes and hospices must have resources to prevent the onset and limit the severity of dementia using proven methods that do not require drugs.”
These alternative methods should include, for example, “changes to the environment to reduce evening-hour disruptions in sleep, noise, and lights,” Dr. Karlawish said, noting that these methods have been effective at his hospital's palliative care center.
Doctors can also limit medications that cause sedation or an anticholinergic effect; treat pain; and make sure patients are hydrated. Nursing staff play a key role, too: “One of most important strategies is providing one-on-one sitters with patients who are beginning to develop delirium – someone who can redirect a patient who's climbing out of bed and provide some personal attention and comfort.”
Dr. Karlawish added that instead of looking toward pharmacologic approaches as a first solution, doctors may need to rethink symptoms of delirium in the context of dying.
Seen through the biomedical lens, delirium may seem like something that ought to be aggressively treated, he said, but in someone who's dying, so-called disruptive behaviors are part of the dying process. “Things people say that seem nonsensical can be interpreted through different lenses of culture and religion. We need to learn to rethink how we respond to them. They may, in fact, be meaningful.”
Dr. Karlawish advised: “Think about a typical case of delirium where someone starts crying out, ‘Help me!’ Rather than say that's a druggable moment, we should think about the meaning of the behavior. It might be distressing to see, but there's a messiness to death that oftentimes is part of the meaning we take from experience. Maybe we should ask, “how can I help you?'”
EXPERTS: ON ANTIPSYCHOTICS FOR MANAGING DELIRIUM IN PALLIATIVE CARE
DR. DAVID S. KNOPMAN: “I think most neurologists would never use these particular antipsychotics under any circumstances. These are drugs that have been around for a long time, and they are known from clinical trials to have a terribly unfavorable side effect profile.”
DR. CHRISTOPHER M. FILLEY: “This is a problem in our health care system, as the use of non-pharmacologic treatment is often more time-consuming than the prescribing of medication, and it is not well reimbursed. An emphasis on the principles of palliative care may assist in altering practice patterns.”
DR. JASON KARLAWISH said that when seen through the biomedical lens, delirium may seem like something that ought to be aggressively treated. “But in someone who's dying, ‘disruptive behaviors’ are part of the dying process. Things people say that seem nonsensical can be interpreted through different lenses of culture and religion. We need to learn to rethink how we respond to them. They may, in fact, be meaningful.”