Ramelteon and Combination Haloperidol/Lorazepam May Curb Delirium

By Marilynn Larkin

March 12, 2019

NEW YORK (Reuters Health) - For delirium, haloperidol plus lorazepam may be the best treatment and ramelteon, the best preventive medication, researchers say.

Dr. Kuan-Pin Su of China Medical University in Taiwan and colleagues analyzed 58 randomized controlled trials of delirium treatment or prophylaxis in patients with varied conditions, including hospitalization in general wards or ICUs, cancer, extreme old age, major surgical procedures, and hospice care.

Twenty trials compared outcomes of treatment in 1,435 participants (mean age, 63.5; 65% men) and 38 trials examined pharmacologic approaches to prevention in 8,168 participants (mean age 70; 53.4% women).

As reported online February 27 in JAMA Psychiatry, the team's network meta-analysis demonstrated that haloperidol plus lorazepam provided the best response rate for treatment (odds ratio, 28.13) compared with placebo/control. Other pharmacologic interventions studied included lorazepam, rivastigmine, chlorpromazine, lorazepam, quetiapine, amisulpride, ziprasidone, olanzapine, dexmedetomidine hydrochloride, haloperidol plus rivastigmine, risperidone, and ondansetron.

No statistically significant differences in all-cause mortality were found across the tested medications.

In tests of prevention strategies, odds of delirium were significantly lower with ramelteon (OR 0.07), olanzapine (0.25), risperidone (0.27), and dexmedetomidine (0.50).

None of the treatments was significantly associated with a higher risk of all-cause mortality.

"The rationale of this work was to provide a general principle of medication prescription to manage delirium symptoms rather than the etiology behind the delirium," Dr. Kuan-Pin Su of China Medical University in Taiwan told Reuters Health on behalf of the authors.

"It is important to treat underlying diseases (that contribute to delirium) - e.g. dehydration, adverse drug reaction, or metabolic imbalances - as well as the neuropsychiatric symptoms," he said by email.

With respect to prevention, he added, "the action of melatonin agonists like ramelteon is to re-establish a disturbed circadian rhythm. A combination of simple behavioral interventions - e.g. exposure to diurnal light-dark cycles, familiar objects, clocks/calendars, etc. - has been commonly recommended to help prevent delirium in clinical settings."

Dr. Dan Blazer of Duke University Medical Center in Durham, author of a related editorial, told Reuters Health, "Delirium is one of the most frequent and frustrating disorders which physicians encounter in the hospital. We are constantly seeking new treatments, and our desire for an effective pharmacological intervention may lead us to draw conclusions which jump ahead of the empirical studies available."

"For this reason, we must carefully review data which support novel treatments," he said by email. "A detailed review of the individual randomized clinical trials supporting a new treatment derived from a meta-analysis is therefore essential to delivering appropriate care to our patients."

Dr. Peter Shapiro, Professor of Psychiatry at Columbia University Irving Medical Center in New York City, commented, "It may be that determining effectiveness depends on the patient population and the very specific criteria used to define a good response."

"This study has blurred together many kinds of patients and many definitions of good response," he said by email. "Still, overall, I think it will tend to reinforce the practice of using haloperidol, maybe with the addition lorazepam more often now, at least to calm delirious patients with severe agitation that puts them at risk of injuring themselves, for example by pulling out IV lines and endotracheal tubes."

"One concern about using haloperidol or other antipsychotics to treat delirium is that, in the elderly with cognitive impairment, long-term use of these medicines to manage behavior disturbance is associated with increased mortality," he noted. "So, it behooves us to discontinue them once the acute problem is treated."

"The other important point is that delirium is an acute problem that occurs in a context of something else going on medically - for example, an infection, or a metabolic problem, or a side effect of a drug - that's affecting the brain," he said. "Treating that underlying problem is the most important part of managing delirium."

"As far as prevention goes, the beneficial effect of ramelteon looks pretty strong, but the amount of evidence for its efficacy is actually pretty low," he said. "More work needs to be done on this."

"Avoiding over-sedating patients, getting them up and moving, and treating pain vigorously - but without opiates, as much as possible - are key aspects of prevention that don't require giving an extra drug," Dr. Shapiro concluded.

SOURCE: http://bit.ly/2ChJPbs and http://bit.ly/2CgCtVx

JAMA Psychiatry 2019.

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