Melatonin does not reduce delirium incidence in older hip-fracture patients

By Will Boggs MD

NEW YORK (Reuters Health) - Melatonin does not reduce the incidence of delirium among patients aged 65 and older who are hospitalized with hip fracture, researchers from the Netherlands report.

"At this stage it is uncertain what the exact role for melatonin is as there are only a few studies, but it is still promising," stressed Dr. Annemarieke de Jonghe from Academic Medical Center at the University of Amsterdam.

"Three randomized controlled trials (RCTs) for the prevention of delirium with melatonin have been performed, and of these two did show a huge positive effect on the incidence of delirium," she told Reuters Health by email. "Our study did not show an effect on the incidence but in a post hoc analysis we found that more patients in the placebo group more often had a longer-lasting delirium."

Delirium is associated with disturbance of the sleep-wake cycle, suggesting that changes in the neurotransmitter melatonin might be involved in its pathogenesis, Dr. de Jonghe and colleagues write in CMAJ, online September 2.

The researchers assessed the effects of melatonin on the incidence of delirium among elderly patients admitted to hospital as an emergency following hip fracture.

Patients (mean age, 84 years) were randomized to receive 3 mg melatonin (186 patients) or matching placebo (192 patients) on five consecutive evenings, beginning with the day of admission.

The incidence of delirium did not differ significantly between the melatonin group (29.6%) and the placebo group (25.5%). Results did not change after adjustment for treatment center and baseline imbalances (benzodiazepine use at home and prior delirium).

The median duration of delirium (two days) was the same in both groups, although significantly fewer patients in the melatonin group (25.5%) than in the placebo group (46.9%) experienced a delirium lasting more than two days.

The severity of delirium and the median length of hospital stay were similar for both groups. Moreover, cognitive and functional outcomes and mortality rates did not differ at three months.

The researchers also found that patients with cognitive impairment at baseline had similar delirium incidence in the two treatment arms.

They speculate that improvements in the perioperative care of patients like these have decreased the incidence of delirium to such an extent that it may be difficult to achieve any additional treatment effect with melatonin.

"More studies are warranted to explain these differences found and to determine specific patient groups that could benefit most from a prophylaxis with melatonin," Dr. de Jonghe said. "It is also important to determine the dosage of melatonin."

Meanwhile, she said, doctors may consider using melatonin, "especially because of the absence of other safe and effective medical interventions."

Dr. Tareef Al-Aama from the University of Western Ontario in London, Canada, worked on one of the trials showing a beneficial effect of melatonin on delirium.

"The 2 fundamental differences between this and our study are the patient population (medical vs. surgical) and more importantly the dose," he told Reuters Health by email. "We meant to use a much smaller dose (0.5mg) that is closer to the physiological dose in order to try to keep the melatonin-cycle balance without inducing more sedation or hypoactive delirium."

"I think we need to invest more in studying melatonin in delirium given its relative safety and affordability, as well as the large adverse impact of delirium," Dr. Al-Aama concluded. "I would, however, strongly advocate adhering to lower doses on future studies."

Dr. Rajesh R. Tampi from University of Texas Health Science Center at San Antonio recently co-wrote a review of melatonin and melatonin agonists for delirium in elderly patients.

"Delirium in late life has devastating consequences and hence all efforts should be made the reduce its incidence," he told Reuters Health by email.

"All older adults should have a delirium-prevention protocol started when they are admitted to acute care facilities," said Dr. Tampi, who was not involved in the new study. "These include non-pharmacological methods (reorientation, early ambulation, correction of vision and hearing, etc.) and pharmacological agents like melatonin or ramelteon used to correct the sleep-wake-cycle disturbances. It is easier to prevent delirium than treating it."

SOURCE: http://bit.ly/Z5OtTB

CMAJ 2014.

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