Adelaide, South Australia—Pharmacists might want to caution older patients using certain anxiety and insomnia drugs that they might be more likely to suffer postoperative delirium after some surgical procedures.

That was especially the case with nitrazepam and antidepressants, according to the Australian study, which said delirium was twice as likely after hip and knee surgery for those patients.

In the article in the journal Drug Safety, University of South Australia (UniSA) researchers urged that older patients temporarily cease those medications or change to safer alternatives prior to surgery.

The study team focused on data from 10,456 patients aged 65 years and older who had undergone knee or hip surgery in the past 20 years. About a fourth of them had experienced delirium after surgery.

Researchers point out that in addition to nitrazepam and antidepressants, five other benzodiazepine medications often prescribed for anxiety, seizures, and insomnia were linked to delirium risk. Those include:

• Sertraline
• Mirtazapine
• Venlafaxine
• Citalopram
• Fluvoxamine.

On the other hand, no link was found between opioids and delirium.

"Our findings show that different classes of medicine are riskier than others when it comes to causing delirium after surgery, and the older the patients are, the greater the risk," said lead researcher Gizrat Kassie, PhD, BPharm, MSc.

Until now, according to the authors, while it was known that medicines acting on the central nervous system can increase the risk of postoperative delirium, exactly which ones remained unclear. That's why the study team examined the risk of individual central nervous systemÐacting medicines used preoperatively on delirium after hip or knee surgery.

The matched case-control study was conducted using data from the Australian Government Department of Veterans' Affairs. Included were patients aged 65 years or older who had knee or hip surgery between 2000 and 2019. For purposes of the study, the 2,614 patients with hip or knee surgery who developed postoperative delirium were considered cases, and the 7,842 controls were those with hip or knee surgery but who did not develop postoperative delirium.

Researchers compared use of medicines, including anxiolytics, sedatives, and hypnotics, opioid analgesics, and antidepressants prior to surgery, comparing cases and controls.

Results indicate that cases were more likely to be exposed to nitrazepam (odds ratio[OR] = 1.81, 95% confidence interval [CI] 1.24-2.64), sertraline (OR = 1.50, 95% CI 1.20-1.87), mirtazapine (OR = 1.38, 95% CI 1.11-1.74), venlafaxine (OR = 1.42, 95% CI 1.02-1.98), citalopram (OR = 1.54, 95% CI 1.19-1.99), escitalopram (OR = 1.42, 95% CI 1.06-1.89), or fluvoxamine (OR = 5.01, 95% CI 2.15-11.68) prior to surgery than controls.

As for drug classes, researchers report that exposure to benzodiazepines (OR = 1.20, 95% CI 1.05-1.37) and antidepressants (OR = 1.64, 95% CI 1.47-1.83) prior to surgery was significantly higher in cases than in controls.

The study team calculates that the numbers needed to treat to harm for one additional delirium case were 43 for sertraline, 40 for citalopram, 57 for mirtazapine, and 26 for nitrazepam. The article adds, however, that the numbers needed to treat to harm were found to be 20 for sertraline, 17 for citalopram, 19 for mirtazapine, and 10 for nitrazepam in the age 85 years or older group, however, indicating that the harmful effect of the medicines worsens with age.

"People who developed delirium following hip or knee surgery were more likely to be exposed to nitrazepam, sertraline, mirtazapine, venlafaxine, citalopram, escitalopram or fluvoxamine at the time of admission for surgery," the authors conclude. "Planning to reduce use of these medicines well prior to surgery may decrease the risk of postoperative delirium."

Dr. Kassie adds that smoking, alcohol use, multiple health conditions, polypharmacy (taking five or more medications), psychoactive drugs, and impaired cognition also raises the risk, noting, "Many of these factors can't be altered but we can do something about medications," he said.

Delirium affects up to 55 percent of older patients undergoing hip surgery and is associated with an increased risk of death, prolonged hospital stays, and cognitive decline.

"In people undergoing elective procedures, it should be practical to taper specific medications well in advance. It's important that people are weaned off these riskier drugs well before surgery because abrupt withdrawal can have even worse consequences," Dr. Kassie advises.

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