To blunt postoperative pain and reduce the need for opioid drugs following surgery, anesthesiologists often give patients low doses of the drug ketamine during operations. Recent research even suggests that the drug might alleviate postsurgical delirium and confusion in older adults.

But a new study led by anesthesiologists at Washington University School of Medicine in St. Louis, the University of Michigan Medical School and Weill Cornell Medicine suggests that ketamine doesn’t lower levels of pain or reduce the need for pain-killing opioid drugs in the days after an operation. The findings, published May 30 in The Lancet, also reveal that older patients who receive ketamine during surgery are more likely to experience hallucinations and nightmares in the recovery room and for several days following their procedures.

“Finding an agent that can prevent postoperative delirium is something of a holy grail in perioperative medicine because it is associated with complications and mortality after surgery, especially in the elderly,” said study co-author Dr. Kane Pryor, associate professor of clinical anesthesiology and of anesthesiology in clinical psychiatry at Weill Cornell Medicine. “Several smaller studies suggested that low doses of ketamine help reduce postoperative pain and delirium, and we’ve seen this lead to changes in practice over this last decade. But this study really challenges what has been a significant trend.”

To evaluate the clinical effects of ketamine, the researchers followed 672 surgery patients in the United States, Canada, India and South Korea. During surgery, the patients – all at least 60 years of age – either received no ketamine, a very low dose of the drug or a slightly higher dose. Patients who experience pain after surgery are usually treated with opiate medications, but these drugs have a number of side effects. Anesthesiologists frequently give their surgery patients low doses of ketamine to lower their levels of postoperative pain and reduce the amount of opiate required to achieve good pain control.

The patients then were evaluated for several days after surgery. Researchers asked them about their pain, kept track of the amount of opioids needed to control the pain, and evaluated the patients twice daily for delirium – a state that can include confusion, agitation and an inability to recognize friends and family members.

“When patients become delirious after surgery, they tend to spend more time in the intensive care unit, have longer hospital stays and have a greater chance of dying,” said first author Dr. Michael Avidan, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology and a professor of anesthesiology and of surgery at Washington University. “Overall, patients who develop delirium have worse outcomes and are at higher risk for long-term cognitive decline. So it’s really important to try to prevent it if we can.”

Many in the anesthesiology field were excited when recent, smaller studies suggested that low doses of ketamine during surgery might reduce the chances that patients would develop delirium after surgery. Further, Dr. George Mashour, an anesthesiology professor at the University of Michigan Medical School and co-principal investigator, had found that ketamine could speed recovery from anesthesia in rodents, suggesting that the drug might help protect the brain.

The new findings present a less encouraging picture.

“We were particularly surprised by the lack of an effect on postoperative pain,” Mashour said. “Giving single doses of ketamine during surgery to prevent postoperative pain is increasingly common, but our data challenge that practice and suggest that even after decades of use, more research is required if we hope to understand ketamine.”

Pryor said clinicians should reconsider giving low doses of ketamine during surgery, especially if it is for the purpose of preventing delirium. He has already changed his own practice based on the findings.

“I have for several years used low-dose ketamine in the majority of patients that I have cared for,” said Pryor, vice chair for academic affairs, director of clinical research and director of education in the Department of Anesthesiology at Weill Cornell Medicine.

“I now find it far more difficult to justify,” he said. “There still may be situations in which ketamine is beneficial, but this study definitely tells us that we need to do more research to identify exactly what those situations are. Simultaneously, we can’t give up the quest to find a drug that helps prevent delirium, and need to continue conducting clinical trials on agents that show promise.”

This work was supported by the National Institute on Aging, the National Institute of General Medical Sciences and the National Cancer Institute of the National Institutes of Health.

A version of this story first appeared here.

Jim Dryden is a writer for Washington University. Alyssa Sunkin-Strube is an editor at Weill Cornell Medicine.