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Novel Combination of Oral Ketamine and Aspirin Is Safe Form of Pain Medication after Total Knee Replacement Surgery

In response to the opioid crisis, researchers at Hospital for Special Surgery (HSS) are looking for alternate ways to reduce pain after orthopedic procedures. In an innovative pilot study that was recently completed, investigators led by Michael P. Ast, MD, hip and knee surgeon and Chief Medical Innovation Officer at HSS, showed that a combination of oral ketamine and aspirin was safe and had few adverse effects in people undergoing total knee replacement surgery. Based on these findings, the team is planning a much larger, randomized clinical trial to compare it to standard opioid treatment.

“There’s been considerable research and effort into reducing opioid consumption after elective surgeries, and specifically after knee replacement. Many people consider knee replacements the most painful elective surgery someone can have,” says Dr. Ast. “We’ve done a lot of great work, and we’ve already cut the amount of opioids that patients take by approximately 75% as compared to 10 years ago. But there’s still room to go, which is why we want to focus on developing novel forms of non-opioid pain medication.”

Ketamine is a well understood drug that has been approved by the US Food and Drug Administration for postoperative pain management, but it is currently only administered intravenously in the inpatient setting. A noteworthy feature of the new formulation evaluated in this study was that it was an oral medication. “Our goal was to find an effective medication that patients could take home with them,” explains Dr. Ast. “This is especially important because the average stay after total knee replacement surgery is only 24 hours, but we know that the worst postsurgical pain arises between days 3 and 10.”

Oral ketamine is already being studied as a safe alternative to opioids but has low bioavailability in its isolated form. Additionally, there are concerns about ketamine being abused, due to the feelings of dissociation that it creates. The ketamine used in this study was specially formulated for oral use and is manufactured in a way that potentially limits its ability be abused by melting or crushing.  “We’ve learned through basic science studies that nonsteroidal anti-inflammatories like aspirin can buffer the effects of other drugs by adjusting the pH. Aspirin and ketamine work together synergistically on the body’s pain receptors,” says Dr. Ast. “This allows you to use relatively low doses of the ketamine, which also aids in preventing the dissociative feelings even at larger doses.”

The trial enrolled 22 men and women between the ages of 47 and 81 who were undergoing elective total knee replacement. The criteria for enrollment were tightly controlled, including being generally in good health and having no history of opioid use. All the study participants received an oral dose of aspirin and ketamine four times a day until discharge (up to 72 hours) and were monitored for the duration of the study, including being assessed for pain using standard pain scales.

“At HSS, nothing matters more than patient safety,” Dr. Ast says. “That’s why it was so important to do this pilot study with a small number of patients who were closely followed for the entirety of their treatment before developing a larger trial.” Overall, 18 of the 22 patients reported no side effects at all from the treatment. Two of them reported feelings of dizziness. Two others withdrew from the study early because they felt they needed more pain relief.

“If this treatment proves to be as effective as we hope it’s going to be, we can imagine a world where — even after something as painful as knee replacement surgery — patients go home with only a few opioid pills to take if needed, rather than a more typical amount of 25 or 30 pills that are often provided today,” Dr. Ast says. “This could dramatically reduce the number of opioid pills that end up out on the streets every year, just from this one procedure.”

For Dr. Ast, the quest to find alternatives to opioids is personal: “Unfortunately, I grew up in an area that has been hit hard by the opioid epidemic and have seen people I knew pass away from opioid overdoses,” he says. “That’s one of the main reasons the focus of my research for the past 10 years has been on finding new forms of pain medication that can minimize opioid use and ultimately be developed and commercialized.”

A manuscript of this study is in preparation for presentation and publication. The next phase clinical trial is expected to begin at HSS in the near future.

About HSS

HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 14th consecutive year), No. 2 in rheumatology by U.S. News & World Report (2023-2024), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2023-2024). In a survey of medical professionals in more than 20 countries by Newsweek, HSS is ranked world #1 in orthopedics for a fourth consecutive year (2023). Founded in 1863, the Hospital has the lowest readmission rates in the nation for orthopedics, and among the lowest infection and complication rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. In addition, more than 200 HSS clinical investigators are working to improve patient outcomes through better ways to prevent, diagnose, and treat orthopedic, rheumatic and musculoskeletal diseases. The HSS Innovation Institute works to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 165 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.