HSS Study: Ketamine + Aspirin for Pain Management

Can the combination of oral ketamine and aspirin manage post-op pain effectively after total knee arthroplasty? And, if it can, how does it compare with opioid treatment?

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used by physicians as a treatment for depression and as a pain management tool.

Authors of a May 26, 2023, National Institutes of Health (NIH) article wrote: “Ketamine (ketamine hydrochloride) has been approved for general anesthesia either alone or in combination with other medications. It is a superb drug for use in short-term medical procedures that do not require skeletal muscle relaxation, and it has approval for the induction of general anesthesia as a pre-anesthetic to other general anesthetic agents.”

The Hospital for Special Surgery (HSS) research team, led by Michael P. Ast, M.D., a hip and knee surgeon and chief innovation officer at HSS, designed a pilot study to gather data on the use of oral ketamine + aspirin as a post-operative pain management tool for total knee arthroplasty patients.

Dr. Ast spoke to OTW about this interesting study and notably, his personal experience with the overuse of opioids to manage post-operative pain. “My childhood was spent in an area that has been hard hit by the opioid epidemic and I personally know people who have died from opioid overdoses. The orthopedic community has made great strides in finding alternatives to opioids, but my colleagues and I knew there was room for improvement.”

Dr. Ast and his team enrolled 22 men and women between the ages of 47 and 81 who were scheduled to have a total knee replacement procedure. The participants had no history of opioid use. Each person received an oral dose of aspirin and ketamine four times a day until discharge (up to 72 hours).

OTW asked Dr. Ast about the specially formulated ketamine used in the study, Dr. Ast said, “This formulation of ketamine allows for oral use and is also manufactured in a way that it cannot be abused by melting or crushing. It allows the patient to let the pill’s coating dissolve for about 20 seconds and then swallow, which primes the system to absorb the drug. That mechanism of action seems to change the bioavailability of ketamine, which was always a huge challenge.”

“The combination of oral ketamine and aspirin had previously been studied in a Brooklyn, New York emergency room where that particular research team compared opioids to an oral ketamine/aspirin combination for pain relief. They reported excellent results so that made me think that this might work for TKR [total knee replacement] as well.”

“Prior basic science studies have found that nonsteroidal anti-inflammatories like aspirin can mitigate the effects of other drugs by adjusting the pH/altering the environment. You can use fairly low doses of ketamine, which can prevent the dissociative feelings and perhaps reduce the potential for abuse.”

Laser focused on patient safety, Dr. Ast told OTW that his team strategized to undertake a small pilot study to lay the groundwork for a larger research initiative. “We kept a close eye on patients to ensure overall safety and that there were no dissociative side effects.”

“Because of this formulation’s unique bioavailability and the low dose, we found the use during this study to be extremely safe. Anecdotally, patients obtained excellent pain relief. The majority of patients—18 of the 22—reported no side effects from the treatment. Two patients reported feelings of dizziness. Two others withdrew from the study early because they felt they needed more pain relief.”

Eventually, rather than sending patients home with 20 or more opioid pills, Dr. Ast wants to be able to release patients with only a few—safe and effective—pills.

“Our manuscript is being prepared for presentation and publication and we look forward to the next study, which will be a randomized controlled trial in TKR. It’s been exciting so far and has been great to see the interest of the orthopaedic community and beyond. We look forward to continuing this journey.”