A new meta-analysis is suggesting that ketamine may be effective against persistent post-surgical pain (PPSP) and provide long-term benefits with just short-term use. Researchers from Australia reported at Euroanaesthesia 2016, which was held in London from May 27th to the 30th, that ketamine may have the potential to save health systems billions of dollars globally by being used in place of other drugs to prevent PPSP.
Philip Peyton, MD, PhD, and colleagues recently finished a pilot study of 80 patients for a proposed large phase III/IV multi-center randomized trial of ketamine for PPSP. The researchers performed an updated meta-analysis and included data from the 80 patients. A systematic PubMed literature review was performed of papers reporting randomized clinical studies that investigated the effect of intravenous ketamine at standard analgesic doses.
“A total of 8 studies with 563 participants were found with data that met our inclusion criteria,” said study investigator Philip Peyton, MD, PhD, who is Associate Professor in the Department of Surgery at Austin Hospital and University of Melbourne, Melbourne, Australia.
The researchers determined that a patient had PPSP if the pain was still present 3 to 6 months after surgery and was rated at 3 or higher on a 10-point scale. A patient was also classified as having PPSP if they still required ongoing use of painkillers 3 to 6 months after surgery. Dr. Peyton and his colleagues found that patients given ketamine were almost half as likely to experience PPSP compared with those given placebo (risk ratio 0.49 for ketamine compared to placebo).
Ketamine is a non-selective potent NMDA antagonist and it is typically used as a second or third line agent to treat refractory acute post-operative pain. However, not all patients can tolerate ketamine. “The common side effects of ketamine following anesthesia are hallucinations, emergence agitation and dysphoria. These are described in up to 10% of patients where higher doses are used. There is a group of patients where its use is best avoided, such as those with psychiatric illness, drug abuse or previous intolerance or side effects,” Dr. Peyton told Clinical Pain Advisor. “Given these data from small studies, a large definitive multi-center randomized trial is warranted to determine whether ketamine has a significant effect on the risk of chronic post-surgical pain after major or high risk surgery.”
He said developed countries spend billions of dollars on treatment of PPSP. If further studies confirm these data on ketamine, healthcare systems would have a cheap and effective means to treat this condition. “Persistent pain (chronic pain) costs the US economy about $700 billion a year in lost work days and is the number one complaint patients present to their doctors. Depending on the type of surgery, up to 10% of all surgeries result in persistent pain,” said pain expert David Edwards, MD PhD, an Assistant Professor of Anesthesiology and Pain Medicine at Vanderbilt University Medical Center, Nashville, Tennessee. “Ketamine has been shown to prevent serious acute pain, and as its use grows, studies like this will help us know if there are long-term benefits of short-term use. It looks promising.”
Dr. Edwards told Clinical Pain Advisor the number of patients living with chronic pain continues to rise. He said a host of studies have investigated how to prevent the development of chronic pain. “Ketamine is commonly used for pain control under anesthesia and to reduce post-surgical acute pain, and becoming more common for the treatment of chronic pain. However, less is known about its potential to prevent chronic pain,” said Dr. Edwards, who is Chief of the Chronic Pain Service at Vanderbilt.
A number of drugs and interventions have been studied to reduce the risk for PPSP, including N-methyl D-aspartate (NMDA) receptor antagonists (such as ketamine), lidocaine and gabapentinoids such as pregabalin. However, a Cochrane Review concluded that ketamine was the only agent with current evidence of a potential benefit in preventing PPSP1. Ketamine was discovered in 1962 and is available as a generic medication.
Carl Noe, MD, who is a Professor of Anesthesiology & Pain Management and Clinical Psychology at the University of Texas (UT) Southwestern, Dallas, Texas said ketamine has been used for preventing PPSP for decades. However, it is now being looked at more closely due to the problem with opioid abuse. “It is being renewed because of the prescription opioid epidemic,” Dr. Noe told Clinical Pain Advisor. “The optimal dose of ketamine isn’t really established, but it is a reasonable option for some patients. It does have side effects that include behavioral changes. I think more studies need to be done to define the role of ketamine but I applaud the author’s work.”
Tim Ness, MD, who is a professor in the Department of Anesthesiology and Perioperative Medicine at University of Alabama at Birmingham, said the American Pain Society (APS), the Veteran’s Administration (VA) and the American Society of Anesthesiologists (ASA) recently jointly published guidelines for the treatment of post-operative pain that strongly recommended ketamine use. This current analysis strengthens those recommendations.
“Ketamine has a checkered history as an anesthetic and analgesic agent with a long history of use and more recent history of abuse. This meta-analysis further supports use of ketamine intra-operatively for acute post-operative pain control by demonstrating effects that stretch into a more chronic time period,” Dr. Ness told Clinical Pain Advisor. “As practicing pain clinicians, we are very concerned with the conversion of acute to chronic pain. Any intervention that could be performed in a controlled setting that might reduce this difficult-to-treat disorder would be welcomed. Much of what we do lacks a firm scientific basis.”
Pain expert Jeanmarie Perrone, MD, a professor of Emergency Medicine and director of Medical Toxicology at Penn Medicine, Philadelphia, Pennsylvania said this meta-analysis is important for several reasons. “When patients receive high doses of opioids during surgical procedures, it is thought that this may contribute to hyperalgesia, or increased pain sensitivity. If the overall dosing of opioids can be decreased, or the use of concomitant drugs like ketamine which act at NMDA receptors and not opioid receptors can be used, then the findings of less PPSP makes physiologic sense,” Dr. Perrone told Clinical Pain Advisor. “It is consistent with many other new and novel uses of ketamine, including using its use as an adjunct treatment for chronic pain and for depression.”
1. Chaparro L. et al, 2013. Pharmacotherapy for the prevention of chronic pain after surgery in adults (Review), The Cochrane Database of Systematic Reviews, 7:CD008307