Examining the role of NMDAR antagonists
Analgesics like ketamine, methadone, and magnesium may have merit in unexpected clinical settings, including mental health, neurology, and chronic pain management.
Since the development of methadone and ketamine in the 1930s and 1960s, respectively, there has been great progress in understanding their mechanisms of action. The advancement has led to adaptation of the agents for novel applications.
This was the subject of the Saturday session “N-Methyl-d-Aspartate Receptor (NMDAR) Antagonists in Perioperative Medicine and Chronic Pain Management.”
Much of the session was focused on ketamine and its surrounding controversy. The three presenters referenced a multitude of published papers on the effects of ketamine, but most of them have mixed or contradicting results.
According to one systematic review, “Perioperative Intravenous Ketamine for Acute Postoperative Pain in Adults,” presented by Laura F. Cavallone, MD, MSc, FASA, there is consensus that ketamine is beneficial for patients having thoracic, major abdominal, or major orthopedic surgery. The authors concluded that ketamine helps reduce postoperative pain scores and opioid use as well as side effects like nausea and vomiting.
Ketamine was first used as a battlefield analgesic during the Vietnam War, said session presenter Magdalena Anitescu, MD, FASA, a Professor of Anesthesia and Critical Care at the University of Chicago. She said she often hears ketamine referred to as “messy” or “dirty” because it is difficult to research due to its systemic complexity.
While ketamine has the potential for significant benefits in treating postoperative pain, it also can produce significant adverse events, Dr. Anitescu said. These include severe nausea, increased heart rate, increased intracranial pressure, and hallucinations. The risk-benefit calculation for using ketamine is dependent on the combination of dose, duration, setting, and monitoring.
There is moderate evidence of patient selection for clinical practice use, said Dr. Anitescu, who referenced the 2018 Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management.
“Ketamine is a great drug, but choose it carefully,” she said. “When selecting patients, look for NMDA-dependent amplification. A phenotype-based approach is safer than ‘ketamine for chronic pain.’”
Dr. Anitescu indicated to define success first, then consider ketamine’s ability to improve outcomes based on the patient. Individuals who have complex regional pain syndrome (CRPS) with sensitization, neuropathic pain with allodynia, or a high opioid tolerance have a higher plausibility of success.
Panelist Ehab Farag, MD, FRCA, FASA, closely examined ketamine’s probable advantages as a treatment for depression. Dr. Farag is a Professor of Anesthesia at Cleveland Clinic and Case Western Reserve University School of Medicine in Ohio.
One way ketamine supports antidepressant therapeutic properties, he said, is through circuit balancing and enhancement of the thought/mood network via stimulation of the estrogen receptor. A potential hazard to this scenario is that its effects are shaped by sex-dependent metabolism, which requires additional analysis.
Ketamine also supports myelination of the brain, Dr. Farag said, which further contributes to its effects as an antidepressant, anti-inflammatory, and potential PTSD prophylactic.
Dr. Farag said ketamine is a versatile drug that has proven effective in acute settings where patients are closely monitored. It is not encouraged for outpatient or long-term use.
Some questions remain, said Dr. Cavallone, who is an Associate Professor of Anesthesiology at the University of Washington in Seattle. For example, does ketamine prevent the development of postsurgical delirium, hyperalgesia, or chronic pain? Research on these conditions has been inconclusive and requires further analysis.
The panelists also briefly discussed research results and practical applications of methadone and magnesium. Magnesium sulfate (MgSO4) is more difficult to agree on, said Dr. Cavallone, because of the heterogeneity in its research. Vast fluctuation in dose, delivery mode, and timing across studies, as well as small sample sizes, has led to mixed results, though the evidence shows an indication of MgSO4 reducing postoperative pain and morphine consumption.
Methadone is a promising NMDAR agent because of its favorable relationship between onset time and origin of action, Dr. Cavallone said. On the other hand, it has longer postoperative duration. She said there is potential for using methadone to treat surgical pain, but further research is needed to better understand dosage and methods.
