Since its synthesis in the 1960s, ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has found use on the battlefield, in emergency rooms, in surgical arenas, and in psychiatric clinics. Researchers from St. Michael’s Hospital, Unity Health Toronto, recently showed that when combined with psychotherapy, ketamine might not only reduce pain intensity but also improve quality of life among patients with neuropathic pain.

The pilot study, published online on August 13 in Med, joins other literature demonstrating the benefit of combining the two modalities.

“We know that once pain becomes chronic, it becomes a disease in its own right and affects every facet of patients’ lives; it’s a biopsychosocial disease,” lead author Akash Goel, MD, MPH, assistant professor of anesthesiology and pain medicine at the University of Toronto and attending anesthesiologist and interventional pain medicine specialist at St. Michael’s Hospital, told Medscape News Canada.

Research has underscored that ketamine not only has significant pain-relieving qualities but also might induce a state of neuroplasticity, Goel explained. In his mixed-methods, randomized pilot study, 30 patients with chronic neuropathic pain received ketamine infusions, weekly psychotherapy sessions, or both. The study demonstrated the feasibility and safety of combining ketamine and psychotherapy.

The research was not powered to evaluate the interventions’ efficacy. But roughly 80% of patients receiving both treatments experienced a reduction in pain interference scores of 2.5 points or more by week 20. About 63% of patients in the ketamine group and 56% of patients in the psychotherapy group achieved this outcome. Improvements in other pain outcomes (eg, pain catastrophizing and functionality) were also reported.

The Montreal Model

Ian Mitchell, MD, an emergency physician at Royal Inland Hospital in Kamloops, British Columbia, and a clinical associate professor of emergency medicine at the University of British Columbia, has used ketamine in clinical practice for almost three decades. He’s also on the board of the Ketamine Assisted Therapy Association of Canada, which was established in 2019 to advance clinical practice standards, support clinicians pursuing ketamine training, and foster research.

Ketamine-assisted therapy has taken a page from depression studies, Mitchell said. “Ketamine is a natural antidepressant. You get an effect for a week to 10 days where you feel better, can do things, and have more emotional regulation,” said Mitchell. Ketamine’s rapid action on NMDA receptors and activation of brain-derived neurotrophic factor signaling pathways promote the growth of new synapses and reverse neuronal atrophy in the brain.

Ketamine has been shown to provide rapid improvements in depression and suicidality among patients with treatment-resistant depression. These effects are often short-lived, however. They last for days to weeks after the final dose.

To address this limitation, researchers at McGill University’s Faculty of Medicine in Montreal, Jewish General Hospital, the University of Montreal, and other institutions developed the Montreal model, which has since gained prominence in the field. This therapeutic strategy pairs ketamine with conventional psychiatric care (ie, psychotherapy) and occasional maintenance treatments.

Kyle Greenway, MD, psychiatrist and clinician-scientist at the Jewish General Hospital, investigator at the Lady Davis Institute, and assistant professor of psychiatry at McGill University, Montreal, was directly involved in the model’s development. It is meant to take advantage of the window of opportunity that ketamine provides, a window during which behavioral and psychological work may help patients maintain and sustain ketamine’s benefits.

The approach, he said, also helps bridge the divide between psychedelic and biomedical treatment strategies. The former typically involves a psychiatrically guided session in a calm, pleasant environment, and the latter focuses on ketamine infusions in sterile, clinical environments.

“A key component is that even before planning the first ketamine day, we first do a thorough assessment and establish mutually understood goals for the changes they want to make to get themselves back to a healthier way of living,” said Greenway.

“Ketamine is delivered in a psychedelically inspired manner — ie, in a quiet, comfortable, pleasant environment with music, psychological support, and guided mindfulness — which generates a meaningful, personal, emotional experience instead of a dissociative, altered state of consciousness. The last component is making sure people are in regular psychotherapy outside our teams for at least 1 h/wk, which helps them make meaning of the experiences and translate them into behavioral changes,” he said.

“When it works well, it creates a process that feeds all the different components and leads to something greater than the sum of its parts,” said Greenway.

A Versatile Drug

Ketamine has been studied in thousands of patients. Data have shown that when combined with psychotherapy, ketamine benefits patients with conditions ranging from pain and substance use disorders to various psychological conditions such as major depressive disorder, treatment-resistant depression, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and obsessive-compulsive disorder.

Ketamine is “one of the jackknives of emergency departments,” said Mitchell. “The most common reason it’s used is for procedural sedation, and secondly for control of agitated patients. It’s useful for respiratory function support during extreme asthma attacks and for treating migraines. There’s research that ketamine can decrease hyperalgesia, especially in patients whose pain has been treated with opiates,” he added, noting that hyperalgesia is moderated by the NMDA system.

Royal Inland Hospital’s ketamine program is actively increasing the number of patients who are receiving ketamine for depression and chronic pain, said Mitchell. Researchers are also examining its utility in addiction. But limited accessibility and affordability are concerns because ketamine is not routinely covered by provincial public health plans. “There aren’t many places in our area, and because it is typically administered intravenously [IV], it takes a lot of money and resources,” said Mitchell.

One solution recently adopted by Jewish General Hospital is to transition to intramuscular dosing. “It’s much easier to give one dose, like a vaccine in the shoulder, than to install an IV, maintain access, run a pump, etc. And a dose costs $3 instead of $1000 or $2000,” said Greenway.

For clinicians who work with ketamine or refer patients to ketamine centers for treatment, Greenway suggests what he referred to as “humility” about its pharmacologic or phenomenologic effects.

“It’s a chameleonic drug,” he said. Research has shown that its effects are shaped by the environment and context in which it is used and by the condition for which it is used. Arguably, it is a safe compound with broad utility, especially for mental health and pain conditions, which often occur together. With the addition of psychotherapy, the opportunity to maximize its effects appears promising.

Goel, Mitchell, and Greenway reported having no relevant financial relationships.

Liz Scherer is an independent health/medical journalist who frequently writes for Medscape Canada. She has been reporting on advances in psychedelic therapy in Europe and Canada for several years.