Medical Editor: Dr. David Cox, PhD, ABPP

From the battlefield to the operating room to the dance floor, ketamine is something of a legend. It made history when the FDA approved its use for treatment-resistant depression, becoming the first FDA-approved psychedelic drug. While this passed in the form of a nasal spray, the majority of evidence supports the use of ketamine infusions. Current science indicates ketamine infusions as a treatment for depression, but as the substance’s popularity grows, so does the range of conditions it potentially treats. Ketamine clinics across the country are making sweeping claims, and it can be hard to know what it does and what it doesn’t do. Here is what the science says so far on ketamine for chronic pain.

The origins of ketamine for chronic pain

Ketamine first made a name for itself on the battlefields of Vietnam. Because this medicine maintains hemodynamic stability or stable blood flow, it’s a safe and effective anesthetic for treating trauma. It’s listed on the World Health Organization Model List of Essential Medicines, which names medications considered to be most effective and safe while meeting a health system’s most important needs.

Ketamine is still used as an anesthetic and analgesic for trauma in emergency rooms today, including with children. Research shows that perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after surgery. But ketamine is popular outside of war zones and operating rooms, too.

While ketamine is considered safer than opioids, it is also used as a recreational drug due to its euphoric effects. Ketamine’s reputation became more colorful due to its use as a club drug. While ketamine is technically a dissociative anesthetic, it’s considered a psychedelic medicine due to its hallucinogenic properties, indicating subsequent therapeutic benefits. In March of 2019, ketamine became the first FDA-approved psychedelic. It gained approval in the form of Spravato (esketamine) nasal spray for treatment-resistant depression.

Generic ketamine is a mixture of two mirror-image molecules, “R” and “S” ketamine. The FDA-approved nasal spray, Spravato (esketamine), only contains the “S” molecule. However, in the treatment of depression, there is more evidence supporting the use of generic (racemic) ketamine IV infusions.

A 2017 study suggests that ketamine infusions administered intravenously one to three times per week are the fastest and most effective treatment for depression. But doctors are using ketamine infusions to treat more than depression. Research shows that the drug can also be effective in the treatment of PTSD, suicidal thoughts, and chronic pain.

Current applications of ketamine for chronic pain

Ketamine is still used to treat acute pain in the operating room, but it’s also used to treat chronic pain. A 2014 study suggests that ketamine treats chronic pain, at least in part,  by inhibiting the N-methyl-D-aspartate receptor (NMDA). A five-year retrospective study on 51 chronic pain patients found the pain was reduced or abolished in two‐thirds of patients under ketamine therapy. It was also well-tolerated in patients taking opioids and had few adverse effects.

Research also shows that ketamine could be a safe alternative to opioids. Furthermore, it could also be used for patients recovering from opioid use disorder, which is an epidemic in the U.S. Opioid use disorders affect over 16 million people worldwide, with over 2.1 million in the United States alone. There are over 120,000 deaths worldwide annually attributed to opioids. As a result, doctors are constantly working to find safer ways to treat chronic pain.

While acute pain is a normal part of life that comes with injury or trauma and usually resolves on its own, chronic pain is, by definition, persistent. Signals keep firing, and the ongoing pain can cause significant life stress. Chronic pain may include headache, low back pain, cancer pain, arthritis pain, and neurogenic pain (pain resulting from a dysfunction of the peripheral nerves or to the central nervous system itself). According to a 2020 study, the majority of ketamine administered for chronic pain is done for neuropathic pain. Ketamine for chronic pain has also been tested in conjunction with magnesium; magnesium is an extracellular NMDA receptor blocker that may add to the analgesic effects of ketamine. Despite how hopeful this sounds for treating chronic pain, the same study concluded that the efficacy of ketamine for the treatment of chronic pain is moderate to weak.

Ketamine clinics are rapidly popping up across the United States. While research mostly supports the use of ketamine infusions for depression, treatment centers are providing off-label use for many conditions, regardless of the science. While the rise in ketamine infusions has helped many people who don’t respond to the first line of treatment for conditions such as chronic pain, there can be downsides. Patients may be taken advantage of financially  (with ketamine infusions costing between $300 to $2,000 per treatment) or treated for conditions that are not supported by the scientific evidence and may not be effective.

Guidelines for ketamine for chronic pain and final thoughts

To minimize irresponsible use of ketamine infusions for chronic pain, guidelines have been published on the use of ketamine to treat this syndrome., Comparisons were made to off-label ketamine infusion clinics and the Wild West. These guidelines include:

• Develop meaningful data on the risks of ketamine infusions versus the total doses received. This will help prevent patients from getting stuck in an expensive, long-term, and potentially ineffective treatment schedule. This should include information on comorbidities that might predispose patients to adverse outcomes like cardiovascular disease and liver conditions, or those who have a history of substance use disorders.
• Come to a standard agreement of what constitutes success in terms of ketamine infusions for chronic pain.
• Develop an empirically supported approach to selecting ketamine doses due to the fact that while administered at subanesthetic doses, the amount of ketamine given in an infusion for chronic pain ranges drastically.
• Ensure that ketamine therapy for chronic pain is multidisciplinary and may include non-opioid medication, behavioral therapy, and activity-based therapy.

There is some evidence that ketamine can treat chronic pain, yet there is still not enough. Ketamine may help some people, and is a generally safer option than opioids, although additional science is needed to make a definitive statement. Of course, this does not prevent ketamine clinics across the country from offering this service. To best and most safely serve the people who may benefit from ketamine infusions for chronic pain, suggested standards and guidelines should be followed.