New: Ketamine Found to Be Effective for Chronic Pain

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Ketamine is known to provide pain relief and is sometimes prescribed off-label as a third- or fourth-line treatment for those with chronic pain, but its use has been limited by a lack of protocol standards as well as safety concerns influenced by many factors, including ketamine’s reputation as a risky and potentially dangerous recreational drug. The acute effects of ketamine were cited as the cause of death for actor Matthew Perry, and Elon Musk’s use of ketamine is reported to contribute to his erratic and even bizarre behavior.[1]These challenges and controversies have attenuated the availability of quality data on efficacy and safety and efficacy.

However, a new study—one of the largest of its kind—indicates that low-dose ketamine infusions can be both safe and significantly effective for patients with chronic refractory pain. Chronic refractory pain is a persistent, severe form of pain with adverse mental and emotional, as well as physical effects, and doesn't respond well to standard treatments. This research analyzed data from 1,034 chronic pain patients who participated in a five-day outpatient low-dose ketamine infusion protocol at the Cleveland Clinic’s Center for Comprehensive Pain Recovery between May 2021 and October 2024. It was recently published in Regional Anesthesia & Pain Medicine.[2]

The study protocol utilized subanesthetic doses of ketamine—half a milligram per kilogram of body weight, infused over 40 minutes for five consecutive days. 86.1 percent of the participating patients completed the full five-day treatment regimen. Outcomes were measured using the National Institutes of Health’s PROMIS tool, which assesses physical, mental, and social health. Patients reported notable improvements in pain symptoms as well as quality of life, with 20 to 46 percent of patients achieving meaningful improvements in their daily functioning, fatigue, social role satisfaction, and sleep. Nearly half achieved meaningful improvement in pain catastrophizing, a strong predictor of pain treatment response.

Hallucinations, the most prevalent side effect, were rare, and no serious adverse events were reported across the more than 1,000 participants. Adverse events were defined as requiring discontinuation of infusions and/or an emergency medical response for abnormal ECG findings, symptomatic hypertension, or hypotension.

Subsequently, participants received follow-up assessments at 3 months and 6 months post-treatment, with data demonstrating sustained improvements in depression, social role satisfaction, pain interference, self-efficacy, global health, physical functioning, and pain catastrophizing were maintained at six months post-treatment—providing evidence of lasting benefit.

Continuing Ketamine-Related Questions and Concerns

Currently, ketamine is a Schedule III controlled substance that is FDA-approved only for the induction and maintenance of general anesthesia related to surgery.[3] Because ketamine has not been FDA-approved for chronic pain, the Cleveland Clinic's approach has been to utilize it when other treatments have been ineffective. Contraindications for the use of subanesthetic doses of ketamine include pregnancy and a history of ketamine abuse/addiction.

An increasing number of small-scale clinical trials have demonstrated that subanesthetic doses of ketamine can produce antidepressant effects in patients with mood disorders whose conditions demonstrate resistance to standard therapies.[4] Patients in these trials have been diagnosed with major depressive disorder and bipolar disorder, with sample sizes ranging from 8 to 99. While there is broad agreement that ketamine-like drugs hold therapeutic promise, the recent proliferation of programs and clinicians offering ketamine infusion as an off-label treatment for psychiatric disorders ^[5] has created concern.

Some of these programs came into existence to take advantage of the emerging interest in and buzz about ketamine and evidence questionable qualifications and experience. And there remain significant issues related to the safety and potential risks of repeated ketamine dosing, including the potential for abuse and addiction. These concerns stem in part from reports of cognitive impairment, hallucinations, and bladder dysfunction associated with repeated administration of the drug.

Next Steps

Chronic pain affects as many as one in five adults in the United States. Many people are helped by multidisciplinary care that includes a range of treatments such as over-the-counter and prescription pain medications, physical and psychological therapies, alternative and complementary interventional procedures, and lifestyle modifications. One notable characteristic of ketamine’s pain-relieving quality is that, to this point, the mechanism of action remains unclear.

Ketamine Essential Reads

New Study Raises Questions About Ketamine for Depression

Kitty Flipping: Ketamine and MDMA Stimulant Combinations

The Cleveland Clinic research contributes valuable data that may help carefully administered low-dose ketamine infusions become more widely accepted as a safe and effective intervention for those afflicted with chronic pain who haven’t found relief with other methods. The primary advantages of low-dose ketamine include low tolerance risk, the viability of outpatient administration, and no requirement for anesthesia. The next steps needed for potential FDA approval include randomized controlled clinical trials.

Copyright 2025 Dan Mager, MSW, LCSW