Two major studies published recently present starkly different conclusions about ketamine's role in chronic pain management, highlighting the ongoing debate over this off-label treatment that affects millions of patients worldwide.
Cleveland Clinic Study Shows Promise
A study published in Regional Anesthesia & Pain Medicine followed more than 1,000 patients receiving low-dose intravenous ketamine infusions at 0.5 milligrams per kilogram of body weight. The treatment protocol consisted of 40-minute sessions administered over five consecutive days.
The results showed substantial improvements across multiple measures. Between 20% and 46% of patients demonstrated meaningful improvements in pain levels, physical ability, and sleep quality that persisted for at least six months. Nearly half of the patients also reported reduced anxiety related to their pain condition.
"This study provides evidence for ketamine's role in chronic pain management," said lead researcher Hallie Tankha, a clinical pain psychologist at the Cleveland Clinic's Primary Care Institute. "This matches my experience working with patients—many describe ketamine infusions as 'life-changing.'"
The treatment showed strong patient acceptance, with more than 90% completing all five treatment days and approximately 80% choosing to return for additional ketamine treatments. Safety appeared favorable, with very few side effects reported and no serious health complications. A small number of patients experienced hallucinations, but these cases were rare.
Cochrane Review Challenges Effectiveness Claims
In contrast, a comprehensive Cochrane review led by researchers from the University of New South Wales, Neuroscience Research Australia, and Brunel University of London analyzed 67 randomized controlled trials involving 2,309 participants and reached markedly different conclusions.
The systematic review examined five NMDA receptor antagonists—ketamine, memantine, dextromethorphan, amantadine, and magnesium—comparing them to placebo, standard care, or other drugs across multiple outcome measures including pain levels, side effects, disability, quality of life, and depressive symptoms.
"The group of drugs, and ketamine in particular, are in relatively common use for chronic pain around the world. Yet we have no convincing evidence that they are delivering meaningful benefits for people with pain, even in the short term," said senior author Dr. Neil O'Connell, a professor of evidence-based healthcare at Brunel University of London.
Safety Concerns and Side Effects
The Cochrane review identified significant safety concerns that contrasted with the Cleveland Clinic findings. Intravenous ketamine was associated with a higher risk of adverse events, particularly psychotomimetic effects.
"The most common adverse events we saw were psychotomimetic effects such as delusions, delirium and paranoia, as well as nausea and vomiting," said first author Dr. Michael Ferraro, a clinical researcher at UNSW Sydney and NeuRA. "These effects are distressing for many patients. Clinicians often try to balance the dose for pain relief without triggering those symptoms, but this isn't always achieved."
The review found that oral and topical ketamine formulations also failed to demonstrate convincing benefits, with evidence for other NMDA receptor antagonists rated as weak, inconsistent, and of very low certainty.
Clinical Practice Implications
The conflicting findings highlight a critical gap in chronic pain management, where approximately one in five adults worldwide suffer from the condition. Current treatments such as opioids carry serious risks including addiction, tolerance, and side effects, driving patients and clinicians to seek alternative options.
Dr. Pavan Tankha, medical director of comprehensive pain recovery at Cleveland Clinic's Neurological Institute, emphasized the clinical significance: "Millions of Americans are suffering from chronic pain. This research fills critical gaps in pain management and shows a big step forward in helping patients who have tried everything else."
However, the Cochrane review authors urge caution in clinical practice. "We want to be clear—we're not saying ketamine is ineffective, but there's a lot of uncertainty," said Ferraro. "The data could point to a benefit or no effect at all. Right now, we just don't know."
Research Gaps and Future Directions
Both studies identified critical gaps in the current evidence base. The Cochrane review noted that none of the trials examined whether ketamine helps reduce depressive symptoms or decreases opioid use—two outcomes frequently cited as justifications for prescribing ketamine to chronic pain patients.
Dr. James McAuley, a professor at UNSW and senior researcher at NeuRA, drew parallels to the opioid crisis: "We've seen the harm that can come from taking medicines developed for acute pain and applying them to chronic pain, opioids are a prime example. Now we're seeing a similar pattern with ketamine."
The researchers emphasized the urgent need for high-quality trials that measure not only pain outcomes but also track depressive symptoms, opioid use, and overall quality of life. Future studies should address the methodological limitations identified in current research, including small sample sizes, short-term follow-up periods, and potential bias in study design.
