A large, real-world study of patients with chronic pain who failed to respond to other treatments found that a standardized, low-dose ketamine infusion protocol was safe and had high rates of treatment completion. The research, conducted at the Cleveland Clinic, showed that many patients experienced sustained improvements in physical and mental health for up to six months, offering a potential new framework for managing some of the most difficult-to-treat pain conditions.
Despite these promising findings in a clinical setting, the broader scientific evidence for ketamine’s use in chronic pain remains contentious. A major systematic review of previous trials concluded there is no clear evidence of benefit for the off-label use of ketamine and that it carries a significant risk of side effects. This contrast highlights a growing debate within the medical community about how to balance anecdotal success and emerging clinical protocols with the need for more rigorous, controlled research to definitively establish the drug’s role in pain management.
A Standardized Protocol Under Review
In a retrospective observational study, researchers analyzed outcomes for 1,034 adults with chronic refractory pain who received ketamine infusion therapy at a multidisciplinary pain clinic between May 2021 and October 2024. The standardized protocol consisted of a 0.5 mg/kg dose of ketamine infused over 40 minutes for five consecutive days. This systematic approach was designed to balance safety and efficacy, streamline procedures in a high-volume clinic, and minimize variability in treatment. Treatment completion was very high, with 86.1% of patients completing at least five infusions, and no serious adverse medical events were reported.
Evaluating Patient Outcomes
The study measured effectiveness using a variety of patient-reported outcomes at the start of treatment, at the last infusion, and at three- and six-month follow-ups. While the majority of individual outcomes did not meet the threshold for being “clinically meaningful,” a significant minority of patients reported substantial relief. Between 20.3% and 46.4% of patients achieved a clinically meaningful improvement on various measures, including fatigue, pain interference, and social role satisfaction. These improvements were largely sustained at the six-month mark. The most significant gains were seen in reducing pain catastrophizing, a pattern of negative thinking that can worsen pain.
Broader Scientific Context and Uncertainty
The Cochrane Review Findings
Casting doubt on the widespread use of the drug, a large Cochrane review conducted by researchers from UNSW Sydney, Neuroscience Research Australia (NeuRA), and Brunel University of London found no clear evidence of benefit for ketamine in chronic pain. The review analyzed 67 trials involving over 2,300 adults and rated the certainty of the available evidence as “low to very low,” citing small study sizes and poor methodological quality. The authors of that review urged caution, stating that while they are not saying ketamine is ineffective, the data is inconclusive and could point to either a benefit or no effect at all.
A Profile of Known Risks
Safety remains a primary concern for clinicians considering ketamine. The drug is known to have multiple safety issues, particularly at higher doses or with intravenous use. The most common adverse effects are psychotomimetic symptoms, which can include delusions, delirium, and paranoia. Nausea and vomiting are also frequently reported. Other physiological risks include sympathetic stimulation that can lead to tachycardia and hypertension. While some reports have noted damage to the liver and urogenital tract, this appears to be restricted primarily to individuals who chronically abuse the drug rather than patients receiving it in a controlled medical setting.
The Mechanism of Action
Ketamine functions differently from many traditional pain medications. It is an N-methyl-D-aspartate (NMDA) receptor antagonist. These receptors are involved in amplifying pain signals in the brain. In states of chronic pain, these signaling pathways can become sensitized, leading to persistent pain. By blocking these receptors, ketamine is thought to interrupt this pathological process, providing relief that can sometimes last longer than the infusion period itself. This mechanism has made it an attractive option for conditions like neuropathic pain, fibromyalgia, and complex regional pain syndrome.
Future Research and Clinical Implications
The divergence between the positive real-world data from the Cleveland Clinic and the uncertain conclusions of the Cochrane review underscores an urgent need for more definitive research. Researchers on all sides of the issue agree that large, high-quality, randomized controlled trials are necessary to clarify ketamine’s true effectiveness and safety profile for various chronic pain conditions. The Cleveland Clinic study provides a reproducible framework that other healthcare systems can adapt, potentially accelerating the collection of standardized data. Experts warn that without strong evidence, the medical community risks repeating the mistakes of the past, such as the opioid crisis, where a treatment was widely adopted before its long-term consequences were fully understood.