Low-Dose Ketamine in Perioperative Pain Management: An Opioid-Sparing Breakthrough?

A new retrospective study from the Cleveland Clinic suggests that a standardized, low-dose ketamine infusion therapy (KIT) protocol may offer clinically meaningful relief for a subset of patients with chronic refractory pain—while achieving notably high treatment completion rates and a strong safety profile.

Conducted over a three-year period from 2021 to 2024, the study evaluated 1,034 adult patients who underwent the outpatient infusion protocol at the Clinic’s multidisciplinary pain center. The treatment consisted of 0.5 mg/kg ketamine administered intravenously over 40 minutes across five consecutive days—a regimen designed to balance efficacy with tolerability and minimize psychotropic side effects that have historically limited ketamine’s broader use in chronic pain management.

The findings offer a cautiously optimistic picture: although only a portion of patients achieved clinically meaningful improvement, the proportion who did—ranging from 20% to 46.4% depending on the outcome measure—was consistent through 6-month follow-up. Additionally, mean scores across key patient-reported outcomes showed statistically significant improvements in fatigue, pain interference, social functioning, and depression.

Pain interference, fatigue, and social role satisfaction showed the most robust improvements, with mean score reductions of −2.0 to −2.1 points—approaching clinical relevance. Depression scores, pain catastrophizing, and measures of self-efficacy also trended positively, with gains generally sustained over six months. While many individual patient improvements did not cross the threshold for clinical significance, the consistent directional benefit across multiple domains adds weight to the findings.

Importantly, the completion rate stood out: more than 86% of patients completed all five infusions, and no adverse events were reported—a testament to the tolerability of the low-dose regimen when delivered in a controlled, multidisciplinary outpatient setting.

Chronic refractory pain—defined as pain unresponsive to conventional pharmacologic and non-pharmacologic interventions—remains one of the most vexing challenges in pain medicine. Patients often cycle through opioids, anticonvulsants, antidepressants, and interventional procedures with limited success and significant side effect burden. Ketamine, an NMDA receptor antagonist with well-documented analgesic and antidepressant effects, has gained attention as a potential disruptor in this space. However, variability in dosing, treatment duration, and monitoring protocols has hindered widespread adoption.

This study attempts to bring order to that variability. By applying a consistent protocol across a large patient cohort and integrating it into a multidisciplinary care model, the Cleveland Clinic team offers a potential framework for broader clinical use.

Still, the study’s design—retrospective and observational—limits the strength of its conclusions. Without a control group, it is difficult to isolate the effect of ketamine from placebo responses, natural symptom fluctuation, or concurrent therapies. The authors are clear on this point, calling for randomized controlled trials to validate their findings and explore which patient subgroups may derive the greatest benefit.

In the meantime, this real-world evidence provides a compelling case for incorporating ketamine infusions into the chronic pain armamentarium—particularly within settings that can provide close monitoring and integrated support. For a population often stuck between ineffective options and intolerable side effects, even modest, sustained gains can be life-changing.

As the field of pain medicine evolves toward precision and personalization, studies like this underscore the importance of not only novel treatments, but also the protocols and infrastructure that allow them to succeed in practice.