Ketamine-Lidocaine Infusion: Pilot Outcomes in Refractory Neuropathic Pain (2026, Single-Center Study)

Single IV Ketamine-Lidocaine Infusion Linked to Pain Reduction in Refractory Neuropathic Pain

A prospective, single-center pilot study published on September 20, 2026, found that a single intravenous (IV) infusion of ketamine (15 mg) and lidocaine (4 mg/kg) was associated with significant pain reduction lasting up to four weeks in adults with refractory neuropathic pain (OpenAlex W7213783492). In this observational cohort of 30 adults, mean pain scores on a 0-10 numerical rating scale (NRS) dropped from 7.93 at baseline to 4.93 immediately post-infusion, and remained at 5.63 at the four-week follow-up. Notably, 53.3% of participants maintained at least a 30% reduction in pain at four weeks, and 30% sustained a 50% reduction. Adverse effects were predominantly mild and transient, with no hallucinations or serious events reported.

Mechanisms: Distinct Analgesic Actions and Biomarker Findings

Ketamine and lidocaine act through distinct mechanisms: ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with established dissociative and analgesic properties, while lidocaine is a sodium channel blocker with local anesthetic and anti-inflammatory effects. The rationale for combining these agents is to leverage their complementary pathways for refractory pain syndromes. The study also measured two inflammatory biomarkers—interleukin-6 (IL-6) and C-reactive protein (CRP)—at baseline and four weeks post-infusion. While both biomarkers trended downward (IL-6 from 4.73 to 4.14 pg/mL, CRP from 5.51 to 4.69 mg/L), these changes were not statistically significant (p = 0.086 and p = 0.120, respectively) and did not correlate with pain intensity. This suggests that the analgesic effects observed may not be directly mediated by systemic inflammation, or that the biomarkers chosen do not capture the relevant mechanistic changes for this intervention.

Policy and Research Implications: Informing Future Clinical Trials and Access Pathways

The pilot's findings contribute to a growing body of evidence supporting ketamine-based interventions for chronic pain, but its uncontrolled, observational design precludes definitive conclusions about efficacy. For policymakers and clinical researchers, the study highlights several key points:

• Feasibility and Safety: The protocol—single IV infusion in a monitored setting—was well tolerated, with 70% of patients reporting no post-infusion symptoms and no severe adverse events.
• Durability of Effect: Over half the cohort reported a perceived benefit lasting at least three weeks, suggesting potential for durable outcomes with intermittent dosing.
• Trial Design Considerations: The lack of a control group and the absence of validated functional outcome measures underscore the necessity for randomized, placebo-controlled trials. Future studies should also consider longer follow-up periods and stratification by pain etiology.
• Access and Regulation: While ketamine is approved for anesthesia and certain pain indications, and lidocaine is widely used, their combined off-label use for neuropathic pain remains unstandardized. This pilot may inform expanded access or compassionate use protocols, but regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) will require robust controlled data before considering label expansion.

A non-obvious implication is that the absence of a biomarker-pain correlation challenges the assumption that inflammatory markers are reliable surrogate endpoints in neuropathic pain trials, potentially shifting future research toward alternative mechanistic targets or patient-reported outcomes.

Risks, Limitations, and Unknowns

The primary limitation of this study is its uncontrolled, observational design, which introduces the possibility of placebo effects, regression to the mean, and other biases. The small sample size (n=30) and single-center recruitment further limit generalizability. While adverse effects were mild and no hallucinations were observed, ketamine carries known risks of dissociation, cardiovascular effects, and abuse potential, especially with repeated or higher dosing. The durability of benefit beyond four weeks, optimal dosing intervals, and long-term safety remain unknown. Additionally, the lack of significant biomarker changes leaves the underlying mechanism of analgesia unclear, complicating efforts to identify responders or optimize protocols.

Outlook: Next Steps for Combination Analgesic Research

Controlled, multi-center trials with larger samples and longer follow-up are needed to confirm efficacy, clarify mechanisms, and define the role of ketamine-lidocaine infusions in refractory neuropathic pain management. Investigators should consider incorporating validated functional and quality-of-life measures, alternative biomarkers, and stratification by pain subtype. For clinicians and health systems, the results are hypothesis-generating but not practice-changing; off-label use should remain cautious and closely monitored. For regulators and payers, this pilot underscores both the promise and the complexity of integrating novel combination therapies into chronic pain care pathways.

How we research: This analysis was prepared by Dr. Alex M. Carter, MD, PhD, board-certified in neurology and pain medicine, and reviewed for accuracy and policy relevance on 2026-09-22.