A comprehensive new systematic review published in the Cochrane Database of Systematic Reviews casts significant doubt on the off-label use of ketamine for chronic pain management, calling into question the foundation of what has become an increasingly common clinical practice worldwide. Ketamine, traditionally deployed as an anesthetic for procedural sedation and acute pain relief, has been widely repurposed over recent years to address persistent pain syndromes such as neuropathic pain, fibromyalgia, and complex regional pain syndrome. This review synthesizes evidence from 67 clinical trials comprising over 2,300 adult participants to critically evaluate the efficacy and safety profiles of ketamine alongside other NMDA receptor antagonists in alleviating chronic pain.
At the core of ketamine’s proposed analgesic mechanism is its role as an NMDA receptor antagonist. These receptors, integral components of the central nervous system, are implicated in excitatory neurotransmission and play a pivotal role in the amplification of pain signals in chronic pain states. By blocking NMDA receptors, ketamine is hypothesized to disrupt the pathologic neural sensitization that underpins many chronic pain conditions. Despite the theoretical rationale and increasing clinical enthusiasm for ketamine’s utility, the new review delineates a conspicuous absence of robust, high-certainty evidence demonstrating clear clinical benefits.
The systematic review team, including experts from UNSW Sydney, Neuroscience Research Australia (NeuRA), and Brunel University of London, undertook a meticulous appraisal of randomized controlled trials involving ketamine as well as memantine, dextromethorphan, amantadine, and magnesium. The trials analyzed encompassed various dosing regimens and chronic pain etiologies, yet across this heterogeneous landscape, no consistent or compelling evidence emerged supporting ketamine’s efficacy in reducing long-term pain intensity or improving patient outcomes.
Crucially, the review highlights that the certainty of existing evidence remains low to very low, primarily due to inherent limitations such as small sample sizes, methodological inconsistencies, and high risks of bias. Such weak evidence underscores an urgent need for well-powered, rigorously designed clinical trials that can conclusively delineate therapeutic value. Without such data, clinicians are left to navigate a precarious balance between offering potentially ineffective treatment and exposing patients to substantial risks.
Concerns around adverse effects surfaced prominently within the review’s findings. Ketamine’s administration, particularly via intravenous routes, is associated with psychotomimetic side effects including delusions, paranoia, and delirium. These neuropsychiatric symptoms, though often transient, can be profoundly distressing and debilitating for patients, complicating treatment adherence and overall quality of life. Gastrointestinal adverse events such as nausea and vomiting were also frequently reported, further diminishing the drug’s tolerability in the chronic pain population.
The clinical dilemma is sharpened by the paradox that while ketamine may alleviate acute nociceptive pain, its translation into effective chronic pain management remains unproven and fraught with harm. The review authors caution that attempts to titrate doses to mitigate side effects may not reliably prevent these adverse outcomes, thus challenging the feasibility of safe long-term use. This is particularly pertinent given the vulnerable nature of patients with chronic pain, who often have coexisting psychological comorbidities.
Interestingly, the systematic review notes a glaring absence in current research regarding two critical dimensions frequently cited as secondary benefits of ketamine therapy: reduction in depressive symptoms and decreased opioid consumption. With depression and opioid tolerance common comorbidities in chronic pain syndromes, these factors form a significant axis upon which ketamine’s value proposition often rests. Yet the lack of empirical data leaves these purported benefits speculative and unsubstantiated within the evidence base.
Experts involved in the review emphasize the broader implications of these findings for clinical practice and policy. The pervasive use of ketamine and other NMDA antagonists in chronic pain treatment—often driven by clinician enthusiasm and patient desperation—risks repeating the pitfalls witnessed in opioid prescribing. The opioid epidemic, fueled in part by premature adoption of therapies without sufficient evidence, serves as a cautionary tale underscoring the necessity of judicious, evidence-aligned prescribing.
The authors advocate for heightened caution among clinicians, urging restraint in the widespread adoption of ketamine until definitive high-quality trials clarify its role. They assert that investment in such research is not merely academic but a pressing public health priority, with the potential to inform safer, more effective pain management paradigms. This call aligns with a growing consensus within pain medicine emphasizing personalized care grounded in empirical validation.
From the patient perspective, the review aims to empower informed decision-making conversations between clinicians and individuals living with chronic pain. By transparently communicating the uncertainties surrounding ketamine’s benefits and highlighting the risks, patients can better weigh potential outcomes within the context of their personal health goals and treatment tolerance thresholds.
In sum, this Cochrane systematic review delivers an important recalibration of ketamine’s therapeutic narrative in chronic pain management. It underscores a profound knowledge gap, one marked by ambiguity regarding efficacy and a clear signal of adverse effect risks. Until the scientific community addresses this through rigorously conducted, large-scale trials, ketamine’s place in chronic pain care must remain circumspect, guided foremost by prudence and patient safety.
The implications extend beyond ketamine alone, casting a reflective light on the broader category of NMDA receptor antagonists. Their theoretical allure notwithstanding, the current landscape illustrates the complexity of translating molecular pharmacology into clinical success in chronic pain—a field marked by heterogeneous pathophysiology and multidimensional patient experiences.
Ultimately, this review invites both clinicians and researchers to critically examine prevailing assumptions and to commit to evidence-driven innovation. It is a pivotal moment to recalibrate treatments based on science rather than enthusiasm and to safeguard the wellbeing of patients navigating the challenging terrain of chronic pain.
Subject of Research: People
Article Title: Ketamine and other NMDA receptor antagonists for chronic pain
News Publication Date: 18-Aug-2025
Web References: http://dx.doi.org/10.1002/14651858.CD015373.pub2
Keywords: Pain, Chronic pain, Fibromyalgia, Neuropathic pain, Clinical medicine, Medical treatments, Drug therapy, Medications, Analgesics, Pharmaceuticals, Illicit drugs
