Evidence review questions ketamine’s role in chronic pain treatment

By Dr. Priyom Bose, Ph.D.Reviewed by Lauren HardakerAug 21 2025

Despite growing off-label use, ketamine and related NMDA blockers show no reliable evidence of easing chronic pain, highlighting the urgent need for safer and more effective treatments.

Review: Ketamine and other NMDA receptor antagonists for chronic pain. Image Credit: ANDREI ASKIRKA  / Shutterstock

In a review published in the Cochrane Database of Systematic Reviews, researchers examined the benefits and adverse effects of ketamine and other NMDA receptor antagonists, compared to a placebo, used to treat adults with chronic non-cancer, non-headache pain.

Chronic Pain: Prevalence and Symptoms

Chronic pain is a type of pain that persists for three months or more, affecting approximately 20% of adults in the US, 19% in Europe, and 33% in low- and middle-income countries. Many common chronic pain conditions include lower back pain, osteoarthritis, and neck pain. Many studies have shown that chronic pain negatively affects mood, ability to work, and social participation.

A recent study estimated that the economic burden arising from chronic pain in the USA and Australia has been estimated at USD 560-635 billion and AUD 139 billion per year, respectively.

In 2019, the World Health Organization (WHO) revised the classification of chronic pain, formally separating chronic primary pain from chronic secondary pain. Chronic primary pain occurs persistently and has been associated with emotional distress and disability that cannot be accounted for by another condition. In contrast, chronic secondary pain initially occurs as a symptom secondary to an identifiable underlying disease or condition, such as neuropathic pain.

Investigated Treatments: NMDA Receptor Antagonists

The review focused on NMDA receptor antagonists - a group of drugs whose underlying mechanism of action is the inhibition of the NMDA receptor, a commonly found glutamate-gated ion channel that facilitates excitatory neurotransmission. These include ketamine, memantine, dextromethorphan, amantadine, and magnesium.

Ketamine is a type of non-competitive NMDA receptor antagonist, which acts as an anesthetic at higher dosages and as an analgesic and sedative at lower dosages. Clinicians sometimes prescribe off-label intravenous or oral ketamine to treat chronic pain despite uncertain benefits and harms. Multiple studies have shown that this drug has a rapid plasma half‐life of approximately 2.3 hours. It undergoes oxidative hepatic metabolism through cytochrome P450 CYP3A4 and CYP2B6 enzymes to norketamine, its active metabolite. It must be noted that the higher first‐pass metabolism of ketamine via CYP3A4 enzymes makes it susceptible to interactions with other drugs, mostly opioids and benzodiazepines.

In addition to psychotomimetic effects, ketamine administration is also associated with nausea, vomiting, and hypersalivation. Previous studies have highlighted the risk of dependence, addiction, and withdrawal effects linked with ketamine. The review emphasized that high-quality safety data remain lacking.

About the Review

Although ketamine and other NMDA receptor antagonists are increasingly used for chronic pain treatment, no reviews are available in the Cochrane Library that assessed the benefits and side effects of these drugs. An up-to-date review will help clinicians and policymakers to develop and implement effective treatment guidelines.

The current review included studies on mixed pain populations, randomized controlled trials (RCTs), while excluding studies of cancer or headache pain. Non‐randomised studies, case reports, clinical observations, and experimental studies using pain induction were excluded. Studies that included adults aged 18 years and older reporting chronic pain of at least three months' duration were included. Individuals' pain intensity scores were measured using a visual analogue scale (VAS), a verbal rating scale, a numeric rating scale (NRS), a Likert scale, or an ordinal scale.

Review Findings

A total of 15,759 articles were initially identified from different databases. After removing duplicates, the qualitative synthesis included 67 studies, and the quantitative synthesis (meta-analysis of pain intensity and adverse events) included 28 studies. The 67 selected studies had randomized 2,309 participants, whose symptoms ranged from neuropathic pain, fibromyalgia, and complex regional pain syndrome. Approximately 58% of studies were excluded from quantitative syntheses due to unavailable first-phase data from crossover trials or outcome measurements ≤48 hours.

Most studies indicated the intravenous route of ketamine administration and analyzed its effect by comparing it with placebo treatment. No clear evidence indicated that intravenous ketamine reduces pain intensity at immediate‐, short‐, or medium‐term follow‐up. The confidence intervals were wide, showing possible clinically important effects or no effect. Intravenous ketamine may increase the risk of adverse effects, such as nausea, psychotomimetic effects, and vomiting. Subgroup analyses did not reveal any differences in intravenous ketamine effects based on clinical condition or duration of treatment administration.

No formulation of ketamine (intravenous, oral, or topical) showed clear benefits for pain relief. Based on the study findings, evidence for oral and topical ketamine was inconclusive due to minimal data from small studies. Six studies evaluated the efficacy of oral memantine against a placebo, showing no clear evidence that this intervention reduces pain intensity at immediate-, short-, or medium-term follow-up.

The subgroup analysis revealed that the effects of oral memantine might vary depending on the clinical condition. However, this observation had low statistical power and requires cautious interpretation. Memantine treatment showed no apparent increase in risk for nausea, sedation, dizziness, or headache. For most NMDA antagonists, evidence on adverse events was minimal and uncertain.

The authors found inconclusive evidence for oral dextromethorphan, amantadine, and magnesium (administered intravenously, orally, or intramuscularly) due to a limited number of small studies with imprecise estimates.

Conclusions

The current review highlighted very limited, low-to-very low-certainty evidence on the effects of all studied NMDA receptor antagonists on pain intensity. Although intravenous ketamine treatment was found to increase the risk of adverse effects potentially, the evidence for other formulations and NMDA antagonists remained unclear. Critically, the authors concluded: "Current evidence is insufficient to inform clinical practice."

In the future, adequately powered RCTs are required to determine the efficacy and safety of ketamine and other NMDA receptor antagonists for chronic pain management.