Are NMDA receptor antagonists effective in preventing chronic postsurgical pain?
Myron Yaster MD, Elliot Krane MD, and Rita Agarwal MD
The N-methyl-D-aspartate receptor (NMDA) receptor is involved in the development of chronic pain, including postsurgical pain, therefore NMDA receptor antagonists have been advocated for the prevention of this disabling and costly condition. But do these antagonists actually work? In today’s PAAD Mojica et al.1 reviewed the (mostly non-pediatric) published literature and surprise, surprise found that NMDA receptor antagonists may not be as effective as advocates claim. Myron Yaster MD
Original article
Mojica JJ, Eddy G, Schwenk ES. N-Methyl-D-aspartate receptor antagonists for the prevention of chronic postsurgical pain: a narrative review. Reg Anesth Pain Med. 2025 Feb 5;50(2):160-167. doi: 10.1136/rapm-2024-105612. PMID: 39909540.
“Blockade of the N-methyl-D-aspartate receptors (NMDARs) through the use of NMDAR antagonists can eliminate central sensitization in patients with neuropathic pain.2 Central sensitization is a phenomenon in which the central nervous system (CNS) becomes hyperexcitable3 and often involves altered sensory processing and pain hypersensitivity.4 It can present as an allodynia or a generalized increased sensitivity to pain.5”1
As a review: “Glutamate binds to and activates several glutaminergic ion channels on postsynaptic neurons, but it is the NMDAR that is implicated in the development of chronic pain. The NMDAR is a ligand-gated and voltage-dependent ion channel that requires both glutamate binding and persistent nociceptive input for full activation. In its resting state, magnesium ions block the influx of calcium ions. Persistent nociceptive input from inflammation, tissue damage, and/or nerve injury causes sustained depolarization that displaces the magnesium ion and allows the influx of calcium. Calcium ions activate cell-signaling cascades that contribute to central sensitization,”1
It follows, then, that NMDAR antagonists given perioperatively should prevent the development of CPSP. Drugs that block the NMDA, including the perioperative antagonists include ketamine, magnesium, nitrous oxide, and methadone.
Figure from the article1
Do NMDAR antagonists work?
Mojica et al. (Jefferson University) performed a literature review that included differing patient populations and surgery types and found “improved analgesia in the acute postoperative period but inconsistent evidence that NMDAR blockade actually reduced the incidence of CPSP, even for the most studied antagonist ketamine.”1 There was even less evidence for magnesium and methadone. Let’s drill down on this review:
Their PubMed review used to find articles ignored other sources of potentially valuable literature. The review was very simple: (“the drug”) > “English + Humans” > “RCTs” (for Mg and methadone) or “meta-analyses” (in the case of ketamine).
Importantly, while we are told the inclusion and exclusion criteria, we are told no data regarding the demographic/age/gender/ethnic/race of the subjects in the studies in spite of the well known genetic differences and vulnerabilities of these groups.
Ketamine: : the authors selected 6 papers of meta-analyses for review out of 8 papers that met their PubMed search criteria; these papers analyzed a total of 78 papers, but none were randomized studies against placebo or other drug. How the authors selected the 6 papers for inclusion were not described in the Methods. The definition of CPSP varied in each paper of the 78 papers, and the authors make no mention of the ranges of ketamine dose, duration of treatment, or timing of treatment relative to the surgical procedure in those papers.
Magnesium: The authors’ PubMed search yielded 159 RCTs of magnesium, of which they selected only 3 for inclusion in their analysis. How they selected these 3 by what criteria is not described. We think it goes without saying that it is not reasonable to extrapolate the results of 3 papers into a generalization in the Conclusions, ignoring the findings of 157 papers found in the literature. Another source of frustration is the that the 2 articles that looked at IV magnesium used different dosing strategies and the 3rd article used epidural magnesium.
Methadone: A similar phenomenon here. The PubMed search yielded 70 RCTs of which they selected 3 for generalizing their finding that methadone does not work well for this purpose.
In our opinion, there is nothing in this paper that is a summation or review of the literature, and by no means should influence anyone’s clinical decision making. A review of this type brings to mind the canard “garbage in, garbage out.”
To answer the question posed in the title: Are NMDA receptor antagonists effective in preventing chronic post-surgical pain? The answer is we still don’t really know. We do agree with the authors call call for more and larger studies rather than abandoning these therapies. Amen!
In addition, these PAAD authors call for well conducted unbiased RCTs with well defined dosing and criteria, or reviews of the literature that either embrace all the available literature or precisely describe why the results of some manuscripts were disregarded, plus better scrutiny of submitted manuscripts by peer reviewers for journals.
Are you using NMDAR antagonists in your perioperative management of patients undergoing surgery? Will the results of this meta analysis change your practice? Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Mojica JJ, Eddy G, Schwenk ES. N-Methyl-D-aspartate receptor antagonists for the prevention of chronic postsurgical pain: a narrative review. Regional anesthesia and pain medicine 2025;50(2):160-167. (In eng). DOI: 10.1136/rapm-2024-105612.
2. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. The Lancet 1999;353(9168):1959-1964. DOI: 10.1016/S0140-6736(99)01307-0.
3. den Boer C, Dries L, Terluin B, et al. Central sensitization in chronic pain and medically unexplained symptom research: A systematic review of definitions, operationalizations and measurement instruments. Journal of psychosomatic research 2019;117:32-40. DOI: https://doi.org/10.1016/j.jpsychores.2018.12.010.
4. Lluch E, Torres R, Nijs J, Van Oosterwijck J. Evidence for central sensitization in patients with osteoarthritis pain: A systematic literature review. European Journal of Pain 2014;18(10):1367-1375. DOI: https://doi.org/10.1002/j.1532-2149.2014.499.x.
5. Ji R-R, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 2018;129(2) (https://journals.lww.com/anesthesiology/fulltext/2018/08000/neuroinflammation_and_central_sensitization_in.29.aspx).