New review weighs NMDA antagonists for pain control in dogs

A new WSAVA Pain Committee mini review is putting NMDA receptor antagonists back in focus for canine pain control. Published online September 21, 2026 in the Journal of Small Animal Practice, the paper reviews the science behind this drug class, its role in central sensitization and chronic pain, and the current state of clinical use in dogs. Its central message is measured: these drugs are biologically compelling and already used in practice, but the evidence base is still incomplete. (lifescience.net)

That matters because NMDA antagonists have occupied an in-between space in veterinary analgesia for years. They’re not fringe therapies, but they’re also not backed by the kind of robust, condition-specific evidence clinicians would ideally want. The 2022 WSAVA pain guidelines describe NMDA antagonists such as amantadine and ketamine as tools that may help prevent or treat central sensitization, especially in chronic, invasive, severe, or neuropathic pain states. The Merck Veterinary Manual similarly notes that ketamine’s analgesic effects are tied to NMDA antagonism, while amantadine appears most useful as an adjunct rather than a stand-alone analgesic. (onlinelibrary.wiley.com)

The new review, authored by P. W. Kronen, B. D. X. Lascelles, B. P. Monteiro, and colleagues, specifically flags those unresolved issues. According to the abstract, the paper covers the pathophysiology of chronic pain related to the NMDA receptor, reviews clinical application of selected drugs in the class, and offers suggested dosage regimens. But it also states plainly that more studies are needed to support perioperative use and chronic pain treatment, and that best dosing, safety, efficacy, and condition targeting remain insufficiently defined. (lifescience.net)

Among the agents most relevant to small animal practice, amantadine has some of the better-known canine data, though it’s still limited. A randomized controlled trial published in 2008 found that dogs with refractory osteoarthritis had improved activity and pain-related outcomes when amantadine at 3 to 5 mg/kg once daily was added to meloxicam, compared with meloxicam plus placebo. That study has helped anchor amantadine’s place as an adjunctive option in dogs with chronic pain that isn’t adequately controlled with first-line therapy alone. (pubmed.ncbi.nlm.nih.gov)

Ketamine’s case is broader, but not necessarily cleaner. It is already widely used in anesthesia and analgesia protocols, particularly to reduce central sensitization in perioperative settings. Still, a 2025 systematic review of perioperative systemic ketamine in dogs and cats found only moderate-quality evidence overall. The authors concluded that ketamine may affect postoperative pain scores beyond 12 hours, but did not clearly reduce rescue analgesia requirements, and they called for higher-dose studies across a wider range of clinical procedures. (pubmed.ncbi.nlm.nih.gov)

There does appear to be broad expert alignment on one point: NMDA antagonists make the most sense as part of multimodal analgesia, not as simple replacements for more established pain therapies. That’s consistent across WSAVA guidance, Merck’s clinical reference, and prior reviews discussing chronic and neuropathic pain in dogs. In practical terms, the industry reaction is less about a breakthrough and more about consolidation: this review seems designed to tell clinicians what the evidence supports today, where expert use has outpaced formal data, and where the biggest research gaps still sit. That last point is an inference based on the review’s framing and the wider guideline landscape. (lifescience.net)

Why it matters: For veterinarians, the review is a timely reminder to be precise about when and why they reach for this class. In dogs with chronic osteoarthritis pain, neuropathic features, hyperalgesia, allodynia, or suspected central sensitization, NMDA antagonists may still have a role, especially when standard multimodal plans are falling short. But the paper also underscores the need to set expectations with pet parents: evidence is stronger for some use cases than others, protocols aren’t fully standardized, and response may depend heavily on patient selection and concurrent therapies. (lifescience.net)

What to watch: The next step is likely not a new class-wide recommendation, but better clinical trials, especially around perioperative ketamine protocols, chronic pain phenotyping, and clearer use cases for oral agents such as amantadine; if those data emerge, future WSAVA or other pain guidelines could become more specific about where NMDA antagonists belong in canine pain care. (lifescience.net)