At the end stage of disease processes, pain is rarely simple. Central sensitization, medication tolerance (or intolerance), and maladaptive pain pathways often dominate the clinical picture long before a pet’s final days arrive. Pain treatments and medications gradually increase, escalating the caregiving workload. Behavior changes and clinical signs become harder to interpret. Owners and clinicians alike struggle to know whether pain is being adequately addressed or whether the interventions themselves have stopped providing relief the way they once did. In these cases, subanesthetic ketamine offers something few other analgesics can: an opportunity to interrupt the pain cycle itself, not just pain relief. When used thoughtfully, ketamine may be a powerful tool in veterinary hospice and palliative care, allowing clinicians to re-establish comfort, reassess the patient’s true baseline, and recalibrate daily pain management strategies with greater accuracy. GettyImages/GLOBALP Understanding the problem: Why end-of-life pain is different Chronic pain changes the nervous system. In patients with cancer, degenerative joint disease, neuropathic conditions, or end-stage organ disease, continuous nociceptive input triggers a cascade of neuroplastic changes in the spinal cord and brain. Neurons in the dorsal horn of the spinal cord become hyperexcitable, and the threshold for pain transmission drops, a process known as central sensitization, or “wind-up.” At this point, the peripheral source of pain may be relatively stable, but the nervous system has become its own generator of suffering. Hyperalgesia (an exaggerated response to painful stimuli) and allodynia (pain from stimuli that would not normally be painful) emerge. Standard analgesics like NSAIDs, gabapentinoids, acetaminophen, and opioids can blunt the signal, but they often cannot correct the underlying dysregulation driving it. This is precisely where ketamine’s mechanism of action becomes clinically significant. Why ketamine? The NMDA receptor connection Ketamine’s primary analgesic value lies in its non-competitive antagonism of the N-methyl-D-aspartate (NMDA) receptor. This glutamate receptor subtype plays a central role in the induction and maintenance of central sensitization. As Pozzi, Muir, and Traverso outlined in a foundational review published in the Journal of the American Veterinary Medical Association, NMDA receptor activation is the key driver of wind-up and central sensitization following repeated or sustained nociceptive input; and NMDA antagonists, particularly ketamine, represent the most clinically viable strategy for interrupting this process in veterinary patients.¹ By blocking NMDA receptor activation at subanesthetic doses, ketamine can: Reduce the hyperexcitability of dorsal horn neurons Decrease hyperalgesia and allodynia Improve responsiveness to existing analgesic medications, including opioids Lower overall pain perception beyond its immediate dosing window This last point is particularly meaningful in palliative care. Ketamine’s benefit is not purely pharmacokinetic; the neuroplastic effects of even a single intervention may shift pain processing in ways that outlast the drug’s plasma half-life, creating what clinicians sometimes describe as a “neuroplastic window.” What the research shows The evidence base for subanesthetic ketamine as an analgesic adjunct in veterinary patients has grown substantially over the past two decades. Wagner et al. conducted a prospective, randomized, blinded clinical trial involving 27 dogs undergoing forelimb amputation, a model well-suited to studying severe postoperative and neuropathic pain. Dogs receiving low-dose ketamine as a constant rate infusion (CRI) had significantly lower pain scores at 12 and 18 hours postoperatively and were meaningfully more active by postoperative day three compared to controls.² These findings demonstrated that even short-duration subanesthetic ketamine exposure could produce analgesic effects that extended beyond the infusion itself, a finding directly relevant to its application in chronic and end-of-life pain. Slingsby and Waterman-Pearson similarly found perioperative ketamine administration reduced the need for rescue analgesia in dogs undergoing ovariohysterectomy, with the preoperative group maintaining consistently lower pain scores throughout the observation period.³ While these studies were conducted in acute surgical contexts, the underlying mechanism, preventing or reversing wind-up, applies with equal or greater force in patients whose central sensitization has developed over weeks to months. Research in cats has produced more nuanced findings. Ambros et al. evaluated two subanesthetic ketamine CRI rates (5 µg/kg/min and 23 µg/kg/min) in conscious cats and found only modest effects on thermal and mechanical nociceptive thresholds.⁴ The authors concluded low-dose ketamine infusions minimally affect antinociception in cats under experimental conditions, a finding that underscores the importance of species-specific dosing and the recognition that experimental threshold models may not fully capture ketamine’s clinical utility in animals with established central sensitization. Most directly relevant to veterinary palliative practice, a 2025 retrospective case series from Cornell University evaluated outpatient IV ketamine-lidocaine (KL) infusions in 114 animals (105 dogs and 9 cats) with cancer, the majority of which had osteosarcoma or other tumors causing refractory bone, soft tissue, or oral pain.5 All patients were already receiving multimodal oral analgesia, most commonly gabapentinoids, NSAIDs, and opioids, yet were referred for KL infusions because pain remained inadequately controlled. Following a single 4–6-hour infusion (ketamine 0.15 mg/kg/h with lidocaine 3 mg/kg/h in dogs or 1.5 mg/kg/h in cats), 76 percent of animals showed improvement in at least one clinical sign, with the greatest gains seen in activity level, lameness, and owner-perceived pain. Notably, the likelihood of response was significantly higher at ketamine infusion rates ≥2 µg/kg/min and total doses ≥0.5 mg/kg, suggesting that truly “ultralow” dosing may undertreat central sensitization in some patients. The infusions were well tolerated, with no neurologic toxicity reported and adverse events limited mainly to mild, likely disease-related hematologic changes. This study offers some of the strongest veterinary-specific evidence to date that subanesthetic ketamine, particularly when combined with lidocaine, can provide meaningful palliative benefit on an outpatient basis, directly supporting its use as part of a palliative pain plan rather than reserving it for inpatient crises and perioperative cases. Emerging evidence also supports the benefit in nononcologic chronic pain. A preliminary study by Fry, Rychel, Tearney, and Guedes enrolled 10 senior dogs (median age 12.8 years) with refractory chronic pain due to osteoarthritis, cervical radiculopathy, or intervertebral disc disease. Patients were administered IV ketamine on days one, 15, and 29 and followed through day 57.6 Blinded veterinary pain scores decreased significantly at all three follow-up time points compared to baseline, and owner-reported canine brief pain inventory (CBPI) scores declined significantly by day 29 and were sustained through day 57, suggesting a durable neuroplastic effect well beyond the infusion window. While the study was small, it adds to a growing body of evidence that serial subanesthetic ketamine infusions may confer lasting benefit in patients whose pain has become refractory to conventional management, precisely the population most often encountered in veterinary hospice and palliative care. Routes of administration: Matching the tool to the setting One of ketamine’s practical advantages in palliative care is its flexibility. Depending on the patient’s condition, environment, and goals of care, subanesthetic ketamine can be delivered through several routes. Intravenous (IV) CRI remains the gold standard for inpatient or closely monitored settings. It allows precise titration, rapid onset, and easy rate adjustment. For patients experiencing severe, refractory pain crises, particularly those already hospitalized, IV CRI offers the most controllable approach and the fastest path to reassessment. Subcutaneous CRI has emerged as a viable option for home hospice patients. Recent pharmacokinetic work by Colón et al. demonstrated subcutaneous ketamine administered via a wearable, tubeless insulin pump system in dogs produced plasma concentrations in a clinically relevant range, with absorption occurring over approximately 75 minutes.7 This approach supports steady plasma levels with minimal patient handling, an important consideration for fragile patients in home settings, where stress and repeated interventions carry their own costs. Other wearable devices (Figure 2) offer a similar subcutaneous CRI delivery system and have been used in private practice to affordably deliver low-dose ketamine infusions for canine chronic pain.8 Subcutaneous intermittent injection offers an additional alternative when pumps or IV access are not feasible. It provides flexibility for episodic pain escalation, is well tolerated in most fragile patients, and is considerably less expensive than continuous infusion approaches. While plasma levels are less consistent, intermittent SQ dosing may still provide meaningful analgesic and neuromodulatory benefit, particularly as part of a comprehensive multimodal plan. These protocols and potential clinical benefits remain anecdotal currently. Figure 1.Phaeton, an 11.5-year-old male neutered Great Dane, receives his subanesthetic ketamine infusion at home on his couch. Photo courtesy Tyler Carmack Figure 2. Phaeton wears a medical vest with the RxActuator Mini-Infuser, a clinically validated outpatient medication delivery system, which delivers his 3ug/kg/min ketamine infusion over 48 hours. Photo courtesy Tyler Carmack Regardless of route, subanesthetic dosing is the essential principle, preserving the analgesic and neuromodulatory effects of ketamine while avoiding the dissociation and profound sedation associated with anesthetic doses. Ketamine as a clinical reset: The re-evaluation opportunity Perhaps the most underappreciated role of ketamine in hospice care is not rescue analgesia but clinical re-evaluation. After weeks or months of escalating medication doses in a patient with refractory pain, it becomes genuinely difficult to know how much of the pain and diminished quality of life reflects disease progression and how much reflects the nervous system’s own amplification of pain signals. A ketamine intervention, even a single-session CRI, can provide a window in which the team can reassess baseline pain and behavior with greater clarity. Following the infusion, clinicians can: Determine whether current pain medication doses and treatments remain appropriate, or whether they can be adjusted Evaluate whether adjunctive medications (gabapentinoids, amantadine, local anesthetics) are having a meaningful effect Distinguish worsening peripheral pathology from central pain amplification Recalibrate comfort goals in dialogue with the owner This kind of structured reassessment is especially valuable in hospice, where the therapeutic goal is not cure but quality of remaining life. The more accurately a team can characterize a patient’s pain, the more precisely they can address it. Safety considerations and client communication At subanesthetic doses, ketamine is generally well tolerated in companion animals. Transient effects may include mild sedation, hypersalivation, and occasional behavioral changes, such as dysphoria or restlessness, the latter often managed by reducing the infusion rate. Cardiovascular stimulation is generally mild and well tolerated, except in patients with significant underlying cardiac disease. Clear caregiver education is essential before any home-based ketamine protocol. Owners should understand which behavioral changes are expected and are temporary, which signs warrant immediate contact with the care team, and how the intervention fits within the broader palliative plan. Framing ketamine as a tool to improve comfort, not a form of sedation, helps set appropriate expectations and builds trust. Clinical takeaway Subanesthetic ketamine should not be reserved as a last resort. It is a strategic, evidence-informed intervention in end-of-life pain management, one that addresses the biological mechanisms that conventional analgesics often cannot reach. By targeting central sensitization through NMDA receptor antagonism, ketamine offers something rare in palliative care: the ability to change how pain is processed, even when the underlying disease cannot be changed. Used thoughtfully, whether by IV CRI in a hospital setting or subcutaneous infusion or intermittent injections at home, ketamine gives hospice and palliative care teams a chance to pause, reset, and redesign pain plans in patients whose suffering has outgrown conventional approaches. In the context of end-of-life care, that reset can make an enormous difference in the time a patient has left. Tyler Carmack, DVM, CVA, CVFT, CHPV, CPEV, CVPP, is the director of Hospice and Palliative Care for the Caring Pathways family of practices. She founded Hampton Roads Veterinary Hospice, an AAHA-accredited end-of-life practice, and has practiced exclusively in hospice and palliative care since 2011. She has served on the Board of Directors of the International Association for Animal Hospice and Palliative Care (IAAHPC) since 2016 in various roles, including president in 2020 and 2025. Dr. Tyler holds certifications in animal hospice and palliative care, veterinary pain management, peaceful euthanasia, veterinary acupuncture, TCVM food therapy, and TCVM End-of-Life care. References Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc. 2006;228(1):53–60. https://doi.org/10.2460/javma.228.1.53 Wagner AE, Walton JA, Hellyer PW, Gaynor JS, Mama KR. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc. 2002;221(1):72–75. https://doi.org/10.2460/javma.2002.221.72 Slingsby LS, Waterman-Pearson AE. The postoperative analgesic effects of ketamine after canine ovariohysterectomy — a comparison between pre- and post-operative administration. Res Vet Sci. 2000;69(2):147–152. https://doi.org/10.1053/rvsc.2000.0401 Ambros B, Duke T, Cribb PH. Effect of low-dose rate ketamine infusions on thermal and mechanical thresholds in conscious cats. Vet Anaesth Analg. 2013;40(6):e76–e82. https://doi.org/10.1111/vaa.12057 Iocolano KE, Looney A, Balkman CE, Hume KR, Boesch JM, Sylvester SR. Retrospective evaluation of outpatient intravenous ketamine-lidocaine infusions for the palliation of cancer pain in dogs and cats. J Am Vet Med Assoc. 2025;263(4):499–506. https://doi.org/10.2460/javma.24.09.0595 Fry L, Rychel J, Tearney C, Guedes A. Preliminary study of intravenous ketamine infusions for the management of chronic pain in dogs. Vet Anaesth Analg. 2025;52(1):124.e3–124.e4. https://www.vaajournal.org/article/S1467-2987(24)00353-2/abstract Colón JA, Pypendop BH, Jiménez-Andrade JM, et al. Pharmacokinetics of subcutaneous ketamine administration via the Omnipod® system in dogs. J Vet Pharmacol Ther. 2024. https://doi.org/10.1111/jvp.13440 Fry L. Ketamine: A Novel Approach with a Familiar Tool — Part 1: Review of Ketamine and Chronic Pain; Part 2: Clinical Application and Case Studies. Presented at IVECCS 2022. Available via RxActuator clinical resources: https://rx-actuator.com/pages/clinical-resources
