Background for Fast Fact #513     Ketamine, a dissociative anesthetic with activity at the N-methyl-D-aspartate (NMDA) receptor, is used for a range of indications (1,2). Fast Fact #132 reviews ketamine pharmacology and use for analgesia in palliative care, with examples related to oral, intranasal, transdermal, rectal, intravenous (IV) and subcutaneous (SQ) use. This Fast Fact focuses on the practice of “subanesthetic ketamine infusion” (SKI) when used for refractory, severe pain or opioid toxicity.

Definition    SKI refers to continuous IV or SQ ketamine infusion at subanesthetic doses intended to preserve a normal level of wakefulness and cognition, typically over a period of 3-5 days. The analgesic effects of SKI may be significant enough that opioid doses can be reduced. Although the mechanism is poorly understood, clinically, it appears that SKI sometimes reduces opioid tolerance. This effect can seemingly last several weeks in some patients, well beyond the duration of the SKI treatment itself (3).

Common off-label uses for analgesia in patients receiving specialist palliative care    There are no clear evidence-based indications for SKI. In practice, SKI is considered for patients with severe or refractory pain, when there are signs of opioid failure/opioid-refractory pain including tolerance, dose-limiting opioid side-effects, or suspected opioid-induced allodynia or hyperalgesia. Because long-term continuous ketamine use (greater than 2 weeks) is associated with an escalating risk of urinary and biliary side effects, it is rarely used clinically. Patients better suited to short-term SKI are those with a short prognosis, or for whom clinicians judge there is a reasonable chance of benefit from short-term ketamine exposure. In general, this includes patients undergoing a high-dose/high-risk opioid rotation or de-escalation in the setting of opioid failure/toxicity, or patients with time-limited pain events such as post-operative pain or patients undergoing palliative radiotherapy. Fundamentally, there is no clear evidence base to inform identifying patients who might benefit from SKI and thus the practice remains empiric.

Limited evidence     While several uncontrolled studies and case-series have reported benefit from SKI, the largest randomized controlled trial comparing SKI to placebo for cancer-related pain did not show a clinical benefit from the addition of ketamine to opioids and other standard analgesics (4). As with all studies, the generalizability has limitations, but it arguably solidified SKI in palliative care as an expert intervention mostly used in rare situations of opioid failure (5-7).  Certainly, better evidence is needed.

Example dosing     SKI rates may be started at 0.1-0.2 mg/kg/hr and rate increases are typically made at ~24-hour intervals, by increments of approximately 0.1 mg/kg/hr depending on the patient’s response. The dose may be increased to meet patient-specific analgesic outcomes, or until intolerable side effects develop. While a common maximum rate for SKI is 1 mg/kg/hr, individual institutions may set lower maximum rates between 0.3-0.5 mg/kg/hr due to the increased risk of adverse effects as dosing approaches 1 mg/kg/hr (8,9). Some institutions utilize fixed doses as opposed to a weight-based strategy in adults, with typical starting doses of 5-10 mg/hr up to a maximum of 40-50 mg/hr (10). When used for pain in the setting of opioid tolerance and/or hyperalgesia/allodynia, SKI is typically continued for 3-5 days, after which the infusion is either stopped or weaned by 50% for 6-24 hours prior to stopping. Bolus doses are generally not recommended. Clinicians must be familiar with their institutional policies.

Safety considerations   Side effects with ketamine are common, and often dose-limiting (1,8). They can include dream-like states, vivid imagery, delirium, agitation, confusion, hallucinations, somnolence, increased skeletal muscle tone, nystagmus, respiratory depression, elevated blood pressure or heart rate, headache, lethargy, nausea and/or vomiting, hypersalivation, and increased lacrimation. While many of the common side effects of SKI can be prevented or treated, in some situations the infusion rate needs to be reduced or discontinued. Consider making PRN medications available for agitation, anxiety and excessive salivation or lacrimation. Some experts routinely premedicate with a benzodiazepine, haloperidol, and an anticholinergic before starting the SKI (5,6). SKI should be avoided in patients with hemodynamic instability, active/symptomatic hyperthyroidism, increased intracerebral pressure, increased intraocular pressure, active and severe psychiatric disorders (post-traumatic stress disorder, a psychotic disorder), delirium, chronic alcohol use, or acute intoxication. Severe liver disease is also a relative contraindication. Ketamine metabolism is via P450 pathways, thus drugs that interact with CYP34A may affect metabolism (e.g. azole antifungals, macrolides, protease inhibitors, and cyclosporine).

Additional considerations 

1. Empiric reductions in the scheduled opioid regimen (25-50%) may be appropriate if the reason for using SKI is opioid side-effects or suspected hyperalgesia. An ‘’as needed” (PRN) opioid should remain available. This practice is empiric and requires highly individualized decision-making by a clinician familiar with ketamine and opioid management.
2. SKI is not available in all hospitals and may be unit-restricted (e.g. to an ICU) or discipline-restricted (e.g. to pain specialists). While it is possible to use in the home, this appears to be rare and would require a level of sophisticated interdisciplinary care typically only feasible within a hospice program.

Summary    While high-quality evidence for SKI for refractory pain in palliative care patients is lacking, it is sometimes used in situations of opioid failure or toxicity when there are limited alternatives (11). Thoughtful consideration of potential benefits, contraindications, dosing, and side effects is needed.

References: 

1. Bell RF, Kalso EA. Ketamine for pain management. Pain Rep. 2018 Aug 9;3(5):e674. doi: 10.1097/PR9.0000000000000674. PMID: 30534625; PMCID: PMC6181464.
2. Jonkman K, Dahan A, van de Donk T, Aarts L, Niesters M, van Velzen M. Ketamine for pain. F1000Res. 2017 Sep 20;6:F1000 Faculty Rev-1711. doi: 10.12688/f1000research.11372.1. PMID: 28979762; PMCID: PMC5609085.
3. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014 Feb;77(2):357-67. doi: 10.1111/bcp.12094. PMID: 23432384; PMCID: PMC4014022.
4. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012 Oct 10;30(29):3611-7. doi: 10.1200/JCO.2012.42.1081. Epub 2012 Sep 10. PMID: 22965960.
5. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2017 Jun 28;6(6):CD003351. doi: 10.1002/14651858.CD003351.pub3. PMID: 28657160; PMCID: PMC6481583.
6. Poon P, Bell RF, Good P. Should Subanesthetic Ketamine be Considered When Managing Opioid Refractory Cancer Pain? J Pain Symptom Manage. 2024 Aug;68(2):e146-e151. doi: 10.1016/j.jpainsymman.2024.04.026. Epub 2024 May 8. PMID: 38729533.
7. Mercadante S. The Mistery of Ketamine: The Misleading Conclusion of a Randomized Controlled Trial. J Pain Symptom Manage. 2024 Sep;68(3):e232-e233. doi: 10.1016/j.jpainsymman.2024.05.034. Epub 2024 Jun 6. PMID: 38848791.
8. Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):456-466. doi: 10.1097/AAP.0000000000000806. PMID: 29870457; PMCID: PMC6023582.
9. Sheehy KA, Lippold C, Rice AL, Nobrega R, Finkel JC, Quezado ZM. Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study. J Pain Res. 2017 Apr 5;10:787-795. doi: 10.2147/JPR.S131156. PMID: 28435316; PMCID: PMC5388303.
10. Siegel L, Quirk K, Houchard G, et al. Intravenous Ketamine for Cancer Pain: A Single-Center Retrospective Analysis Comparing Fixed-Rate Versus Weight-Based Dosing. J Pain Palliat Care Pharmacother. 2024 Jul 11:1-9. doi: 10.1080/15360288.2024.2374297. Epub ahead of print. PMID: 38991124; PMCID: PMC11724009.
11. Hardy JR, Spruyt O, Quinn SJ, et al. Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine. Intern Med J. 2014 Jun;44(6):586-91. doi: 10.1111/imj.12442. PMID: 24720500.

Authors’ Affiliations: Dartmouth Hitchcock Medical Center.
Conflicts of Interest: The authors have disclosed no relevant conflicts of interest.
Version History:  Originally edited by Drew A Rosielle MD; first electronically published in May 2025.