Background  Ketamine is FDA approved as a rapid-acting IV dissociative general anesthetic.  There has been increased interest in its off-label use for pain control, administered via various routes.  This Fast Fact provides a general overview of the subanesthetic use of ketamine in palliative care primarily for analgesia. Fast Fact #384 discusses the off-label use of ketamine for management of depression. 

Mechanism of action   The N-methyl-D-aspartate/glutamate receptor (NMDA) is a calcium channel closely involved in the development of central (dorsal horn) sensitization. This channel has a role in opioid-resistant pain, neuropathic pain, allodynia, hyperalgesia, and chronic pain. Ketamine enters and blocks the open channel at a phencyclidine site, thereby inhibiting the excitatory effects of glutamate and aspartate. Ketamine also interacts with nicotinic, muscarinic, and opioid receptors. Pre-clinical data suggests it may also have anti-inflammatory effects.  

Pharmacology   As an anesthetic, ketamine is given intravenously (IV) or intramuscularly.  For pain, the parenteral solution can be delivered at doses much lower than the ones used for anesthesia via oral, intranasal (IN), transdermal, rectal, subcutaneous, and IV routes. Onset of analgesia is 15-30 minutes; duration of action is 15 minutes to 2 hours, possibly longer orally.  A greater portion of ketamine is metabolized to a breakdown product with less affinity for NMDA receptors (norketamine) when taken orally versus IV.  It is not yet clear if this reduces the analgesic properties of oral ketamine in a clinically significant way. Ketamine is physically stable when mixed with morphine, low-dose dexamethasone, haloperidol, and metoclopramide. Drugs that interact with CYP34A may affect its metabolism (e.g. azole antifungals, macrolides, HIV protease inhibitors, and cyclosporine).   

Side effects   Undesirable effects of high dose ketamine used for general anesthesia (1-2 mg/kg IV or 6.5-13 mg/kg IM) include psychotomimetic phenomena (dysphoria, blunted affect, psychomotor retardation, nightmares, hallucinations), excessive salivation, and tachycardia.  Co-administration with either lorazepam or haloperidol is a common empiric practice to minimize the potential for psychotomimetic side effects. Side effects at the lower doses used for pain are dose dependent, with dissociative feelings (“spaced out”), nausea, sedation, delirium, and hallucinations reported more frequently with IV administration. There is increasing concern about the potential for neuropsychiatric, urinary, and hepatobiliary toxicity with long term exposure to ketamine. Delusions, memory impairment, dysuria, and abnormal liver functional tests have been associated with therapeutic analgesic doses of just 2 weeks duration.  Ketamine can enhance its own metabolism via hepatic induction. This likely contributes to the rapid and dangerous tolerance to desired euphoric feelings among abusers.  

Analgesic effectiveness   While there is a large body of case reports, retrospective surveys, and uncontrolled trials suggesting that ketamine effectively relieves cancer and non-cancer pain from neuropathy, ischemia, bone metastasis, or mucositis, the best controlled trials have had mixed results. This may be because ketamine is better suited for pain that is temporary (e.g., postoperative), not from a progressive underlying illness like cancer. If used as an analgesic, a short term, “burst” treatment (e.g. appropriate ketamine dosing given over 2-4 days) should be considered. Evidence suggesting that the analgesic effects of “burst” treatment may extend several weeks via reducing opioid tolerance is limited.

Analgesic effectiveness in children   Literature on the analgesic use of ketamine in children is limited. A systematic review and meta-analysis identified 4 controlled trials evaluating IN ketamine for pain control in children. Ketamine had similar reduction in pain scores compared to the comparison opioid, but it also had a higher risk of non-serious adverse events.  Case series of children with cancer pain report opioid sparing effects as well as subjective improvements in pain and alertness with an IV ketamine infusion dosed at 0.1 to 1 mg/kg/hour. No significant psychotropic side effects were noted.

Other potential analgesic uses of ketamine    

• Single use of IV ketamine (typically 2.5 to 5 mg prn) often in combination with morphine or midazolam has been described for peri-operative use, dressing changes, and orthopedic emergencies.
• Compounded topical ketamine as an oral rinse has been described to treat mucositis, and as a gel applied to the skin for neuropathy.
• Ketamine has antidepressant effects in depressed patients perhaps even within hours after one dose.   

Titration   There are no studies comparing titration or dosing schedules, nor routes of administration.  Usual initial analgesic oral dose in adults is 10-25 mg TID to QID with titration in steps of 10-25 mg.  The maximum reported oral dose is 200 mg QID. A common initial IV dose in adults is 50-100 mg/day, with titration at increments of 25-50 mg/day, and a usual effective dose of 100-300 mg/day.  Careful monitoring of blood pressure, heart rate, and psychotomimetic effects should occur. Some clinicians empirically reduce opioid doses by 25-50% when starting IV ketamine to prevent drowsiness.

Summary     The collection of evidence is likely insufficient to fully assess the potential benefits versus harms of ketamine as an analgesic for patients with persistent pain from an underlying illness like cancer.

References 

1. Bell RF, Eccleston C, Kalso EA.  Ketamine as an adjuvant to opioids for cancer pain.  The Cochrane Library. 2012 May 24.
2. Kotlinska-Lemieszek A, Luczak J. Subanesthetic ketamine: an essential adjuvant for intractable cancer pain. J Pain Symptom Manage. 2004; 28(2):100-2.
3. Fine PG. Low-dose ketamine in the management of opioid nonresponsive terminal cancer pain. J Pain Symptom Manage. 1999; 17(4):296-300.
4. Fisher K, Hagen NA. Analgesic effect of oral ketamine in chronic neuropathic pain of spinal origin: a case report. J Pain Symptom Manage. 1999; 18(1):61-6.
5. De Kock M, Loix S, Land’homme P.  Ketamine and peripheral inflammation.  CNS Neurosci Ther 2013; 19:403-410.
6. Quibell R, Fallon M, et al.  Therapeutic reviews: ketamine. Journal of Pain and Symptom Management 2015; 50:268-278.
7. Cheung KWA, Chan PC, Lo SH.  The use of ketamine in the management of refractory cancer pain in a palliative care unit.  Annals of Palliative Medicine 2020; 9(6):4478489-4474489.
8. 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;30:3611–3617.
9. Goldman N, Frankenthaler M, Klepacz L. The efficacy of ketamine in the palliative care setting: a comprehensive review of the literature. Journal of Palliative Medicine 2019; 22(9):1154-61.
10. Finkel JC, Pestieau SR, Quezado ZMN. Ketamine as an adjuvant for treatment of cancer pain in children and adolescents. The Journal of Pain 2007; 8.6:515-521.
11. e Silva, Lucas Oliveira J., et al. “Intranasal ketamine for acute pain management in children: a systematic review and meta-analysis.” The American journal of Emergency Medicine 2020; 38.9:1860-1866.
12. Gammaitoni A, Gallgher RM, Welz-bosna M.  Topical ketamine gel: possible role in treating neuropathic pain.  Pain Med 2000;1:97-100.
13. Slatkin NE, Rhiner M.  Topical ketamine in the treatment of mucositis pain.  Pain Med 2003; 4:298-303.

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in March 2005. It was re-copy-edited in April 2009; reviewed and updated again in January 2016; and then again in February 2025.
Conflicts of Interest: None to report.