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ASRA Pain Medicine Update

Ketamine for Chronic Pain: Who, When, and How?

Sep 11, 2026, 11:01 by Ahmed Basharat, MD, Omar Hamza, MD, Bhargavi Madhu, DO, Sahil Amin, MD, Revelle Gappy, MD

 

A Problem-Based Learning Discussion

Learning Objectives

  1. Identify candidates and contraindications for ketamine therapy in chronic pain.
  2. Compare the strength of evidence for ketamine across chronic-pain conditions.
  3. Construct a safe ketamine trial with appropriate monitoring.
  4. Evaluate treatment success using pain, function, participation in rehabilitation, and adverse effects.

Case Presentation

A 45-year-old woman with complex regional pain syndrome (CRPS type I) of the right lower extremity presents to a chronic pain clinic for ongoing pain management. Her symptoms started three years ago after an ankle fracture treated without surgery. She reports constant burning pain rated 8/10, significant allodynia, intermittent swelling, and temperature changes in the affected limb. Pain has limited her ability to work and participate in physical therapy.

Her medical history includes major depressive disorder, which is controlled on sertraline, and hypertension treated with amlodipine. She has no history of psychosis, substance use disorder, glaucoma, or renal disease. Prior treatments include gabapentin, duloxetine, topical lidocaine, lumbar sympathetic blocks with short-lived relief, physical therapy, and cognitive behavioral therapy. She asks whether ketamine could help her pain.

1. In which chronic pain conditions is ketamine most likely to be beneficial?

Ketamine has been studied for several chronic pain conditions, although the evidence varies. CRPS has the strongest evidence supporting the use of intravenous (IV) ketamine. Randomized trials have shown meaningful reductions in pain that can last for several weeks, though improvement in function has been less consistent.1,2 Ketamine may also help some patients with refractory neuropathic pain, including spinal cord injury pain, phantom limb pain, and postherpetic neuralgia, but the evidence is less convincing and benefits are often short-lived.1 Evidence for other conditions, such as fibromyalgia, chronic low-back pain, migraine, ischemic pain, and cancer-related pain, remains limited or mixed.1 Overall, ketamine is most commonly considered for patients with refractory CRPS or selected neuropathic pain conditions after other treatments have failed.

2. What is the proposed mechanism by which ketamine improves chronic pain?

Ketamine improves chronic pain through a multifactorial mechanism, with its primary effect coming from noncompetitive NMDA receptor antagonism. This reduces abnormal pain transmission and reverses central sensitization that drives allodynia and hyperalgesia. Ketamine decreases dorsal horn hyperexcitability and wind-up phenomena. In addition, ketamine activates descending inhibitory pain pathways, enhancing noradrenergic and serotonergic modulation of nociceptive signaling. Its analgesic effects also extend beyond sensory pathways, as ketamine reduces pain-related negative emotions through rapid antidepressant actions that dampen the affective motivational component of pain. Finally, ketamine interacts with multiple receptor systems and produces active metabolites that may contribute to and prolong analgesia. This makes its effect on chronic pain the result of combined actions on sensory, emotional, and central modulatory processes.3

3. Which patients are appropriate candidates for ketamine therapy, and who should be excluded?

Ketamine is not a first-line treatment and should only be used by trained clinicians in a structured setting. Good candidates include patients with severe, refractory neuropathic pain who have failed standard medications, procedures, and rehabilitation.

Relative contraindications include poorly controlled cardiovascular disease, pregnancy, and liver dysfunction.1 Many studies also exclude patients with active psychosis, severe renal disease, or glaucoma. Ketamine should be used cautiously in patients with significant heart disease because it can increase blood pressure and heart rate in the short term.2 Older concerns about ketamine increasing intracranial pressure in traumatic brain injury have not been supported by more recent data.4

Access to ketamine therapy may also influence patient selection. Treatment settings vary in their experience, resources, and ability to provide ketamine infusions. Insurance coverage may be limited, particularly for outpatient treatment, leaving some patients responsible for out-of-pocket costs. These financial and logistical barriers should be considered when discussing treatment.5

4. What routes of ketamine administration are used in chronic pain management?

Ketamine is most commonly administered intravenously, as this route has the strongest evidence base and allows for more accurate drug monitoring. Alternative routes include oral, intranasal for intermittent or breakthrough symptoms, and, less commonly, subcutaneous or intramuscular. Oral and intranasal routes may be considered for maintenance or step-down therapy after a successful IV trial but are associated with variable bioavailability and less robust evidence. Furthermore, potential for accidents exists with ketamine use, given impairments in judgment, perception, psychomotor function, and possible hallucinations. As a result, current guidance from ASRA Pain Medicine and collaborating societies emphasizes that non-IV routes should be used cautiously, ideally within a structured program, and generally after demonstrating benefit with IV ketamine.1

Case Progression #1: Planning a Ketamine Trial

After reviewing the available treatment options, the patient elects to pursue a trial of IV ketamine. Before proceeding, the pain team must determine whether she is an appropriate candidate and establish treatment goals.

5. What evaluation should be performed before initiating ketamine, and how should treatment success be defined?

Before starting ketamine, patients should undergo an evaluation to identify potential risks. This should include cardiovascular history, baseline blood pressure, psychiatric history, substance use, and hepatic disease.1 Attention should be given to poorly controlled hypertension, significant cardiovascular disease, active psychosis, and a history of substance misuse. Laboratory testing should be based on the patient’s medical history and anticipated treatment. Liver function testing may be appropriate in patients with hepatic disease or those receiving frequent or high-dose infusions.1 Treatment goals should be established before the first infusion. Pain reduction is important, but improvement in pain scores alone may not represent successful treatment. Response should also consider function, quality of life, and how long the benefit lasts.1 For this patient, goals could include greater participation in physical therapy, increased walking tolerance, reduced allodynia, improved sleep, return to work, and less use of rescue medications. These goals can help determine whether the benefit is meaningful enough to justify additional infusions.1

6. What dosing strategies are typically used for ketamine in chronic pain?

No single ketamine protocol is universally accepted for chronic pain. Dose, infusion duration, number of infusions, monitoring, and follow-up vary across studies and clinical settings. Treatment should follow institutional protocols and be individualized based on patient risk, treatment setting, and therapeutic goals.1 Ketamine is generally administered at subanesthetic doses for chronic pain. IV dosing varies considerably, with some protocols using lower-dose infusions that are gradually titrated based on response and tolerability.1 Studies in CRPS have also used longer or repeated infusions. In one randomized trial, ketamine was administered at approximately 0.43 mg/kg/hour for an average of 4.2 days.3 Given the variability in published protocols, dosing should be individualized rather than based on a single recommended regimen.1

Case Progression #2: Initial Response 

The patient completes her initial IV ketamine infusion without a significant acute complication. Her pain decreases from 8/10 to 4/10, and the improvement persists for five days. However, she does not increase her walking tolerance or participation in physical therapy and remains unable to return to work.

7. Does this represent a successful ketamine trial, and should the infusion be repeated?

The patient had a 50% reduction in pain, which represents a meaningful analgesic response. However, the benefit lasted only five days and did not improve her walking tolerance or participation in physical therapy. Treatment success should not be based on pain scores alone. Function, quality of life, medication use, and duration of benefit should also be considered.1 Before repeating the infusion, the treatment goals should be reassessed with the patient. Another infusion may be reasonable if the period of pain relief allows greater participation in physical therapy or other meaningful activities. If repeated infusions provide only short-term pain relief without functional improvement, continued treatment may not be justified.1

Case Progression #3: Repeated Exposure

After shared decision-making, the patient undergoes additional ketamine treatment while simultaneously participating in a structured rehabilitation program. She reports recurrent temporary analgesic benefit. Before another planned infusion, laboratory testing demonstrates newly elevated serum transaminases.

8. What adverse effects should clinicians monitor during ketamine therapy?

Clinicians should monitor for psychomimetic effects, cardiovascular changes, and hepatotoxicity during ketamine therapy. Psychomimetic symptoms are the most common adverse events at subanesthetic doses and most often include nightmares and hallucinations. These effects are generally mild and self-limited, though emergence reactions may persist beyond the infusion period.6,7  Ketamine also causes sympathetic stimulation, leading to transient hypertension and tachycardia, which necessitates continuous hemodynamic monitoring during IV administration and avoidance in patients with poorly controlled cardiovascular disease.1,6 Hepatotoxicity is typically dose-dependent and reversible, supporting baseline and interval liver function monitoring. Ketamine should be avoided in severe hepatic disease and used cautiously in patients with moderate hepatic impairment.1

9. Where does ketamine fit within the chronic pain treatment algorithm?

Ketamine is best considered a later-line treatment for patients with severe, refractory chronic pain who have not improved with multimodal therapy.1 This includes appropriate pharmacologic treatment, rehabilitation, behavioral interventions, and interventional options when indicated. Evidence is strongest for CRPS, while benefit in other chronic pain conditions remains less consistent.1,3 Ketamine should be used as a monitored therapeutic trial with treatment goals established before the first infusion. Continued treatment should depend on meaningful improvement in pain and function, as well as an adequate duration of benefit.1 The potential benefit of repeated treatment should be weighed against adverse effects, cumulative toxicity, cost, and the risk of misuse.

References

  1. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain 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;43(5):521-6. doi: 10.1097/AAP.0000000000000808
  2. Sigtermans MJ, van Hilten JJ, Bauer MCR, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain. 2009;145(3):304-11. doi: 10.1016/j.pain.2009.06.023
  3. Ma X, Yan J, Jiang H. Application of ketamine in pain management and the underlying mechanism. Pain Res Manag. 2023;2023:1928969. doi: 10.1155/2023/1928969
  4. Patanwala AE, Martin JR, Erstad BL. Ketamine for analgosedation in the intensive care unit: a systematic review. J Intensive Care Med. 2017;32(6):387-95. doi: 10.1177/0885066615620592
  5. Peskin E, Gudin J, Schatman ME. Increased demand for ketamine infusions and associated complexities. J Pain Res. 2023;16:295-9. doi: 10.2147/JPR.S403323
  6. Cadavid AM, Casas FD, Camelo JE, et al. Analgesic low-dose ketamine infusions and central nervous system adverse effects: a prospective cohort study. Pain Physician. 2025;28(6):E657-65.
  7. Aman MM, Mahmoud A, Deer T, et al. The American Society of Pain and Neuroscience (ASPN) best practices and guidelines for the interventional management of cancer-associated pain. J Pain Res. 2021;14:2139-64. doi: 10.2147/JPR.S315585

 

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