In adult palliative‑care patients with refractory cancer‑related pain or opioid‑resistant neuropathic pain, how should ketamine be used, including indications, dosing regimen, monitoring, contraindications, and alternative options?

Use of Ketamine in Palliative Care

Ketamine should NOT be used routinely for cancer pain management in palliative care, but may be considered as a last-resort option only in highly selected patients with opioid-refractory pain who have failed all conventional therapies, particularly those with suspected central sensitization. 1, 2

Evidence Quality and Guideline Position

The European Society for Medical Oncology (ESMO) 2018 guidelines explicitly state there is lack of evidence to support routine use of ketamine in cancer neuropathic pain (Level II, Grade D recommendation). 1, 2 Randomized controlled trials examining ketamine as an adjuvant to opioids in cancer-related neuropathic pain have been consistently negative, with very low quality evidence that does not provide reliable indication of likely effect. 1

The National Comprehensive Cancer Network (NCCN) 2019 guidelines acknowledge that while ketamine has theoretical benefits as an NMDA antagonist, a double-blind RCT found no significant difference between ketamine and placebo for cancer pain. 2 A subsequent systematic review suggested only "modest analgesic potential" despite limited data. 2

Mandatory Prerequisites Before Considering Ketamine

First-line approach: Optimize opioid therapy (morphine, oxycodone, fentanyl) using oral route when possible, including appropriate dose escalation and opioid rotation. 2

Second-line for neuropathic pain: Add gabapentin, pregabalin, duloxetine, or tricyclic antidepressants (≥75 mg/day) as single agents. 1, 2 These medications have strong evidence (Level I, Grade A) with number needed to treat of 3-7.7 for neuropathic pain. 1

Third-line consideration: Only after documented failure of optimized opioids AND appropriate adjuvants should ketamine be considered. 2

Specific Indications for Ketamine Trial

Ketamine may be considered ONLY when ALL of the following criteria are met:

• Pain refractory to optimized opioid therapy (including dose escalation and rotation) 2
• Failure of appropriate adjuvants (gabapentin, pregabalin, duloxetine, or tricyclic antidepressants for neuropathic pain) 1, 2
• Evidence of central sensitization or hyperalgesia ("clinical wind-up" phenomenon) 1, 2

The preclinical evidence suggests patients with central sensitization presenting as "central wind-up" are the potential target population, though this remains an area of research. 1

Dosing Regimen

Initial bolus: 0.5 mg/kg IV push 1, 2

Continuous infusion: 1-2 μg/kg/min (equivalent to 0.06-0.12 mg/kg/hour) 1, 2

Alternative dosing for gradual titration (to minimize psychotomimetic effects):

• Start at 10 mg/day by continuous IV infusion 3
• Increase by 10 mg/day every 4-6 hours up to 50 mg/day 3
• Subsequently increase by 25 mg/day every 12-24 hours until pain relief achieved 3
• Maximum infusion rate: ≤0.5 mg/kg/hour 2, 4

Bolus dosing for acute severe pain: <0.35 mg/kg 2

Continuous infusion range: 0.5-1 mg/kg/hour 2

Monitoring Requirements

Ketamine requires monitoring consistent with general anesthesia standards when used for procedural sedation. 2 Continuous monitoring should include:

• Cardiac rhythm and pulse oximetry 4
• Regular assessment of sedation level 4
• Respiratory status 4
• Hemodynamics (blood pressure, heart rate) 4
• Pain intensity scores 5
• Opioid consumption 5

Absolute Contraindications

• Uncontrolled cardiovascular disease 2, 4
• Pregnancy 2, 4
• Active psychosis 2
• Severe liver dysfunction 2
• Elevated intracranial pressure 2
• Elevated ocular pressure 2

Management of Adverse Effects

Psychotomimetic effects (dysphoria, nightmares, hallucinations):

• Co-administer benzodiazepines (midazolam 0.05-0.1 mg/kg IV) to minimize these effects 4
• If hallucinations or delirium occur, pause ketamine infusion for 1-2 hours, then restart at lower dose while ensuring rate remains ≤0.5 mg/kg/hour 4
• Gradual dose titration prevents psychotomimetic effects at doses <300 mg/day even without psychotropic drugs 3

Common side effects:

• Drowsiness (45.7% of patients) 5
• Hypertension (34.3%) 5
• Nightmares (25.7%) 5
• Mild sedation (7%) 3

The incidence of side effects (nausea, hallucinations, hypoventilation, pruritus, sedation) is not significantly different between ketamine and opioid-alone groups when used at recommended doses. 1

Critical Pitfalls to Avoid

Do not use ketamine as routine adjuvant – the highest quality RCT evidence shows no benefit over placebo for cancer pain. 2, 6

Do not continue ketamine postoperatively – this increases hallucination risk without enhancing analgesia. 2

Do not use ketamine in place of proper opioid optimization – ensure adequate opioid dosing and appropriate adjuvants first. 2

Do not ignore the evidence-practice gap – while RCTs consistently show lack of clinical efficacy, open-label studies and case series show benefit, suggesting possible responder subgroups. 6, 5 This discrepancy may relate to methodological issues and patient selection. 6

Alternative Options When Ketamine Fails or Is Contraindicated

Interventional techniques (for approximately 10% of cancer patients with pain difficult to manage with oral/parenteral drugs):

• Nerve blocks 1
• Neurolytic blocks (including spinal neurolytic blocks and cordotomy) 1
• Intrathecal drug delivery 1

Epidural morphine: Switching from oral to epidural infusion of morphine has shown improvement in pain control and adverse effects in some studies. 1

Steroids: Should be considered in cases of nerve compression. 1

Practical Clinical Algorithm

1. Optimize opioid therapy with appropriate dose escalation and rotation 2
2. Add first-line adjuvants for neuropathic pain (gabapentin, pregabalin, duloxetine, or TCA ≥75 mg/day) 1, 2
3. Screen for contraindications before considering ketamine 2
4. Assess for central sensitization or "wind-up" phenomenon as potential indicator for ketamine response 1, 2
5. Trial ketamine ONLY as last resort in patients who have failed all conventional approaches 2
6. Consider test bolus (0.5 mg/kg) to identify patients likely to respond favorably before committing to continuous infusion 7
7. Use gradual titration protocol to minimize psychotomimetic effects 3
8. Co-administer benzodiazepine prophylaxis to reduce emergence reactions 4
9. Monitor continuously and reassess response within 4-8 days 1
10. Discontinue if no benefit or intolerable side effects occur 5

Nuanced Considerations

Despite negative RCT evidence, retrospective case series show 74.3% favorable response rates in selected palliative care populations, with mean pain scores improving from 7.0 to 4.0 on numerical rating scale. 5 The use of more than one coanalgesic was associated with favorable response to ketamine (odds ratio 3.451). 5 This suggests there may be specific responder subgroups, though these cannot be reliably identified prospectively based on current evidence.

The reduced opioid consumption observed with ketamine (approximately 22 mg morphine equivalents) is only a surrogate outcome and does not necessarily translate to better patient-centered outcomes such as quality of life or functional status. 1