What is the role of NMDA (N-methyl-D-aspartate) antagonists, such as ketamine, in managing refractory pain?

NMDA Antagonists in Refractory Pain Management

Subanesthetic doses of ketamine, an NMDA antagonist, should be reserved for truly intractable pain that has failed standard opioid escalation, adjuvant medications, and other interventional approaches, with the understanding that evidence supporting its use remains limited and side effects often precede meaningful analgesia. 1

Clinical Context and Definition

Refractory pain is defined when standard interventions are: (i) incapable of providing adequate relief, (ii) associated with excessive morbidity, or (iii) unlikely to provide relief within a tolerable timeframe. 1 Before considering NMDA antagonists, ensure optimization of the WHO analgesic ladder with appropriate opioid rotation, adjuvant medications (gabapentinoids, tricyclic antidepressants), and consideration of interventional techniques. 2, 3

Evidence Quality and Recommendations

Guideline-Based Positioning

• The European Society for Medical Oncology (ESMO) states that limited evidence supports the use of subanesthetic doses of ketamine in intractable pain. 1 This represents a Level II, Grade D recommendation from the American Society of Clinical Oncology. 2

• Ketamine is not recommended as first-line therapy and should only be considered after failure of established treatments including strong opioids, neuropathic pain adjuvants (duloxetine, gabapentin 1200-3600 mg/day, pregabalin 300 mg twice daily, tricyclic antidepressants), and appropriate interventional procedures. 2, 3

Specific Clinical Scenarios Where NMDA Antagonists May Be Considered

Cancer-Related Refractory Pain:

• The National Comprehensive Cancer Network suggests ketamine may have potential utility as an adjunct to opioids in challenging cancer pain cases, particularly for opioid-refractory neuropathic pain. 2, 4
• Consider when pain involves central sensitization or "wind-up" phenomena. 2
• Intrathecal drug delivery should be evaluated before or concurrently with systemic ketamine trials. 1

Opioid-Induced Hyperalgesia:

• NMDA antagonists may be particularly useful when CNS toxicity from opioids (myoclonic jerks, hyperalgesia/allodynia) develops, as these symptoms suggest NMDA receptor-mediated mechanisms. 1

Dosing Strategies

Intravenous Ketamine

Acute/Inpatient Setting:

• Initial bolus: 0.5 mg/kg IV followed by continuous infusion of 1-2 μg/kg/min (or 0.5-2 mg/kg/hr, maximum 100 mg/hour). 4
• Use the lowest effective dose to minimize psychotomimetic effects. 4

Key Limitation: The 2025 Cochrane review found no clear evidence that intravenous ketamine reduces pain intensity in immediate term (MD -15.79,95% CI -32.09 to 0.51), short term (MD -5.32,95% CI -15.51 to 4.87), or medium term (MD -8.70,95% CI -31.05 to 13.65), all with low to very low certainty evidence. 5 However, intravenous ketamine may increase the risk of adverse events (RR 3.26,95% CI 1.05 to 10.09). 5

Alternative Routes

Oral Ketamine:

• Limited evidence supports oral administration at 4.0 mg/kg as a nightly dose. 6
• The Cochrane review found no clear evidence of pain reduction with oral ketamine (immediate term MD -2.64,95% CI -13.42 to 8.14; short term MD -9.80,95% CI -23.55 to 3.95). 5

Topical Ketamine:

• No clear evidence of efficacy (short term MD 2.82,95% CI -14.49 to 20.12). 5

Subcutaneous Administration:

• Provides similar analgesia to IV route and may be useful for outpatient management. 4

Critical Side Effects and Monitoring

Psychotomimetic Effects

• Dysphoria, nightmares, hallucinations, and dissociative symptoms occur especially at higher doses. 4, 7
• Co-administration with benzodiazepines (e.g., midazolam 0.05 mg/kg) minimizes these effects. 4, 6
• In clinical trials, appreciable symptomatic relief developed only after the onset of unpleasant drug side effects, and pain relief disappeared before side effects resolved after infusion cessation. 8

Cardiovascular Effects

• Ketamine increases blood pressure (10-50% above baseline), heart rate, and cardiac output through catecholamine reuptake inhibition. 7
• Continuous cardiac monitoring and pulse oximetry are required during infusion. 4
• Contraindicated in uncontrolled cardiovascular disease. 4

Tolerance and Withdrawal

• Tolerance develops with prolonged use, requiring higher doses for the same effect. 7
• Withdrawal symptoms (craving, fatigue, poor appetite, anxiety) occur after discontinuation of frequently used large doses. 7

Respiratory Effects

• Respiratory depression and apnea may occur with overdosage or rapid administration. 7
• Assisted ventilation may be required. 7

Response Patterns and Patient Selection

Research suggests three distinct response patterns to ketamine: 6

1. Long-term responders (30% of patients): Experience 6-24 hour analgesic effect partly dissociated from mental side effects
2. Short-term responders (35% of patients): Experience <2 hour analgesic effect closely associated with mental side effects
3. Non-responders (35% of patients): No pain reduction despite characteristic side effects

This heterogeneity suggests NMDA receptor involvement varies among patients with chronic pain, and NMDA receptor-independent mechanisms may dominate in non-responders. 6

Alternative NMDA Antagonists

Memantine

• Oral memantine has been used as a transition strategy for long-term outpatient management after successful inpatient ketamine trials. 9
• The Cochrane review found no clear evidence that oral memantine reduces pain intensity (short term MD -8.69,95% CI -19.40 to 2.02; medium term MD -1.74,95% CI -43.18 to 39.70), with very low certainty evidence. 5
• No clear evidence of increased adverse events (RR 1.09,95% CI 0.76 to 1.56). 5

Dextromethorphan, Amantadine, and Magnesium

• Evidence is very uncertain or shows no clear benefit for these agents in chronic pain. 5
• These should not be considered viable alternatives to ketamine based on current evidence.

Common Pitfalls to Avoid

1. Using ketamine as first-line therapy: Always exhaust standard analgesic approaches first, including opioid rotation, neuropathic pain adjuvants, and interventional techniques. 1, 2, 3

2. Inadequate side effect prophylaxis: Always co-administer benzodiazepines to minimize psychotomimetic effects. 4, 6

3. Rapid infusion rates: Slow infusion over 2 hours may improve the therapeutic ratio, though side effects still typically precede meaningful analgesia. 8

4. Ignoring contraindications: Avoid in pregnancy, uncontrolled cardiovascular disease, and active psychosis. 4

5. Lack of monitoring: Continuous cardiac monitoring, pulse oximetry, and regular assessment of sedation level are mandatory during infusion. 4

6. Unrealistic expectations: The 2025 Cochrane review demonstrates that evidence for ketamine and other NMDA antagonists remains low to very low certainty, with no clear benefit demonstrated in most analyses. 5

Clinical Algorithm for NMDA Antagonist Use

Step 1: Confirm pain is truly refractory after optimizing:

• Strong opioids (morphine, oxycodone, hydromorphone) at adequate doses 1, 3
• First-line neuropathic adjuvants (duloxetine 60 mg/day, gabapentin 1200-3600 mg/day, or pregabalin 300 mg twice daily) 2
• Opioid rotation if CNS toxicity present 1

Step 2: Consider interventional approaches before or concurrently:

• Radiotherapy for bone metastases or neural compression 1, 3
• Peripheral nerve blocks or intrathecal drug delivery 1

Step 3: If ketamine trial warranted:

• Initiate in monitored setting with continuous cardiac monitoring 4
• Co-administer benzodiazepine for psychotomimetic prophylaxis 4, 6
• Start with 0.5 mg/kg IV bolus followed by 1-2 μg/kg/min infusion 4
• Titrate to lowest effective dose 4

Step 4: Assess response pattern:

• If long-term benefit (>6 hours) observed, consider transition to oral ketamine or memantine for outpatient management 9, 6
• If only short-term benefit or no response, discontinue and pursue alternative strategies including palliative sedation for end-of-life refractory pain 1