What is the recommended approach to using ketamine for a patient with complex regional pain syndrome (CRPS) secondary to a spinal cord injury (SCI)?

Ketamine for Complex Regional Pain Syndrome Secondary to Spinal Cord Injury

For CRPS secondary to spinal cord injury, initiate first-line treatment with gabapentinoids (pregabalin or gabapentin up to 2400 mg daily) or tricyclic antidepressants (amitriptyline 10-25 mg/day titrated upward), and reserve ketamine infusion therapy as a second-line or rescue option for refractory cases, using a 5-day subanesthetic infusion protocol (0.1-0.35 mg/kg/h, maximum 24 mg/h) which provides the optimal balance of pain control and side effects. 1, 2

Initial Management Approach

First-Line Oral Therapy

• Start with gabapentinoids (pregabalin or gabapentin titrated to 2400 mg daily in divided doses) as the primary treatment for neuropathic pain following spinal cord injury 1
• Alternatively, initiate tricyclic antidepressants such as amitriptyline starting at 10-25 mg/day, particularly in patients over 40 years with baseline ECG screening due to cardiac risks 1
• For localized pain, add topical compounded creams containing amitriptyline, or combination baclofen-amitriptyline-ketamine gel after 4 weeks 1

Combination Therapy for Inadequate Response

• If monotherapy fails, combine a gabapentinoid with amitriptyline or add topical treatments 1
• For continued refractory pain, consider adding cannabis oil as adjunctive therapy (particularly in patients with prior cannabis use) or SNRIs like duloxetine 1

Ketamine Infusion Protocol for Refractory CRPS

When to Consider Ketamine

• Reserve ketamine infusion for patients who have failed first-line gabapentinoids, tricyclic antidepressants, and combination therapies 1, 2
• The evidence does not support routine use of ketamine for neuropathic pain, but CRPS represents a specific indication where ketamine may be beneficial, particularly in patients with central sensitization and "clinical wind-up" 3

Optimal Dosing Regimen

• Use a 5-day inpatient ketamine infusion protocol at subanesthetic doses of 0.1-0.35 mg/kg/h (maximum 24 mg/h) administered over 6 hours daily, as this provides the best balance between pain control and side effects 2
• The 5-day regimen demonstrated significantly lower pain scores at 1,2, and 3 months compared to 3-day treatment, with fewer side effects than 7-day treatment 2
• Alternative protocols using continuous infusion over 4-5 days at doses up to 22 mg/h/70kg have shown significant pain relief lasting up to 12 weeks 4

Expected Outcomes

• Complete pain relief occurs in approximately 76% of patients after initial treatment, with partial relief in 18% 5
• Pain relief is most pronounced at week 1 post-infusion, with sustained benefit through 12 weeks, though significance may diminish by week 12 4
• Repeat infusions show even better outcomes: 100% of patients receiving second courses experienced complete relief, with 58% maintaining relief for ≥1 year and 33% remaining pain-free for >3 years 5

Administration Requirements and Monitoring

• Ketamine must be administered by or under the direction of physicians experienced in general anesthetics, with continuous vital sign monitoring and immediate availability of emergency airway equipment 6
• Administer an antisialagogue prior to induction to manage salivation 6
• Do not inject the 100 mg/mL concentration intravenously without proper dilution; dilute with equal volume of Sterile Water, Normal Saline, or 5% Dextrose and use immediately 6
• Obtain baseline liver function tests (including alkaline phosphatase and gamma glutamyl transferase) and monitor at periodic intervals during treatment, as ketamine is associated with hepatobiliary dysfunction with recurrent use 6

Managing Side Effects

• The most frequent side effect is a feeling of inebriation, with hallucinations occurring in approximately 18-76% of patients depending on dose and duration 5, 2, 4
• Psychomimetic side effects are dose-dependent and more common with longer infusion durations (significantly higher in 7-day vs 5-day vs 3-day regimens) 2
• Co-administer benzodiazepines (such as midazolam) to prevent and manage neuropsychological manifestations during emergence and reduce psychomimetic effects 6, 7
• To minimize emergence phenomena: reduce verbal, tactile, and visual stimulation during recovery 8
• Monitor for hepatic enzyme alterations; terminate infusion if abnormalities occur (typically resolve after cessation) 5

Critical Considerations for SCI Patients

Contraindications and Cautions

• Use extreme caution in elderly patients due to significant risk of postoperative confusion and delirium 8
• Monitor for increased intracranial pressure, particularly relevant in SCI patients with potential elevated baseline ICP 6
• Closely monitor respiratory parameters including respiratory rate and pulse oximetry, as concomitant use with opioids, benzodiazepines, or other CNS depressants may result in profound sedation and respiratory depression 6
• Consider cessation if genitourinary pain develops, as chronic ketamine use has been associated with genitourinary symptoms 6

Integration with SCI Rehabilitation

• Ketamine treatment should not delay or interrupt the comprehensive rehabilitation protocol that must begin immediately upon medical stability 9
• Continue multimodal analgesia combining non-opioid analgesics, antihyperalgesic drugs, and opioids as part of the overall pain management strategy 9
• Maintain gabapentinoid treatment for more than 6 months even when adding ketamine, as this represents the foundation of neuropathic pain management in SCI 9

Alternative Approaches for Anesthetic-Dose Ketamine

High-Dose Protocol for Severe Refractory Cases

• For rapidly progressing or generalized CRPS that has failed all standard therapies, anesthetic doses of ketamine (3-5 mg/kg/h) combined with midazolam over 5 days in an ICU setting may be considered as a last resort 7, 10
• This intensive care procedure carries serious risks but has achieved complete remission in 80% of refractory patients at 6 months, with significant improvement in quality of life and ability to work 10
• Complete remission from CRPS has been maintained for up to 8 years following this treatment in case reports 7
• This approach requires ICU-level monitoring and should only be attempted in specialized centers with appropriate expertise 7, 10

Common Pitfalls to Avoid

• Do not use ketamine as first-line therapy; exhaust oral gabapentinoids and tricyclic antidepressants first 1
• Do not use 3-day infusion protocols, as they provide inadequate pain control; do not use 7-day protocols, as they significantly increase side effects without additional benefit over 5-day treatment 2
• Do not administer ketamine without benzodiazepine co-administration to manage psychomimetic effects 6, 7
• Do not fail to obtain baseline liver function tests or monitor hepatic function during treatment 6
• Do not use in patients receiving theophylline or aminophylline due to lowered seizure threshold 6