What guidelines are available about ketamine use in the management of complex regional pain syndrome?

Background
Complex Regional Pain Syndrome (CRPS) is a chronic pain condition typically affecting an arm, leg, hand, or foot, often following an injury or medical event like surgery, trauma, stroke, or heart attack.1 It is categorized into 2 types: CRPS-1, which occurs without specific nerve damage, and CRPS-2, associated with identifiable nerve injury; the majority of CRPS cases are CRPS-1. Symptoms of CRPS can vary between individuals, but common symptoms can include severe, prolonged pain disproportionate to the initial injury, along with changes in skin color, temperature, and swelling in the affected area. While CRPS can be acute or chronic (lasting longer than 3 months), early diagnosis and treatment are crucial for improving outcomes.

Several treatment options can reduce pain severity and improve function in patients with CRPS.1 Rehabilitation and physical therapy are key to helping maintain movement, flexibility, and strength in affected limbs. Behavioral adjustments like limb elevation and compression can manage swelling, while psychotherapy addresses associated mental health challenges. Medications, including non-steroidal anti-inflammatory drugs (NSAIDs), nerve pain drugs, and corticosteroids, may provide relief, though none are FDA-approved specifically for CRPS. Advanced interventions include spinal cord stimulation, nerve stimulation, drug pumps, and, in severe cases, ketamine therapy. Alternative therapies like acupuncture may help symptom management, but outdated treatments like nerve cutting and amputation are ineffective.

Guidelines
Ketamine has emerged as a promising but still investigational treatment for CRPS, particularly for patients with severe, refractory pain. The American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published consensus guidelines on the use of intravenous (IV) ketamine infusion for chronic pain in 2018, which highlight use in CRPS.2 Ketamine, which is an N-methyl-D-aspartate (NMDA) receptor antagonist, works by modulating central sensitization and reversing the effects of chronic pain on the nervous system.3 For CRPS, ketamine infusions (22 mg/h for about 4 days using an individualized stepwise tailoring of doses based on

pain relief and tolerability or 0.35 mg/kg per hour over 4 hours daily for 10 days) have a moderate level of evidence supporting their effectiveness in reducing pain for up to 12 weeks (Grade B recommendation, low to moderate level of certainty).2 The 2 randomized controlled trials (RCTs) included in the guideline have shown that ketamine infusions can provide significant short-term pain relief.4,5 However, results have been inconsistent, with variability in dosing regimens, duration of treatment, and patient selection criteria. Higher dosages and longer infusion durations have been associated with more prolonged pain relief, though they also increase the risk of side effects such as psychomimetic reactions, cardiovascular changes, and potential liver toxicity. Apart from CRPS, there is no evidence indicating that ketamine infusions provide sustained pain relief over the intermediate or long term for other chronic pain conditions.

In 2022, guidelines sponsored by the Reflex Sympathetic Dystrophy Syndrome Association were also published.6 The guidelines stated that sub-anesthetic ketamine dosing has shown effectiveness in 2 CRPS RCTs (the same 2 RCTs mentioned in the previous guideline), using either 10 consecutive outpatient infusions or a 4.5-day inpatient regimen with patient-specific doses. Some centers offer low dose (subanesthetic level) IV ketamine despite limited long-term outcome data, and development of tolerance which reduces its duration of benefit. Side effects such as dysphoria, hallucinations, and euphoria make it less appealing to many patients. High-dose ketamine coma therapy carries significant risks and is not recommended. Additionally, there is no clinical trial evidence supporting oral ketamine for CRPS. Despite these limitations, the positive RCTs suggest that CRPS involves central sensitization, which may be temporarily reversed by IV ketamine treatment.

Conclusion
Ketamine infusions have emerged as a potential treatment for CRPS, with evidence suggesting short-term pain relief lasting up to 12 weeks. Current guidelines recognize IV ketamine as a promising but investigational option, with sub-anesthetic infusions being the most studied approach. However, long-term efficacy remains uncertain, and concerns about tolerance and side effects limit widespread adoption; further research is needed to optimize dosing, duration, and long-term benefits of this treatment for patients with CRPS.

References

  1. Complex Regional Pain syndrome. National Institute of Neurological Disorders and Stroke. Updated August 16, 2024. Accessed February 20, 2025. https://www.ninds.nih.gov/health-information/disorders/complex-regional-pain-syndrome
  2. 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):521-546. doi:10.1097/AAP.0000000000000808
  3. Ketamine. DailyMed: National Library of Medicine. Accessed February 2025. https://dailymed.nlm.nih.gov/dailymed/index.cfm
  4. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107-115. doi:10.1016/j.pain.2009.08.015
  5. 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):304-311. doi:10.1016/j.pain.2009.06.023
  6. Harden RN, McCabe CS, Goebel A, et al. Complex regional pain syndrome: Practical diagnostic and treatment guidelines, 5th Edition. Pain Med. 2022;23(Suppl 1):S1-S53. doi:10.1093/pm/pnac046

Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

March 2025

The information presented is current as February 20, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.