What is the role of ketamine in the treatment of complex regional pain syndrome (CRPS)?

Updated: Jun 20, 2018
  • Author: Gaurav Gupta, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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The rationale for using ketamine to treat CRPS is based on its strong ability to block NMDA receptors. [127, 128, 129, 130] Experimental evidence suggests that the symptoms of CRPS are generated by a sufficiently intense or prolonged painful stimulus that causes increased and prolonged glutamate release from nociceptive first-order afferents. The glutamate stimulates NMDA receptors on second-order neurons within the spinal cord that produce wind-up and central sensitization. Therefore, blocking NMDA receptors might also block cellular mechanisms supporting that sensitization. [129, 131, 132]

Although the rationale for using ketamine seems reasonable, studies to date have not yet validated its benefit using objective outcome parameters with double-blind, randomized, controlled methodology. Furthermore, several different research teams have struggled to determine (1) the optimal dosing and duration of infusions, (2) whether the infusions are more effective in an inpatient versus outpatient setting, (3) whether ketamine is best used as an adjunct to regional anesthetic blocks rather than on its own, (4) whether it is best used in cases of established refractory CRPS, (5) when it should be applied during the evolution of symptoms, and (6) if treatment is more beneficial when adjunctive medications are used in concert with IV ketamine. [133, 134]

A 2004 study examined 33 patients who were diagnosed with CRPS and underwent ketamine treatment at least once. Due to a relapse of symptoms, 12 of the 33 were offered a second course of therapy, and 2 received a third. Following the initial course of therapy, 25 (76%) of the 33 patients experienced complete pain relief, 6 (18%) experienced partial relief, and 2 (6%) received no relief. When the therapy was repeated, all 12 patients experienced complete relief of their pain due to CRPS. [134]

In a 2008 study, 20 patients with refractory CRPS received IV ketamine in anesthetic doses over 5 days to determine the efficacy of ketamine in improving pain, any associated movement disorders, quality of life, and ability to work. Significant pain relief was observed at 1 month (93.5 ± 11.1%), 3 months (89.4 ± 17.0%), and 6 months (79.3 ± 25.3%) following treatment. The complete suspension of CRPS was observed in all patients at 1 month, in 17 at 3 months, and in 16 at 6 months. Quality of life, associated movement disorders, and the ability to work were significantly improved in most patients at 3 and 6 months. [135]

Sixty patients with chronic CRPS type I and severe pain participated in a double-blind, randomized, placebo-controlled parallel group trial that was published in 2009. Thirty patients were given a 4.2-day IV infusion of low-dose ketamine, and the other 30 were given a placebo, using an individualized, stepwise tailoring of dosage based on the extent of pain relief relative to side effects such as nausea, vomiting, and psychomimetic symptoms. The primary outcome of the study was measured in the pain score (numerical rating 0-10) throughout the 12-week study. The lowest pain score (2.68 ± 0.51 with ketamine, 5.45 ± 0.48 with placebo) occurred at the end of week 1. By week 12, any significant differences in pain relief between groups was lost. Treatment did not cause significant functional improvement; however, treatment with ketaminewassafe,withpsychomimetic side effects that were acceptable to most patients. [136]

A randomized, double-blind, placebo-controlled study followed patients for 3 months after treatment. All patients were infused intravenously with normal saline with or without ketamine for 4 hours (25 mL/h) daily for 10 days. The maximum ketamine infusion rate was .35 mg/kg/h and did not exceed 25 mg/h over a 4-hour period. Patients in both groups received clonidine and versed. This study reported statistically significant reductions in many pain parameters only in the treatment group. The placebo group reported no benefit from treatment along any parameter. [137]

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