◊ SUMMARY:
Complex Regional Pain Syndrome Type 1 (CRPS-1) responds poorly to standard pain treatment. We evaluated if the N-methyl-d-aspartate receptor antagonist S(+)-ketamine improves pain in CRPS-1 patients. Sixty CRPS-1 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n=30) or placebo (n=30) using an individualized stepwise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0–10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1–31.9) years. At the end of infusion, the ketamine dose was 22.2±2.0mg/h/70kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P<0.001). The lowest pain score was at the end of week 1: ketamine 2.68±0.51, placebo 5.45±0.48. In week 12, significance in pain relief between groups was lost (P=0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P<0.001). In conclusion, in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. Treatment with ketamine was safe with psychomimetic side effects that were acceptable to most patients.
◊ Reviewed by L. Kapural MD PhD
CCLCM at Case Western University Cleveland Clinic , Cleveland, USA
AND
◊ Reviewed by M. Stanton Hicks MD PhD
CCLCM at Case Western University Cleveland Clinic , Cleveland, USA
This is a well planned and nicely done double-blind, randomized, placebo-controlled, parallel-group trial in which sixty severely disabled CRPS-1 patients underwent intravenous (IV) infusions of either ketamine or placebo. Patients in the treatment group received low-dose ketamine (22.2 ± 2.0 mg/h/70 kg) for 4.2 days. Pain scores over the 12-week trial period were lower in the ketamine group, but this gain was lost at week 12 (P=0.07). No functional improvement was observed under ketamine, but patients had mild to moderate psychomimetic side effects during infusion (76% versus 18%, P<0.001). The authors concluded that in a population of mostly chronic CRPS-1 patients with severe pain at baseline multiple day ketamine infusions resulted in significant pain relief without functional improvement.
Ketamine is a non-competitive antagonist of N-methyl-D-asparate (NMDA) receptors and can also act on a variety of other receptors (nicotinic, muscarinic, and opioid) and ion channels (Na+ and Ca2+). It has been used as an anesthetic for the past 35 years. Ketamine may be an effective analgesic in a variety of clinical settings and ketamine-induced analgesia has been successfully achieved after oral and IV administration.
Despite the well-documented therapeutic utility of IV ketamine and its well-established clinical use (Bell, 2009), this study, as several previous ones (1; 2; 3), leaves us with more questions than answers. First, what should be considered long-term pain relief in chronic pain management? Is it worthwhile to expose patients to potential risks of lengthy infusions (human error, technical failure, infection) to achieve relatively short-term relief from pain? Who will pay for such lengthy and expensive infusions which are seldom reimbursed by third-party payers?
Ideally, ketamine infusions should provide long-term pain relief and decrease the use of opioids in an outpatient setting to keep costs relatively low. Over the last 10 years, it became common practice across the United States to provide ketamine infusions, mostly as IV rescue infusions, to poorly selected outpatients when “nothing else works”. Some physicians use IV ketamine in doses ranging from 50-250 mg/hour for several hours in various protocols of daily/weekly infusions. According to anecdotal reports several months of pain relief and opioid-sparing can ensue (4). However, controlled studies are lacking and the optimal procedure for ketamine treatment in an outpatient setting remains to be described.
The excessive cost of low-dose ketamine infusion trials conducted over many days in an inpatient setting and/or of anesthetic-dose ketamine infusion trials in intensive care settings may be a major obstacle for this approach to become routine. Several recent studies such as this one suggest that prolonged low-dose ketamine infusion (i.e., 4.2 days) may improve pain scores over a relatively short period of time (12 weeks) in patients with CRPS. When such an article is sanctioned by the editor/reviewers of this journal, the expression “long-term” in the title should have been questioned and replaced by the duration of pain relief that was actually observed.
What is considered long-term pain relief in chronic pain management? When it comes to spine care, any spinal injections (including epidural steroids), surgeries or minimal invasive procedures need to justify their cost by demonstrating long-term functional capacity improvements. The journal “Spine”, for example, accepts for review only articles with at least one year of follow-up. Repeated epidural steroid injections have been penalized when they failed to provide pain relief over >6 months or 24 weeks in similarly disabled patient groups, despite costs of only several hundred US dollars per injection (5; 6). How can we then recommend the use of continuous ketamine infusions over 4 days or more in an inpatient, monitored setting with attendant costs of tens of thousands of US dollars?
Unless future studies document a real long-term benefit, there are many better therapeutic options for severe CRPS, including spinal cord stimulation (7; 8).
◊ References
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[2] Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous MS, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 2009;145:304-311.
[3] Corell GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic Ketamine Infusion Therapy: A Retrospective Analysis of a Novel Therapeutic Approach to Complex Regional Pain Syndrome 2004;5:263-275.
[4] Kapural L, Sessler DI, Kapural M, Cywinski J, Bensitel T. Opioid-sparing effect of intravenous, outpatient ketamine infusions may be short-lasting in chronic pain patients with high opioid requirements. Anesthesiology 2009;111:A145.
[5] Armon C, Argoff CE, Samuels J, Backonja MM; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: use of epidural steroid injections to treat radicular lumbosacral pain: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68(10):723-9
[6] Manchikanti L, Singh V, Derby R, Helm S 2nd, Trescot AM, Staats PS, Prager JP, Hirsch JA. Review of occupational medicine practice guidelines for interventional pain management and potential implications. Pain Physician. 2008;11(3):271-289.
[7] Van Eijs F, Smits H, Geurts JW, Kessels AG, Kemler MA, van Kleef M, Joosten EA, Faber CG. Brush-evoked allodynia predicts outcome of spinal cord stimulation in Complex Regional Pain Syndrome type1. Eur J Pain 2009, in press.
[8] Kumar K, Rizvi S. Spinal cord stimulation is effective in management of complex regional pain syndrome (CRPS) 1: Fact or Fiction Neuromodulation 2009;7(4):A32.
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