CRPS Ketamine Research
What is ketamine and how does it work in CRPS?
Ketamine has a critical effect on receptors along nerves in the brain and body called N-methyl-D-aspartate (NMDA) receptors. NMDA receptors have received much attention over the last few decades due to their key role in many types of neural plasticity and their involvement in neuronal excitotoxicity that contributes to pain. An important goal of much recent research is to identify clinically relevant NMDA receptor antagonists capable of preferentially blocking NMDA receptor activation without interfering with NMDA receptor function needed for normal nerve transmission and plasticity.
Researchers have shown that activation of the NMDA receptor increases excitatory transmission in afferent pathways, contributes to sensitization of nociceptive (pain) neurons, and is involved in induction and maintenance of central sensitization (how the brain perceives pain), thus playing a key role in the development of chronic pain.
Ketamine is an NMDA receptor antagonist, and is an anesthetic agent that has been used to treat pain due to CRPS. There is a growing body of clinical evidence to support the use of ketamine in the treatment of neuropathic pain, especially CRPS.
Ketamine can induce complete remission in treatment resistant CRPS patients
The upregulation of inflammatory pathways in CRPS sensitises excitatory nociceptive pathways that use N-methyl-D-aspartic acid (NMDA) as a neurotransmitter (1).
The central sensitisation and alteration of brain plasticity that occurs could potentially be reversed with the use of the NMDA receptor antagonist ketamine, which can be administered topically or intravenously. Placebo-controlled studies have shown both topical and intravenous administration of ketamine to be effective at alleviating pain and inducing complete remission in treatment resistant patients (2, 3).
Ketamine produces effective and long-term pain relief in CRPS
The research team at Leiden University Medical Center in Leiden, The Netherlands, led by Sigtermans looked at 60 CRPS-1 patients (48 females) with severe pain in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4-day intravenous infusion of low-dose ketamine (n=30) or placebo (n=30) using an individualized stepwise tailoring of dosage based on 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. At the end of infusion, the ketamine dose was about 22 mg/h/70 kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo. Sigtermans concludes that in a population of mostly chronic CRPS-1 patients with severe pain, a multiple day ketamine infusion results in significant pain relief (4).
Sub-anesthetic doses of ketamine is effective for CRPS
The research team at Pomeranian Medical University, Szczecin, Poland, led by Puchalski investigated the efficacy of ketamine in anaesthetic dosage in chronic, refractory CRPS patients that had failed available standard therapies.
Five female patients with a mean age of 34 years with long-standing CRPS with a mean duration of 8 years received ketamine in sub-anesthetic dosage over 10 days. The patients received 1 to 5 ketamine courses. The effect of gradual pain reduction was observed beginning on the 4th to 5th infusion, associated with a decrease in the intensity of the allodynia (pain with light touch). This beneficial analgesic effect lasted 1.5 to 2.5 months after treatment (5).
CRPS pain is very sensitive to ketamine
The research team at George Washington University School of Medicine and Health Science in Washington, USA, led by Sheehy examined the effects of subanesthetic ketamine infusions on pain intensity in children and adolescents with chronic pain syndromes treated in an outpatient setting. They looked at patients with CRPS, POTS, and a history of trauma-related chronic pain. Over a 15-month period, 63 children and adolescents (median age 15) with chronic pain received 277 ketamine infusions.
Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity. and yielded greater pain reduction in patients with CRPS than in patients with other chronic pain syndromes (p = 0.029) (6).
Treating CRPS is an off-label use of ketamine
Data from controlled and noncontrolled trials suggest beneficial effects of subanesthetic ketamine infusions in the management of CRPS, particularly in patients diagnosed with CRPS-1. However, the dosage range varies considerably and an optimal dosage has not been established.
In addition, inpatient administration or close patient monitoring in an outpatient clinic setting is recommended due to a high incidence of psychomimetic reactions (eg, hallucinations). Further studies are warranted.
1. The use of ketamine in complex regional pain syndrome: possible mechanisms. Schwartzman RJ, Alexander GM, Grothusen JR. Expert Rev Neurother. 2011 May; 11(5):719-34.
2. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Kiefer RT, Rohr P, Ploppa A, Dieterich HJ, Grothusen J, Koffler S, Altemeyer KH, Unertl K, Schwartzman RJ. Pain Med. 2008 Nov; 9(8):1173-201.
3. Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine. Finch PM, Knudsen L, Drummond PD. Pain. 2009 Nov; 146(1-2):18-25.
4. Sigtermans MJ, van Hilten JJ, Bauer MC, 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 Oct;145(3):304-11. Epub 2009 Jul 14.
5. Puchalski P, Zyluk A. Results of the Treatment of Chronic, Refractory CRPS with Ketamine Infusions: a Preliminary Report. Handchir Mikrochir Plast Chir. 2016 Jun;48(3):143-7. Epub 2016 Jun 16.
6. Sheehy KA, Muller EA, Lippold C, Nouraie M, Finkel JC, Quezado ZM. Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study. BMC Pediatr. 2015 Dec 1;15:198.