In the early 1990s, the conditions of causalgia and reflex sympathetic dystrophy were made subtypes of an umbrella condition now known as complex regional pain syndrome (CRPS).1 Since then, CRPS has been used to describe peripheral chronic pain and can be subtyped based on the presence or lack of peripheral nerve injury. Variations exist in the presentation and duration of symptoms, which has presented great challenges in the management of these symptoms.
The current approach to pain care is to combine several modalities, including physical, behavioral, and medicinal therapies.2 Perhaps the most difficult challenge when trying to manage CRPS is in the selection of appropriate pharmacologic therapies given the abstract nature of pain symptoms. When commonly prescribed pain medications failed, researchers began exploring alternative medications to manage symptoms experienced by patients with CRPS.
Use of Low-Dose Ketamine
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is most widely known for use as an anesthetic agent; however, research exists that attempts to expand utility of the drug to CRPS treatment at lower doses.3,4 Several routes of administration and outcomes have been assessed in varying types of studies. Topical dosages have been studied as 10% creams and as 1.5% ointments. Ketamine administered as a cream was effective at reducing allodynia in patients but was deemed not effective for pain reduction.5 Ketamine as an ointment was seen to reduce pain in 4 out of 7 patients treated.6Use of oral ketamine is limited by uncertain dosing strategies, low-quality studies demonstrating limited benefit, and poor tolerance due to adverse effects.7 Ketamine was seen to reduce average morphine equivalents from 151 to 18 in addition to reducing pain in a case study of use in treating CRPS.8
Currently, most evidence supports intravenous administration of ketamine. The American Academy of Pain Medicine position is that the use of ketamine in CRPS remains unclear due to toxicity at therapeutic doses.2 However, evidence exists that may support the utilization of ketamine therapy.9-11 One randomized double-blind, placebo-controlled trial included adult patients up to age 65 and who had CRPS for a minimum of 6 months.10 Another notable inclusion criterion was the need to have trialed 1 of the following: nerve blocks, opioid analgesics, nonopioid analgesics, NSAIDs, antiseizure medications, antidepressants, muscle relaxants, or physical therapy. Baseline pain (+ SE) in the most affected area was 7.66 + 0.4 in the ketamine group and was similar to placebo. Ketamine was administered at 0.35 mg/kg/h and not to exceed 25 mg/h in 4 hours with a study duration of 10 days.
These study findings indicated that overall pain scores (using a numeric rating scale, 0 to 10) were reduced for all patients (Table 1). 10
After 12 weeks of treatment, pain scores did not differ statistically between ketamine and placebo.10 Other medications given to both the trial and placebo groups included 0.1 mg clonidine orally, for which animal models demonstrated a reduction in neuropathic pain and less neurotoxic effects characterized by NMDA antagonists, and 2 mg midazolam, which can introduce minor anxiety relief and mild sedation at the selected dose, intravenous push before and after 4-hour infusion.10 Safety data revealed side effects of nausea, headache, tiredness, and dysphoria at rates greater in the ketamine group.2,10
A double-blind, randomized, control trial from 2009 tested effectiveness of intravenous ketamine against a placebo control group for Type 1 CRPS.11 Sixty patients with varying time since diagnosis and number of extremities affected were enrolled in the study. Baseline pain scores were similar between the placebo and experimental groups (7.0 + 1.3).11 Several patients involved in the study were on additional medications, such as NSAIDs, benzodiazepines, tramadol, and several others. The treatment group was initiated on ketamine at an infusion rate of 1.2 mcg/kg/min with regular interval titration when needed to a maximum dose of 7.2 mcg/kg/min.11 Ketamine was administered over a 5-day period in an inpatient setting.
Pain score reductions were seen most significantly over the first week of therapy, with treatment group average pain score of 2.68 + 0.51 vs placebo 5.45 + 0.48, but remained statistically significant for up to 10 weeks. As early as week 2 pain scores in the ketamine arm began to increase (above 4) and only during week 1 were pain scores reduced 50% from baseline, indicating substantial benefit.11 Moderate benefit (30% reduction from baseline) was only noted with ketamine up until week 3. Other endpoints assessed a patient’s ability to walk, which resulted in no significant change from baseline.
Patients in the control group were given an option to participate in an open label phase in order to receive ketamine therapy. Twenty of the 30 patients opted to be treated and experienced substantial pain relief (50% or more reduction) lasting until around the 4th week.11 This data indicates that patients in the open label phase of the study obtained more substantial and longer lasting moderate pain relief (30% or more reduction) until week 10. The lack of sustained benefit in the blinded arm demonstrates likelihood that a placebo effect exists in managing this pain syndrome.6,11
The Cochrane collaboration conducted a systematic review for treating pain and disability in adults with CRPS.9 With regard to ketamine therapy, the review focuses on the data surrounding 2 main studies with dosing strategies of mean dose of 22.2 mg/h for 4.2 days and 0.35 mg/kg/h over 4 hours for each business day for 10 days.10,11 The conclusion was that insufficient evidence exists to make a definitive statement on the usefulness of ketamine. The authors commented that more rigorous studies were needed to confirm the efficacy of ketamine, but there was clearly potential for its use.9
The clinical trials mentioned above were included in the Cochrane review as low-evidence studies that yielded results showing statistically significant pain reduction. An additional systematic review reported similar results to the stance seen in the Cochrane database.4 There is currently no high-level evidence that suggests that ketamine is a completely effective option for the treatment of CRPS. The highest level of evidence was of weak quality, and a question of placebo effect exists to confound interpretation.6
According to Sigtermans et al,11 adverse events reflected an incidence of nausea at 63% (17% placebo), vomiting at 47% (10% placebo), psychomimetic effects 93% (17% placebo), and headache 37% (33% placebo).11 Other adverse effects included: sedation, dysphoria and dizziness. Another study found that patients on long-term, frequent ketamine therapy suffered significant cognitive impairment as opposed to patients who were not on long-term, frequent therapy.12 The package insert lists concerns for dependence and withdrawal symptoms with psychotic features following long-term use of ketamine.13
In summary, there is sufficient data to support a favorable discussion for the application of ketamine as a therapeutic agent to reduce the symptoms associated with CRPS. However, the strength of existing evidence is low, sample sizes are small, and further research is necessary.
There is currently no standard test to diagnose CRPS in order to guide treatment strategies. As such, the role of ketamine therapy remains unclear. A concern for its clinical significance arises with the need for 5 days of monitored outpatient treatment and only 1 week of pain reduction that is > 50% from baseline scores at the expense of added side effects. No efficacy or safety data are available for the redosing of ketamine, and quality of life improvement has not been studied. More research is needed to better determine if and what role, if any, ketamine might have in the treatment of CRPS.