By Annette M. Boyle
BETHESDA, MD — For patients with intractable complex regional pain syndrome (CRPS), treatment with high doses of ketamine may offer a cure or dramatically reduce pain and improve functioning. Better still, this innovative treatment soon might be available on an outpatient basis.
Researchers at Walter Reed National Military Medical Center (WRNMMC), Bethesda, MD, already have treated two patients with severe CRPS as outpatients.
Navy Cdr. James S. Houston, MD, Director, Wounded Warrior Pain Care Initiative, and Director, Interventional Pain Clinic, WRNMMC
“Patients who have not responded to conventional treatments for CRPS or phantom-limb pain, such as medications, nerve blocks and spinal-cord stimulation, can find good relief with an outpatient infusion of ketamine,” said Navy Cdr. James S. Houston MD, director, Wounded Warrior Pain Care Initiative, and director, Interventional Pain Clinic, WRNMMC. “We have treated two patients here, and both are doing extremely well.” Outpatient treatment of CRPS with ketamine infusion currently is available only at WRNMMC.
Patients receive a subanesthetic dose of ketamine, about 120 mg per hour for an average adult male, for four or five hours. After the infusion is finished, patients wait two hours, or until any side effects have resolved, then go home. “Compared to inpatient infusion, this treatment is far more cost-effective and much more convenient for patients,” Houston told US Medicine.
“Patients experience significant relief for one to two months, with either a 50% reduction in overall pain or a 50% reduction in the area of pain. One patient had CRPS that involved the entire leg, from foot to hip. After treatment, the pain was pushed down to just the ankle. That level of pain reduction enables patients to be more functional, return to work, go shopping, rather than be bedridden,” Houston explained.
A previous study at Mackay Base Hospital in Queensland, Australia, reported that, of 33 patients with CRPS who received subanesthetic infusions of ketamine, 25 (76%) obtained complete pain relief, while six (18%) had partial pain relief after one course of therapy. More than half remained pain-free for more three months or longer, and 31% had no pain for at least six months.
Twelve patients relapsed and had a second course. All 12 experienced complete pain relief; 58% were pain-free for more than year after treatment, and one-third had no pain for more than three years.
“Ketamine works extremely well for neuropathic pain, phantom-limb pain and CRPS — conditions for which opioids and other medications work poorly,” Houston said.
Hyper-regulation and central sensitization triggered by stimulation of the N-methyl-D-Aspartate (NMDA) receptors appear to be the primary neurological processes involved in CRPS and neuropathic pain, according to the guidelines for very high dose ketamine infusions developed at Walter Reed. Ketamine blocks the NMDA receptors.
“At higher doses, ketamine changes central pain-processing. In lay language, it’s like hitting the ‘reset’ button or control/alt/delete on your computer. It restores normal pain processing,” said Houston. “For patients who have opioid-induced hyperalgia or neuropathic pain, ketamine can provide immediate and dramatic relief.”Ketamine ‘Resets’ System for Normal Pain Processing in Complex Syndrome Patients
Initial research on ketamine for CRPS focused on the inpatient setting.
“While we don’t really know all the reasons patients develop CRPS, data from Europe and Mexico show that using very high doses of ketamine in an intensive care (ICU) or post-anesthesia care unit (PACU) setting produces a dramatic reduction in CRPS,” noted Houston. “With a ‘ketamine coma,’ one-third of patients have full resolution of symptoms: They are cured. One-third experience dramatic, permanent reduction in pain. Others have temporary relief. There is a much higher response rate than with other treatment modalities.”
Hospitalized patients who are intubated and ventilated receive an average of 500 mg of ketamine per hour for five days. Prior research showed that three days was insufficient and that no additional benefit was seen after five days. Patients typically leave the hospital two days after terminating the infusion.
To monitor the neurocognitive effects of ketamine, patients undergo psychological assessments prior to treatment, immediately following treatment and six weeks later.
“Immediately following treatment, we note some vision changes, some hallucinations. But at the six-week mark, patients are actually better and more functional than at baseline. With the severe, chronic pain resolved, they can focus, function and respond better,” Houston said.
“We’ve had about two-dozen patients in ketamine comas in the ICU to treat pain. Some of them had neuropathic pain, and, when they went in for surgery, we used ketamine for sedation and kept them intubated,” he added.
Not everyone with CRPS, phantom-limb pain or other neuropathic pain is a candidate for ketamine treatment. Inducing a coma and ventilating a patient for five days is a high-risk procedure, Houston explained, and patients must have tried injections, nerve blocks, spinal-cord stimulation and other conventional treatments first. Typical candidates have disabling pain that has made them nonfunctional or created severe psychological distress.
“CRPS can make people suicidal. We want to help them before they get to the point of considering suicide or amputation for a limb involved in CRPS. Some patients think that removing a limb will eliminate the pain, but CPRS is a disorder of nerve processing, not of the limb, so amputation is ineffective. We want to provide a treatment that will work,” said Houston.
Proactive Use of Ketamine
The best approach to chronic pain is prevention, and ketamine may be able to help there, too. “We are using the treatment now for patients coming in from Afghanistan with multiple injuries. Using ketamine for sedation, we could prevent potential phantom-limb pain. There isn’t a lot of data yet, but it seems that using a higher dose of ketamine closer to the time of trauma may prevent some cases of neuropathic pain and phantom limb pain,” Houston recounted.
For now, the team at Walter Reed is focused on presenting the results of the international research and their own experience, as well as the protocol they’ve developed for use of ketamine in patients in military hospitals.
“Our goal is to identify more patients and get the information about this therapy out so more patients can find relief,” Houston said.
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 Correll 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. Pain Medicine. 2004;3:263-275. http://www.thblack.com/links/RSD/PainMed2004_5_263_ketamine_infusion_therapy.pdf