Ketamine Combination Regimen Shows Promise For Long-term CRPS-1 Relief

Experts expect further refinement of treatment protocols for pain syndrome

by Gabriel Miller

Over the past 10 years, ketamine has emerged as a viable and potent treatment for patients with refractory complex regional pain syndrome type 1. In a new study, investigators show that combining epidural analgesia with inpatient ketamine infusion, followed by outpatient ketamine “boosters,” is an effective therapeutic protocol for this difficult-to-treat disease.
Ketamine was recognized as a potential treatment for complex regional pain syndrome type 1 (CRPS-1) in the United States approximately eight years ago. Since that time, two modalities have emerged: an “awake technique” in which subanesthetic ketamine is continuously infused, and a more dramatic protocol in which patients receive extremely high doses of ketamine while in a medically induced coma.

The high-dose method is currently not practiced in the United States, but a select group of centers has been using ketamine and studying the subanesthetic approach.
Advocates of ketamine for CRPS-1, previously known as reflex sympathetic dystrophy (RSD), say that the ketamine protocols first “turn off the pain” and then “reset the whole system” of pain transmission.
CRPS-1 appears to be caused by central sensitization and pain “wind-up,” a gradual, cumulative hyper-excitable neuronal response resulting from repeated painful stimulation of peripheral nerves. The N-methyl-d-aspartate (NMDA) receptor complex appears to play a major role in the development of this overall central sensitization; additionally, evidence shows that NMDA receptors are present in the peripheral nerves.

“Pain begets more pain,” said Robert Schwartzman, MD, professor and chairman of the Department of Neurology at Drexel University in Philadelphia. “When NMDA receptors are open, calcium enters the pain transmission neuron and initiates cascades that end up making pain transmission neurons more easily fired. This calcium entry causes something akin to long-term potentiation—it makes those cells more excitable—and that’s clearly one of the mechanisms in at least 80% of RSD patients.”

NMDA receptor antagonists, such as ketamine, have long been thought to be a viable treatment for both chronic pain conditions in general and CRPS-1 in particular.
“What [an NMDA receptor antagonist] does is block that mechanism of calcium entry into cells; once you’ve turned this system off, you’ve turned off the genetic transformation that occurs with persistent pain,” said Dr. Schwartzman, who has treated more than 500 patients with CRPS-1 using ketamine. “We are tuning back the hypersensitivity in the pain transmission neurons that is caused by pain.”
But psychomimetic effects, including hallucinations or paranoid delusions, and central nervous system (CNS) side effects have previously limited the therapeutic impact of the strongest-acting NMDA receptor antagonists, such as ketamine.

What’s more, in order to prevent the rapid re-sensitization of the CNS, the primary source of pain must also be controlled. Before beginning ketamine therapy for CRPS-1, a patient’s initial source of chronic pain, such as an improperly healed fracture, a neuroma or pressure on a nerve, must be identified and treated.
Thus, a typical ketamine protocol for CRPS-1 requires first treating any primary sources of pain, and then following with five to 10 days of inpatient low-dose, continuous ketamine infusion coupled with a high-dose benzodiazepine to minimize CNS side effects.

Finally, despite exceptional initial results—in prospective trials, between 80% and 100% of patients refractory to pharmacologic treatment for CRPS-1 report significant relief with ketamine—the treatment effect fades over time. To compensate, clinicians have now been using outpatient ketamine “boosters” in an attempt to extend the initial treatment effect.

Innovative Protocol
The current study is unique in that it also adds an additional epidural anesthetic during ketamine infusion, concomitantly blocking pain while the NMDA receptor complex is “reset” with ketamine. The new research was presented by lead study author Hai Nguyen, MD, an anethesiologist in Cleveland, Ohio, at the annual meeting of the American Society of Regional Anesthesia and Pain Medicine (ASRA) in San Antonio (abstract ID: 9).
Patients received a five-day inpatient, continuous IV ketamine infusion (0.6-0.8 mg/kg per hour; maximum, 60 mg/h) combined with continuous epidural analgesia (bupivacaine, dilaudid and clonidine) as well as 1 mg lorazepam every six hours. Patients were then given an outpatient, IV ketamine “booster” of 100 to 250 mg combined with 2 mg midazolam every two to four weeks for two months. The booster was given over a four-hour period on two consecutive days.

Forty-two patients were studied, and prior to ketamine treatment, 92.9% (39 of 42) had CRPS-1 involvement in all four extremities, 95.2% (40 of 42) experienced pain affecting the entire body and 100% had a numeric pain scale (NPS) rating of 10 on a 10-point scale.
At 12 weeks, 61.9% of patients reported moderate pain improvement, defined as a decrease of three or more points on the NPS. At 24 weeks, 30.9% reported continued moderate pain relief.
“The novel element [of the study] is combining the epidural component,” said Michael Goldberg, MD, professor and chief of anesthesiology at Cooper University Hospital in Camden, N.J., who uses continuous brachial plexus blocks as a peripheral anesthetic during his ketamine treatments.
“But the interesting thing to notice with this study, and all of our studies, [is that] we find that at about 12 weeks we have less significant pain relief. So it doesn’t stick and that’s the problem with the ketamine treatment for all of us,” Dr. Goldberg said.

With the somewhat complex interaction of drugs, side effects can be significant in ketamine protocols, particularly in the patients receiving moderate doses. These patients require more ketamine to control their CRPS-1 but not enough to necessitate a dose that requires deep sedation, Dr. Goldberg said.
In the 42 patients studied, significant side effects included nausea (64.3%), vomiting (38.1%), mild liver function test elevation (4.8%) and delirium (2.4%).
Overall, side effect risks associated with ketamine therapy have been overinflated, said Dr. Schwartzman, and in a population of patients with completely debilitating refractory pain, the risk for severe side effects is justified.
“[Side effects] have been grossly overexaggerated in the literature,” said Dr. Schwartzman. “Even in this study they didn’t use enough midazolam, but when you use [ketamine] properly, it’s a very safe drug. We’ve done it thousands of times.” Randomized controlled trials have further confirmed the efficacy and safety of ketamine therapy, said Dr. Schwartzman, who authored one such study (Pain 2009;147:107-115).
Anecdotally, he said, patients are willing to put up with side effects, even at a cost of as much as $10,000 for a treatment cycle.
“Insurance companies don’t pay for this,” he said. “When Americans are paying for stuff out of pocket, you know it has to work.”