Ketamine Treatments

Ketamine, a potent anesthetic, is being used as an experimental and controversial treatment for Complex Regional Pain Syndrome. The theory of ketamine use in CRPS/RSD is primarily advanced by neurologist Dr Robert J. Schwartzman of Drexel University College of Medicine in Philadelphia, and researchers at the University of Tübingen,in Germany, but was first introduced in the United States by Doctor Ronald Harbut of Little Rock Arkansas. Doctor Harbut and Doctor Graeme Correll (of Queensland, Australia) first began studying the use of ketamine in the treatment of CRPS patients. Dr Harbut's first CRPS patients in the USA were successfully treated in 2002 with the low-dose ketamine infusion; also called the "Awake Technique" and he soon began work with FDA on an approved protocol. In early 2003 Dr Harbut began sharing his treatment methods with the Doctors at Drexel University College of Medicine, including Doctor Schwartzman. The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity.

A 2004 article discussing ketamine infusion therapy states, "Although ketamine may have more   one more

mechanism of action, the basis for using it to treat CRPS may reside in its strong ability to block NMDA receptors. Experimental evidence suggests that a sufficiently intense or prolonged painful stimulus causes an extraordinary release of glutamate from peripheral nociceptive afferents onto dorsal horn neurons within the spinal cord. The glutamate released, in turn, stimulates NMDA receptors on second-order neurons that produce the phenomena of windup and central sensitization. It is reasonable to consider that, by blocking NMDA receptors, one might also be able to block cellular mechanisms supporting windup and central sensitization . Ketamine is the only potent NMDA-blocking drug currently available for clinical use. Our interpretation is that an appropriately prolonged infusion of ketamine appears to maintain a level of ketamine in the central nervous system long enough to reverse the effects of the sensitization process and associated pain."

There are two treatment modalities; the first consist of a low dose subanesethesia Ketamine infusion of between 10–90 mg per hour over several treatment days, this can be delivered in hospital or as an outpatient in some cases. This is called the awake or subanesethesia technique.

One study demonstrated that 83% of the patients that participated had complete relief and many others had some relief of the symptoms. Another evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded that "A four-hour ketamine infusion escalated from 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation". Unfortunately, these study designs are very prone to bias, which means we still need high quality randomised controlled trials of ketamine infusion for CRPS to know about its effects and side effects.

​​
The second treatment modality consists of putting the patient into a medically-induced coma, then administering an extremely high dosage of ketamine; typically between 600 and 900 mg. This version, currently not allowed in the United States, is most commonly done in Germany but some treatments are now also taking place in Monterrey, Nuevo León, Mexico.

According to Dr Schwartzman, 14 cases out of 41 patients in the induced-coma ketamine experiments were completely cured. "We haven't cured the original injury," he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone."

"No one ever cured it before," he adds. "In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system." 

No replicated case series, or controlled trials have been done for the coma induced method to date, so care should be taken when interpreting these reports. Proper clinical trials are required before we know the effects and the risks of this procedure.

The ketamine coma method gained attention in pop culture through season 3 of the FOX television drama House, M.D., which opens a few months after the title character, Gregory House, was placed into a ketamine coma to treat ongoing neuropathy in his right leg. House is shown to have recovered significant use of his right leg (he even goes running regularly), but the treatment eventually wears off and House is once more left in pain and significantly disabled. House, M.D. also featured an episode in which an amputee with many years of severe phantom limb pain gained immediate and complete, and apparently long lasting, relief of his pain through a single use of a mirror box. There are no credible reports in the peer-reviewed literature of such immediate and long lasting effects from this treatment.

Overview of Ketamine Infusion Therapy
By Philip Getson, DO 

Patricia Curiale led an active life until an auto accident in 1998 triggered CRPS. After five years of living with pain that she rates “50 on a scale of 10,� she was enrolled in our outpatient program that uses ketamine to treat CRPS when other conventional treatments fail. Ketamine is an anesthetic previously used in the operating room and for emergency situations in patients with unknown medical history (eg, traffic accidents).

Ms. Curiale frankly credits the ketamine with saving her life. “I can understand putting a gun to your head to stop the pain,� she says. Although she currently rates her pain at “about a 5,� she can live with that. Plus, she has been able to get out of her wheelchair and walk, something a previous physician swore would never happen.

She is one of many people who have CRPS and who have taken part in a program that I run with Robert J. Schwartzman, MD, Drexel University College of Medicine in Philadelphia. Currently we are collecting data on an outpatient “awake� ketamine protocol for patients who have tried more conventional therapies without long-term benefit.

Elena King-Stoltz, who has full-body CRPS, had tried Bier blocks, spinal blocks, an intrathecal pump and other treatments since being diagnosed in 1992, but still experienced high levels of pain. She has been on the ketamine program for almost a year now. “I mowed my lawn for the first time in 10 years,� she says.

The program can be done on both an inpatient and outpatient basis. Before beginning either therapy, we do laboratory, cardiac, and psychological evaluations.

While we have had NO significant adverse events, we have been extremely cautious in screening patients with concurrent medical problems. The two most common reasons a patient would be eliminated are a psychiatric history of note (apart from the depression due to chronic pain) and cardiopulmonary disease.






Hospital-based infusions

The hospital-based infusions require a five-day in-patient stay. An intravenous (IV) line is inserted and the patient is started on a dose of 20mg of ketamine per hour, which is increased by 5mg increments to a maximum of 40mg per hour. As an adjunct, we are using clonidine, 0.1 mg (per FDA). We use small doses of lorazepam (Ativan®), 1-to-2 mg, for any dysphoria or hallucinations. Other medications are utilized to treat such problems as nausea and vomiting, headache etc.

The most common adverse event is fatigue. There have been some instances of short-term hallucinations related to dosage, but these have disappeared within an hour of lowering the dosage.

The accumulated data over three years has heretofore shown no significant lasting adverse events. Dr. Schwartzman and I have treated more than 100 patients. We had one patient with bradycardia in which the 5-day infusion was terminated.

Following discharge from the hospital, patients enroll in an outpatient infusion program of varying degrees and lengths. Initially, they are treated 1-to-2 times a week for a 4-hour IV infusion of 100 mg to 200 mg of ketamine. The frequency of outpatient treatments is weaned over time. Currently, we are using a protocol that consists of two outpatient treatments a week every other week for one month, then one treatment every other week for a month then monthly for three months then every three months. This protocol is merely a general guideline however and varies at times. Then one outpatient treatment the following month, after which we reassess the patient. Outpatient visits are then monthly, or at 3-month intervals, depending on the patient.


Outpatient protocol

Alternatively, the patients are given therapy only on an outpatient basis. They are given 10 daily treatments initially in two consecutive weeks in an outpatient infusion suite. They are administered from 70 mg-to-200 mg of ketamine per day in titrating doses over the 10-day timeframe and then they are placed in the outpatient program as described above. Again, there have been few adverse events and most of them have been dosage related. As before, the most common is fatigue on the day of the infusion. There have been NO long term side effects. Most patients are given 2 mg of midazolam and sleep through the procedure. Other medications are given as needed for side effects such as nausea and headache.

Ms. King-Stoltz, an exception to the aforementioned protocol, does the outpatient protocol once or twice a week. She spends 4 hours in the hospital and says she has no serious side effects. She is a little tired afterwards, but it goes away quickly. Ms Curiale found the treatment very draining and the drug left her “loopy� but she noted results from the beginning.

Results

The results obtained so far have been promising. We measure outcomes using pain scales, physical exams, psychologic profiles, and activity increase.

Rough estimates show approximately 85% of those undergoing the hospital stay protocol have improvement measured by increased activity, reduction of medication, and improved lifestyles. For example, some have discarded wheelchairs, walkers, and canes, and others have increased activities or have returned to work. Those beginning with outpatient therapy have similarly improved, but to a lesser degree (approximately 60% to 70%). All patients receive the follow-up outpatient boosters.

Ms. King-Stoltz says that although she still has pain, it is manageable and she is doing things she hadn't done for years, such as walking and doing chores around the house. The ketamine treatment has given her back some degree of independence. 

The one major problem with ketamine infusion therapy is the inability to “hold� the improvement achieved by the five-day inpatient or 10-day outpatient regimen. Without the infusion boosters, the patients almost universally return to their pre-treatment state. It is therefore necessary to combine the initial start-up therapy on an inpatient or outpatient basis with follow-up boosters in order to maintain the level of pain relief.

Virtually all participants in the program have continued the out-patient ketamine infusions. None of the patients treated by Dr. Schwartzman and me have discontinued due to side effects. More study will be necessary to determine such factors as dosages and long-term time frame to be treated.

Studies are currently ongoing to combine other drugs on an outpatient basis with ketamine to try and “hold� the improvement for a longer duration. The concurrent use of sympathetic blocks and ketamine is being studied. Lifestyle change, dietary adjustment and physical therapy are all being stressed as improvement is noted. The use of nutritional support vitamins, neutriceuticals, and counseling is also under review.

Most patients get sustained relief for 4 to 6 months. Some have been fortunate enough to get a longer term benefit.

I believe that ketamine provides the best chance of improvement from all therapeutic modalities available today. While it involves the use of medications besides ketamine, the use of IV drug therapy, a great deal of time and effort on the part of the patients and their families, it has certainly shown great promise in patients who do not find relief from other treatment.

Certainly the drug is not for everyone—approximately 20% of people show little to no improvement. However, some have benefitted dramatically. We continue the treatment program in the hope that more patient evaluations and the use of concurrent medication can affect a more long-lasting improvement in individuals with multi-limb or multi-system disease.

For now, however, we at least appear to be heading in a positive direction, helping many individuals who, up to this point in time, have received no or little benefit from the more “conventional� treatment modalities.

Philip Getson, D.O. is a Board Certified Family Practitioner and an Associate Professor of Neurology at the Drexel University College of Medicine in Philadelphia. He can be reached at 856-983-7246 or PGetson@aol.com.

RSDSA Review, Spring 2006.


Inpatient Ketamine Insurance codes
Inpatient Ketamine Insurance codes
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