Research Protocol
3/11/06
RESEARCH PROTOCOL
A Pilot Study of a 5-Day Infusion of
Ketamine for Intractable
Complex Regional Pain Syndrome
1.3 Open Label Trial in Germany
An open label trial in Germany (Section 5.0, Reference 6) suggests therapeutic effectiveness of ketamine-midazolam anesthesia in treating severe, intractable neuropathic pain due to CRPS. The first patient was a 16 year-old German girl who developed CRPS following an injury to the right hand with rapid spreading to her entire right upper extremity. Despite aggressive treatment with all available modalities, including sympathetic nerve blocks, the CRPS continued to progress rapidly. On a compassionate basis, she received ketamine-midazolam anesthesia. At this point, nine years later, she plays the guitar and is completely symptom free.
These same physicians conducted the first open label study in Germany. Their study has not been published in a full length, peer reviewed scientific report. However, a series of ten subjects were studied and the results were published as an abstract [6], which is available in APPENDIX 4 and on the Internet:
http://www.rsdfoundation.org/en/en_research_updates.html
Currently, subjects in the German study are screened by Robert Schwartzman, MD at Drexel University, Professor and Chairman, College of Medicine, Department of Neurology, Philadelphia, Pennsylvania. These subjects must have tried and failed all reasonable treatments and the CRPS had to involve multiple extremities or be rapidly spreading. Ketamine-midazolam anesthesia studies have not been reported outside of Germany.
1.4 Principle Investigator and German Study
The principal investigator (Anthony F. Kirkpatrick, MD, PhD) is Chairman of the Scientific Advisory Committee for the International Research Foundation for RSD / CRPS. A list of the members of his committee is available in APPENDIX 5 and at:
www.rsdfoundation.org
Dr. Schwartzman and the German investigators, who conducted the first clinical trials on 5-day ketamine anesthesia (Dr. Ralph-Thomas Kiefer, Eberhard-Karls University, Tuebingen and Dr. Peter Rohr, Klinikum Saarbrücken Teaching Hospital of the University, Saarland Saarbrüecken), are members of this committee. The design of the present study will be similar to that of the German studies.
1.5 Update on German Trial
Dr. Schwartzman provided the following update and outcomes on the first series of 10 subjects. (Personal communication: January 6, 2005). The intensity of pain prior to the study intervention was determined according to a numeric rating scale (NRS end point 0:no pain, I0:worst pain imaginable). All 10 subjects rated their pain at least at NRS = 8 prior to the study intervention. After awakening from anesthesia, all subjects had complete pain relief. Spontaneous pain, hyperalgesia, mechanical allodynia and other associated CRPS signs and symptoms were absent. Complete relief from all components of CRPS lasted for more than 2 months (mean 3.8 months, ± 1.5) in all. Pre and post study intervention neuropsychological testing (intellectual functioning, attention, memory, process speed, motor, and mood) demonstrated no cognitive impairment in any sphere. Ketamine specific side effects included dizziness, muscular weakness, fatigue, and slight anxiety, which resolved within 2-4 weeks. During the five day general anesthesia intervention, transient and reversible rises in liver enzymes and CPK occurred. There were nosocomial infections (respiratory infections -5/10, urinary tract infections -2/10). The infections required intravenous antibiotic treatment and resolved without incident.
At three months, 7 subjects continued with complete pain relief, 1 experienced recurring minor pain (NRS 1-2) at the original site of injury. All 7 subjects with complete pain relief had been withdrawn from narcotics during the study intervention and required no pain medication. The two subjects who had a relapse of CRPS required reduced amounts of narcotics <25% of the pre-study intervention levels. Subjects with recurring symptoms maintained significant pain relief (41-62%).
At 6 months, 5 subjects were pain free, 2 had a recurrence of their original neuropathic pain (NRS<3) and a third subject had a CRPS relapse (NRS 5-6). Subjects with recurring symptoms reported significant pain relief (33-65%). The 5 subjects with complete pain relief required no pain medication. The symptomatic subjects had a significant reduction of prior pain medication. One subject was weaned from her intrathecal morphine pump, was totally pain free and required no medication. Six subjects rated their social and professional rehabilitation as complete, 2 as significantly improved and 2 as only minimally improved.
As of July 5, 2005, the 5-day ketamine trial has been completed in 27 volunteers in the German study. Thus far, there have been no long-term adverse events.
On October 3, 2005, Dr. Schwartman provided the Principle Investigator with tabulated neuropsychological data on nine subjects that entered the 5-day ketamine trial in Germany. [Appendix 8]. These patients were evaluated with a battery of neuropsychological and personality tests pre and post treatment with Ketamine anesthesia. Compared to their baseline estimates preceding treatment, there were no decline on tests of attention, processing speed, memory, and manual speed or on tests of mood and personality. Where significant change occurred, it was typically indicative of improved functioning. Mood and personality remained stable on pre and post tests. There was significant decline in the pain index on a questionnaire.
Thus, 5-day deep ketamine anesthesia has been effective in the treatment of severe, unremitting pain refractory to other interventions. The results of German study suggest no adverse affects on neurocognitive, memory or emotional functioning as a result of this treatment and suggest a positive relationship between the relief of pain and improved functioning in these behavioral domains.
Upon returning to the United States from Germany, some patients have occasionally required infusions of low dose ketamine in sessions lasting approximately four hours in order maintain a remission of their CRPS. Some health insurance companies have been paying for low dose booster infusions. Each 4-hour infusion is about $400. During the infusion, patients are monitored for heart rate, pulse oxygenation, mental status, and blood pressure. Some patients get a headache and are nauseated. Phenergan and Zofran are used to treat nausea and Fioricet for headache.
The following is an update dated March 8, 2006, on the results from thirty (30) research subjects as reported to Dr. Kirkpatrick by Dr. Robert Schwartzman.
Nine of 30 patients have experienced complete and permanent remission from previous intransigent symptoms. One of these subjects had a complete remission for nine years and the other for greater than five years.
Of the remaining 21 subjects, all of whom had at least a partial remission, seven were entirely pain-free for six to seven months, after which the pain slowly returned.
Ten of the subjects are now being treated with 4-hour subanesthetic (low) doses of ketamine in an attempt to boost the initial effect.
Pneumonia developed in five of 30 subjects, and kidney infections in six, but all responded to treatment.
Detailed psychological tests performed in 15 of 30 patients before and after 5-day infusion with ketamine have shown no change of mental function.
Dr. Schwartzman treated approximately 100 patients with subanesthetic doses of ketamine. He found that subanesthetic doses help but do not cure patients. Anesthetic doses of ketamine appear necessary for a cure.
Dr. Schwartzman and his colleagues in Germany have had no addiction problems related to the use of ketamine in research subjects. He has stopped low-dose ketamine boosters for any patient who did not have pain greater than 3 on a 0-10 pain scale. Those patients who have been pain-free after the 5-day infusion have a hard time accepting a pain score of 3/10. In that case, the German investigators stop the ketamine boosters and try to use non-narcotic pain medicines like anti-inflammatory drugs and Neurontin.
