NOTE: THE RESEARCH PROTOCOL DRAFT BELOW WAS PREPARED FOR A RESEARCH STUDY WHICH HAS NOT YET BEEN APPROVED BY THE INSTITUTIONAL REVIEW BOARD AT THE UNIVERSITY OF SOUTH FLORIDA. NEITHER DR. KIRKPATRICK NOR THE UNIVERSITY OF SOUTH FLORIDA ARE PARTICIPATING IN OR CONTROLLING THE MEXICO RESEARCH. THESE FORMS ARE ONLY PROVIDED AS A GUIDE TO HELP YOU FORMULATE QUESTIONS YOU MAY HAVE REGARDING THE MEXICO RESEARCH
KETAMINE RESEARCH PROTOCOL
Revised: September 4, 2006
RESEARCH PROTOCOL
A Pilot Study of a 5-Day Infusion of
Ketamine for Intractable
Complex Regional Pain Syndrome
PRINCIPAL INVESTIGATOR:
Anthony Kirkpatrick, MD, PhD
CO-INVESTIGATORS:
Hans Schweiger, MD
Robert Schwartzman, MD
Rafael Miguel, MD
Richard Hoffman, PhD
Rob Nickeson, MD
Mark McLaughlin, PhD
Thomas Freeman, MD
CONSULTANTS:
Srinivasa Raja, M.D.
Research Consultant
Professor of Anesthesiology
Johns Hopkins University
Dennis Bandyk, MD
Professor of Surgery
Research Consultant
Director, Division of Vascular & Endovascular Surgery
University of South Florida
Patricia Schuster, R.N.
Nurse Consultant
Tampa General Hospital
DATA SAFETY MONITORING BOARD
Oscar A. de Leon-Casasola, MD
Giancarlo Barolat, MD
Timothy R. Lubenow, M.D. Robert Walker, MD,
INDEX
1.0 Introduction
1.1 CRPS
1.2 Ketamine
1.3 Open Label Trial in Germany
1.4 Principal Investigator and German Study
1.5 Update on German Study
2.0 Proposed Study
2.1 Goals of Protocol
3.0 Study Design
3.1 Inclusion Criteria
3.2 Exclusion Criteria
3.3 Potential Risks to Subjects
3.4 Administration of Drug
3.5 ICU Data Collection during Study Interventions
3.6 Neuropsychological Tests
4.0 Significance of Study
5.0 References
Co-Investigators
Consultants
Data Safety Monitoring Board
Hospital Expenses
Appendix
Proposed Experimental Revision Of CRPS Diagnostic Criteria.
Riker Sedation-Agitation Scale (SAS).
Descriptions of the Neuropsychological Tests.
Reference Articles.
Internet Material.
DVD Production : Ketamine Research From A Volunteer’s Perspective.
Video Information Release Agreement
Neuropsychological Data on Nine Subjects
1.0 Introduction
1.1 CRPS
Complex regional pain syndrome (CRPS) is a severe neuropathic pain that is out of proportion to the extent of initial injury. Characteristic symptoms are severe unrelenting burning and deep pain, associated with mechano- and thermal allodynia (defined as any type of tactile stimulation perceived as painful) and hyperpathia (defined as repetitive tactile stimulation becoming progressively more painful). Swelling, autonomic dysregulation, movement disorder, atrophy and dystrophy are associated to varying degrees. Some patients experience spreading of symptoms to large segments of their body. The pain syndrome frequently becomes the “primary relationship” of the affected individual’s life. The consequence in terms of significant pain, quality of life, social factors, and economic loss and in some cases suicide is staggering. [1]
CRPS can sometimes be palliated with interventional procedures, but often it is no longer amenable to nerve blocks. Current therapies are inadequate both due to variability and lack of permanent efficacy in many cases. Alternative therapies are warranted including the use of high risk procedures including sympathectomies and other surgical procedures. [2]
1.2 Ketamine
Windup and central sensitization are key neurological processes that appear to be involved in the induction and maintenance of CRPS/neuropathic pain. Because over excitation of the N-methyl-D-Aspartate (NMDA) receptor complex appears to play a major role in the development of these phenomena, there have been efforts made by many over the past 20 years to treat chronic pain using NMDA antagonists. [3-5]
Ketamine was used for most of these studies as it is the most potent clinically available NMDA-antagonist. Drugs such as dextromethorphan, amantadine, and memantine, although relatively safe (from a central nervous system side effect standpoint), have relatively weak NMDA receptor-inhibition activity and appear to have a low potential for blocking the sensitization process.
While animal experiments have shown evidence that ketamine can inhibit sensitization, the clinical usefulness of these findings have been limited due to lack of meaningful efficacy and/or excessive CNS side effects in conscious subjects such as dizziness, anxiety and hallucinations.
In the proposed study, ketamine will be used at a dosage level and duration commonly employed in treating certain patient populations. For example, administration of IV ketamine for periods longer than five days is useful in providing anesthesia for burn patients that require frequent dressing changes. In addition, I.V. ketamine is useful in treating patients with asthma when anesthesia is required for periods longer than five days because of ketamine’s bronchodilating properties. Ketamine is also used in the ICU for long-term general anesthesia of severe head injury patients, especially when hypotension is a potential problem.
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:
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:
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 others 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 eight 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.
2.0 Proposed Study
In this proposal, we will evaluate the use of general anesthesia using ketamine for approximately five days to evaluate the safety, tolerability and possible effectiveness of this intervention for the treatment of advanced CRPS in subjects who have failed standard interventions (Section 3.1, Inclusion Criteria). The study will be conducted at Tampa General Hospital (TGH).
The duration of ketamine-midazolam anesthesia for our study is five days, which is based on the experience of the German investigators. Dr. Schwartzman and his German colleagues found that the objective signs of CRPS began to disappear after 3 days of ketamine-midazolam anesthesia and reached a plateau at about 5 days. These objective signs included reduction in swelling, color changes from blue to pink skin and normalization of skin blood flow as measured by a laser doppler flowmeter.
The dose of ketamine for our study is based on the experience of the German investigators. They found that low dose ketamine is not effective in inducing a remission in subjects with advanced, generalized CRPS. For example, four subjects in their series were first treated with low dose ketamine for 10 days at doses sufficiently high to cause serious side effects (hallucinations). None of these subjects benefited from low dose ketamine and all required a higher dose ketamine-midazolam anesthesia in order to achieve a remission. (Personal Communication, Ralph-Thomas Kiefer MD, January 2, 2005) A recent report from Australia suggests that some patients with relatively mild CRPS might benefit from receiving low doses of ketamine. [7] The authors caution, however, that their report represents a retrospective review and that controlled studies are needed to determine the safety and efficacy of low-dose ketamine in patients with CRPS.
In the proposed study, labs will be drawn daily to monitor the subject.
Orphan Pilot Study
Our study on ketamine-midazolam anesthesia will be an "orphan technique" pilot study in subjects in desperate need of therapeutic options which are virtually nonexistent.
Re: “Orphan Technique”
The Orphan Drug Act (ODA) provides incentives for sponsors to develop products for rare diseases. The aim of ODA grant program is to support clinical development of techniques for use in rare diseases or conditions where no current therapy exists or where the technique will improve the existing therapy. CRPS is listed as a rare disease by NIH: http://www.fda.gov/orphan/grants/2005RFA.htm.
2.1 Goals of Protocol
The goal of the current protocol is to repeat and extend the observations from the German study. Several questions need to be addressed.
Are these important observations reproducible in a second center in another country?
Is this therapy safe and tolerable?
Is any potential benefit reasonable in relation to the expected risk of a five-day course of general anesthesia?
Half of the subjects demonstrated long-term benefit (i.e., pain-free at 6 months) and 80% had improvement in social/professional reintegration. Is there an optimal patient selection group with respect to the duration of the disease where better improvement can be noted?
Could higher doses or longer anesthesia time be more effective?
In those subjects who fail therapy after six months, is there a priming effect that would allow a repeat administration of the protocol to have longer effect?
Can this therapy be verified in a larger, randomized, placebo-controlled and/or active controlled trial?
In the current study we will address the most immediate of these questions, those related to safety and tolerability. We will also seek to determine preliminary evidence of efficacy in the two most important patient groups, those with early stage failure and those with late stage failure of standard therapy in order to acquire adequate data to statistically power a rigorous placebo controlled trial and/or active controlled trial, a necessary requirement for the evaluation of a novel therapy in the treatment of any pain syndrome.
Specific Aims
Determine the safety and tolerability of a 5-day course of the ketamine-midazolam anesthesia in subjects with fixed CRPS and significant pain and disability.
If safe in this subject population, determine the safety of a similar protocol in subjects with early onset failed therapy.
Determine preliminary evidence of efficacy in the two above subject groups. The results from that analysis will help to determine which group will present the best primary end point for efficacy in statistically powering of a larger, randomized, placebo-controlled and/or active controlled trial.
3.0 Study Design
The study design will be observational, open-label, non-randomized study to examine safety, tolerability and possible efficacy of five day ketamine-midazolam anesthesia for CRPS.
Once IRB approval is received, one patient will be studied under this protocol. Subsequent enrollment of subjects will require submission of a new application for review by TGH’s Administrative Research Review Committee (ARRC) before proceeding. In addition, all future approval and study continuation are conditioned upon of an annually approved Continuation Review by the USF IRB. TGH reserves the right to terminate the study at any time if necessary.
Seven subjects with advanced CRPS (defined as subjects with CRPS for one year or longer) will be enrolled in the trial according to the inclusion criteria. Three subjects will undergo general anesthesia for five days. One subject will be studied at a time.
A summary of patient treatment and status will be made after each patient’s discharge from the hospital and submitted to USF IRB and TGH ARRC. Findings of these summaries will be added to the protocol as part of safety and monitoring. Any findings will be discussed with the PI, USF IRB and TGH ARRC prior to implementation of any changes in protocol. In addition, after completion of the trial for the first three subjects, the Data Safety Monitoring Board (DSMB) will evaluate results for safety and tolerability as well as possible evidence of efficacy. If the DSMB finds that appropriate criteria have been met for safety and tolerability, then the trial will continue with enrollment and study performance for the remaining four subjects in the first group of subjects (advanced CRPS). The DSMB will then evaluate safety and tolerability data for these first seven subjects before proceeding further.
If the Data Safety Monitoring Board finds that the first seven subjects were treated with adequate safety and tolerability, then the second seven subjects will be treated. The second set of subjects consists of those that meet the same inclusion criteria but with early stage failure of CRPS therapy (defined as subjects with CRPS for less than one year).
The primary end points will consist of activities of daily living (ADL) scores and pain scores, comparing baseline scores to those at 3 and 6 months. Changes in objective signs of CRPS such as normalization of asymmetrical skin temperature, skin color, skin piloerection, sudomotor changes and swelling will be used as secondary end points.
There is no washout period. Subjects will continue on their medications. The only difference is that the subject will be under general anesthesia for five days with midazolam and ketamine. There are two exceptions:
Ketamine potentiates the effects of narcotics. The German investigators were able to completely withdraw about 16 patients from narcotics during the 5-day infusion. Subjects will only need non-narcotic home medications during the infusion and, if successful, after the 5-day infusion as well.
Clonidine will be administered via the NG at 0.1 mg TID. Clonidine is an antihypertensive medication that might counteract possible side effects from ketamine such as elevated blood pressure. In addition, a study in rats suggests that clonidine might have a neuroprotective effect.
3.1 Inclusion Criteria:
Physical status I-III (NOTE: Anyone with systemic CRPS would never be considered an ASA-1. In fact, several of these subjects might even be considered ASA-3 with "severe limitations in the activities of daily living").
All subjects will fulfill the IASP diagnostic and modified research diagnostic criteria for CRPS. [8] The research diagnostic criteria for CRPS are based on objective findings during a physical examination. (See APPENDIX 1)
Subjects must have failed all available treatment as determined by at least two independent pain practitioners. Failed treatments might include medications, nerve blocks, sympathectomy, and spinal cord stimulation.
CRPS has spread to involve at least two regions of the body or is rapidly spreading.
Participant has decision-making capacity as assessed by Clinical Psychologist Richard Hoffman, Ph.D. (MacArthur Competence Assessment Tool for Clinical Research. Sarasota, Professional Resource Press or similar measure).
Participant has someone they identify who is willing to serve as a proxy decision-maker while the participant is unconscious in the ICU.
3.2 Exclusion Criteria:
"Morbid obesity” is defined as having a BMI greater than or equal to 35.
Actiq (Fentanyl Lozenge) – German investigators found that it was difficult to wean subjects from this medication after a 5-day ketamine intervention.
History of resistance to antibiotics
History of deep vein thrombosis, increase intracranial pressure, increase intraocular pressure, uncontrolled hypertension, psychosis, CHF, or any one with a significant history of cardiac ischemic disease
Subjects taking nitrates will be excluded
History of MI and alcohol abuse.
Impaired kidney or liver function.
Subject less than 18 or greater than 65 years of age.
Non-English speaking subjects where informed consent may be compromised.
History of pulmonary hypertension, asthma, existing lung pathology and any significant medical problems that might confound pain problems such as diabetes.
History of ischemic heart disease
Pregnant women or anyone with positive pregnancy test prior to inclusion.
3.3 Potential Risks to Subjects:
Respiratory infection
Urinary tract infection
Systemic infection due to invasive procedures such as IV, arterial line, etc., placements
Extended dependency on mechanical ventilation
Oral-tracheal injury due to intubation and/or extubation
Deep vein thrombosis and pulmonary embolism
Radial nerve injury due arterial line placement
Unexpected anaphylactic/anaphylactoid reaction to study medications
Weight loss, abnormal appetite and abnormal sweating for a month or longer after five days of general anesthesia with ketamine.
Midazolam can cause side effects such as respiratory depression and confusion. Most side effects will go away as the effects of midazolam wear off.
Although side effects from clonidine are not common, they can occur. The following symptoms can be severe: dry mouth, drowsiness, dizziness, constipation, tiredness, headache, nervousness, decreased sexual ability, upset stomach, vomiting, rash, fainting, increased or decreased heart rate, irregular heart rate and swollen ankles or feet
Ketamine specific side effects include:
PSYCHOLOGICAL
Emergence reactions have occurred in approximately 12 percent of patients. The psychological manifestations vary in severity between pleasant dream-like states, vivid imaginary hallucinations and emergence delirium. In some cases these states have been accompanied by confusion, excitement and irrational behavior which a few patients recall as an unpleasant experience. The duration ordinarily is no more than a few hours. In a few cases, however, recurrences have taken place up to 24 hours after administration of ketamine. No residual psychological effects are known to have resulted from use of ketamine.
The incidence of these emergence phenomena is least in the young (15 years of age or less) and elderly (over 65 years of age) patient. Also, the incidence is reduced as the physician’s experience with the drug is gained.
The incidence of psychological manifestations during emergence, particularly dream-like observations and emergence delirium, may be reduced by using ketamine in conjunction with an intravenous benzodiazepine such as midazolam.
CARDIOVASCULAR
Blood pressure and pulse rate are frequently elevated following administration of ketamine alone. However hypotension and bradycardia have been observed. Arrhythmia has also occurred.
RESPIRATION
Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine. Laryngospasms and other forms of airway obstruction have occurred during ketamine anesthesia.
EYE
Diplopia and nystagmus have been noted following ketamine administration. It may also cause a slight elevation of intraocular pressure measurement.
NEUROLOGICAL
In some patients, enhanced skeletal muscle tone may be manifested by clonic and tonic movements sometimes resembling seizures.
GASTROINTESTINAL
Anorexia, nausea and vomiting have been observed; however, this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining consciousness.
GENERAL
Anaphylaxis. Local pain and exanthema at the injection site have infrequently been reported. Transient erythema and/or morbilliform rash have been reported.
Gastrointestinal dysfunction and/or discomfort and muscle weakness due to prolonged general anesthesia.
Death
Ketamine has been approved by the FDA as the sole anesthetic agent for general anesthesia but has not been approved by the FDA as a treatment for RSD / CRPS. This pilot study is a high risk study involving participants with an orphan condition. In addition, there are a number of vulnerabilities requiring special protection, e.g., stress, desperation, extended period of unconsciousness during the study in which the subject cannot participate in decision making or remove themselves from the study or otherwise advocate for themselves. The subject is prone to confuse research with therapy, and they are prone to under appreciate the risks and overestimate the benefits of participation. The study includes potential short-term and long-term physical, mental, and economic risks, all of which may be serious.
The key in this pilot study, from a research ethics perspective, is to focus on
1) minimizing risks, including considering additional protections given the vulnerabilities of the prospective participants, and
2) ensuring a robust consent process to maximize comprehension and voluntariness.
The protocol includes several steps to minimize risks:
Participants who have failed all reasonable alternative therapies.
Studying one participant at a time.
A battery of tests during administration of study drugs, and using a DSMB.
Additional protections will include:
Dr. Hans Schweiger is the primary clinical investigator identified as having primary responsibility for study participants’ care in the ICU.
Clinical investigators from the German study will be available to consult directly with Dr. Schweiger. In addition, a senior investigator from the German study has offered to provide direct consultation in Tampa. Dr. Robert Schwartzman, Professor and Chairman of Neurology, Drexel University, College of Medicine, Philadelphia, Pennsylvania has offered to travel to Tampa for consultation with the Principal Investigator and Dr. Schweiger and be present when the first patient is enrolled in the study.
The following steps will offer additional protections to the vulnerable participants, and ensure voluntary informed consent:
The Principal Investigator and the primary clinical investigator (Dr. Schweiger) will be assigned recruitment responsibilities to help prospective participants realize that the invitation is to a study and not to therapy, and to decrease the prospect that they will feel pressured to participate. Following the subject’s written consent to be video taped, this interview will be video recorded. A family member will be invited to be present and encouraged to participate during the video interview. The patient will have a copy of the video recording to evaluate during the waiting period. [See Appendix 7 for Video Information Release Agreement]
There will be a waiting period of two weeks into the consent process. During the waiting period participants will be encouraged to review the video recording of the consent process and invited to ask questions.
Subjects will have a durable power of health care in advance of participation.
The subject will be required to sign an agreement to meet financial obligations, retain a guarantor, and prepay for the estimated hospital costs
While participant is unconscious for five days in ICU, someone independent from the study team (for example, a family member) will be assigned to serve as participant’s advocate.
The patient’s primary physician will be informed of the subject’s participation in the study.
3.4 Administration of Study Drug:
Ketamine and midazolam will be given as an open label standardized protocol based on clinical experience in Germany with lCU subjects. Anesthesia will be induced with intravenous ketamine (0.5-1 mg/kg) and midazolam (bolus of 2.5-6 mg) and adjusted to deep anesthesia. The primary guide for assessing the depth of anesthesia / sedation will be the Riker Sedation Scale. (APPENDIX 2, page 11) Many research publications utilize this scale in the ICU, and the ICU nurses are very familiar with its application.
Oral clonidine will be administered through the NG tube at a dose of 0.1 mg TID. Clonidine belongs to a class of drugs that may not only protect against the neurotoxic effects, psychometric and cardiovascular side effects of ketamine, but may even enhance the pain-relieving action of NMDA antagonists. (7)
The anesthesia will be maintained for 5 days by infusions of ketamine (3-7 mg/kg/h). Midazolam (0.15-0.4 mg/kg/h) will be utilized to attenuate ketamine specific psychomimetic side effects. Based on the Principal Investigator’s clinical experience with ketamine, some subjects may require higher doses of midazolam and ketamine to maintain an appropriate depth of anesthesia. Mechanical ventilation with tracheal intubation will be used, the mode to be determined by the attending physician. All subjects will receive placement of an arterial line, Foley catheter and NG tube. During the study intervention in the ICU, liver enzymes, CPK and chest X-ray will be monitored according to the schedule below. Subjects will be monitored closely for respiratory infections and urinary tract infections using the standard ICU protocol at TGH. As in the German study, subjects will be monitored daily for changes in objective signs of CRPS such as normalization of asymmetrical skin temperature, skin color, skin piloerection, sudomotor changes and swelling. After 5 days, infusions will be tapered and the subjects will be weaned from mechanical ventilation.
The pharmacokinetics of ketamine (norketamine/ketamine) and midazolam during the 5-day ketamine-midazolam anesthesia will be studied. A blood sample will be drawn from the arterial line once every 24 hours for analysis at USF. Co-investigator Mark Mclaughlin, PhD and co-investigator Stephanie Weiss will quantify the serum concentrations norketamine/ketamine and midazolam using HPLC columns.
After awakening from anesthesia, all subjects will be assessed for pain relief. Spontaneous pain, hyperalgesia, mechanical allodynia and other associated CRPS signs and symptoms will be determined. The subject will be evaluated for the need for continued hospitalization, CRPS symptoms and the need for continued pain control by the attending physician. If the subject meets hospital release criteria, they will be sent home. If the patient requires continued hospitalization, they will be transferred to the neurosciences floor (9-A) and standard care nursing and medical care will continue until the patient meets discharge criteria.
The protocol calls for a single seven-day inpatient stay, barring any adverse events or complications. The hospital stay consists of five (5) ICU-level days in a coma-induced state, followed immediately by two (2) days of post-therapeutic observation.
At completion of treatment and hospital discharge for each patient a summary of treatment, status and patient condition will be generated and submitted to the TGH ARRC and the USF IRB. Any concerns of these two boards will be discussed with the principal investigator, and if deemed necessary, modifications to the protocol will be submitted for IRB approval and implemented. Pre and post study intervention pain scores and neuropsychological testing (intellectual functioning, attention, memory, processing speed, motor function, and mood) for cognitive or emotional impairment will be carried out. Following discharge from TGH, subjects will be evaluated as an outpatient in the USF Pain Management Clinic for six subsequent and related visits (at 3,6 and then every 6 months for two years). For each of these six visits, the subjects will again undergo the same battery of neurological tests received prior to hospitalization, as well as other diagnostic services and tests related to CRPS symptoms.
Follow-up testing will occur at 3 months, 6 months and 12 months.
3.5 ICU Data Collection Schedule during Study Intervention:
Liver Enzymes and CPK: Days 1, 3 and 5
12-lead ECG with interpretation
Arterial Blood Gases: Every morning
Arterial Blood for Drug Concentrations of Ketamine and Midazolam: Every morning
Chest X-ray: Daily
Riker Sedation/Anesthesia Scale: Every 2 hours
Pre-therapy duplex ultrasound test to verify a normal deep venous system. Use of pneumatic compression device placed on the calves – bilaterally. A venous duplex scan will be performed at the end of the 5-day ketamine treatment procedure to exclude development of DVT.
DVT prophylaxis: A pre-therapy duplex ultrasound test to verify a normal deep venous system. Use of pneumatic compression device placed on the calves – bilaterally. A venous duplex scan at the end of the 5-day ketamine treatment procedure to exclude development of DVT.
Subjects will be monitored for changes in objective signs of CRPS such as normalization of asymmetrical skin temperature, skin color, skin piloerection, sudomotor changes and swelling. The Principal Investigator will document these clinical parameters daily in the morning.
3.6 Neuropsychological Tests
Cognitive Testing
RBANS Test
Rey Auditory Verbal Learning Test
Rey Complex Figure Test
FAS and Category Fluency Test
Ruff figure Fluency Test
Stroop Color Test
Trail Making A and B Test
Motor Function
Finger Tapping Test
Hand Dynamometer Test
Grooved Peg Board Test
Personality and Pain Tests
PAI Test
Multi-Axial Inventory Test
P-3 Test
(A description of each neuropsychological test is provided in APPENDIX 3).
The neuropsychological testing will be conducted prior to the ketamine infusion and at 3 month and 6 month visits. Subjects will be evaluated as outpatients in the Principal Investigator’s office. (MDC Room 2177) Ketamine specific side effects, which include dizziness, muscular weakness, fatigue, and anxiety, will be documented during outpatient visits. The utilization of opioids by subjects (including via the intrathecal morphine pump) for pain control will be documented pre study intervention and for two years post study intervention. Subjects will be monitored for changes in ADLs. They will asked to rate their social and professional rehabilitation as complete, significantly improved, no change, lightly worsened or significantly worsened during outpatient visits for two years.
4.0 Significance of Study
The results from the first series of 10 subjects conducted in Germany suggest that ketamine-midazolam anesthesia can be accomplished safely and is effective in severe generalized CRPS where all other conventional therapies have failed. In the absence of an effective treatment for severe generalized CRPS, ketamine-midazolam anesthesia might become a treatment option that offers significant pain relief over considerable lengths of time. Hopefully, this research will save lives by restoring hope in patients who might otherwise contemplate suicide.
Side effects, mainly infectious complications related to intensive care, can be controlled with antibiotic therapy. No long-term emotional, cognitive or medical complications were noted in any subject treated thus far in Germany. However, due to potentially serious complications, only those subjects that have failed all conventional treatments will be selected.
The future challenges are strategies to maintain the initial treatment success, to define ideal patient profiles, to optimize the timing for treatment and to determine the minimally effective dosage and duration of treatment. In addition, this study might help determine if there is a role for ketamine-midazolam anesthesia in patients with less severe forms of CRPS. For example, would a shorter duration of infusion of high dose ketamine provide a remission in a subgroup of patients with less severe CRPS?
Freeman and other clinical investigators have argued that placebo controlled trials are warranted for the evaluation of novel therapies with more than minimal risk where placebo response is noted to be a significant variable in evaluation of a therapy in the particular disease state [9] This pilot study will serve to support application for a NIH grant by aiming to determine the best primary end point for efficacy in statistically powering of a larger, randomized, active controlled trial. The active control might be an IV analgesic that has a mechanism of action entirely different from ketamine such as fentanyl.
2. Bandyk DF, Johnson BL, Kirkpatrick AF, Novotney ML, Back MR, Schmacht DC. Surgical sympathectomy for reflex sympathetic dystrophy syndromes. J Vasc Surg 35:269-77, 2002.
3. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nature Reviews 2 (2001) 83-91.
4. Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med 343 (2000) 1765-1768.
5. Woolf CJ, Salter MW. Neuronal Plasticity: Increasing the gain in pain. Science 288 (2000) 1765-1768.
6. Kiefer T, Rohr P, Unertl K, Altemeyer K, Grothusen J, Schwartzman R. Ketamine-Midazolam Anesthesia for Intractable CRPS-I. 10th World Congress on Pain, San Diego, CA, August 17-22, 2002
7. 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 5 (2004) 263-275
8. Bruehl S, Harden RN, Galer BS, Saltz S, Bertram M, Backonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M. External validation of lASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain 81 (1999) 147-54.
9. Freeman, T.B., Vawter, D.E, Leaverton, P.E., Godbold, J.H., Hauser, R.A., Goetz, C.G., Olanow, C.W. Placebo controlled surgical trials. N. Engl. J. Med 341 (1999) 988-992.
CO-INVESTIGATORS
CRITICAL CARE MEDICINE
Co-investigator Hans Schweiger, MD, has had a distinguished career at USF as an intensivist. Dr. Schweiger is familiar with the high quality of critical care medicine in Germany.
PAIN MEDICINE
Co-investigator Robert Schwartzman, MD, has been conducting research on CRPS for over 30 years. He was a co-investigator in the German studies. Dr. Schwartzman is Professor and Chairman of Neurology at Drexel University, College of Medicine, Philadelphia, Pennsylvania.
Co-investigator Rafael Miguel, MD, has successfully used the ketamine-midazolam anesthesia technique in a patient on a compassionate basis. Dr. Miguel is a specialist in Pain Management. He is Professor and Interim Chairman of Anesthesiology at the University of South Florida.
CLINICAL PSYCHOLOGY
The protocol requires significant pre and post study intervention neuropsychological testing (intellectual functioning, attention, memory, process speed, motor, and mood). Co-investigator Richard Hoffman, PhD is a Clinical Psychologist who has treated hundreds of patients with CRPS. Included with this submission is a DVD of Dr. Hoffman treating children with CRPS. A shorter version of the DVD is available on the Internet at:
Although there have been no large-scale studies on the incident of CRPS in children, some generalizations can be made about the children who get this condition. Published case studies indicate that the incident of CRPS increases dramatically between 9 and 11 years old, and it is found predominantly in young girls. Teenagers have been candidates for 5-day infusion of ketamine in the German studies. One of those children was interviewed by ABC NEWS: [APPENDIX 5]
Lindsay Wurtenberg, 14, says her life was turned upside down by CRPS after she was bitten by a spider. She ended up with such crippling pain that she needed a wheelchair. Six months after completing the 5-day course of ketamine-midazolam anesthesia in Germany, her mother told ABC NEWS that the treatment had given her daughter’s life back.
Co-investigator Rob Nickeson, MD, is a Pediatric Rheumatologist at USF, with a special interest in CRPS in children. He will closely monitor the study from the perspective of possible enrollment of subjects less than eighteen years of age in the future.
CLINICAL RESEARCH
Co-investigator Thomas Freeman, MD., is internationally renowned for his work in the area of high risk brain research. He was the first in the world to prove that fetal grafts survive in the human brain. He has advocated for the use placebo and/or active controls in studies with more than minimal risk in the New England Journal of Medicine. [9] Such trial designs are now accepted by the FDA, NIH, and in Europe. Dr. Freeman has received extensive funding from NIH to support his work. At USF, he is Professor of Neurosurgery and Medical Director, Center for Aging and Brain Repair.
PHARMACOKINETICS
Co-investigator Mark McLaughlin, PhD will quantify the serum concentrations norketamine/ketamine and midazolam. Dr. McLughlin is Professor of Chemistry at USF and also Professor of Interdisciplinary Oncology and a faculty member in the Drug Discovery program at Moffitt.
CONSULTANTS
Srinivasa N. Raja, MD, is Professor of Anesthesiology and Director of Pain Research in the Pain Division in the Department of Anesthesiology and Critical Care Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr. Raja’s research efforts are aimed at understanding the peripheral and central mechanisms of neuropathic pain and in determining the role of the sympathetic nervous system in mediating or maintaining chronic pain states. He is also conducting clinical trials to develop better pharmacological strategies for the treatment of neuropathic pain states such as complex regional pain syndromes. He is on the Editorial Board of ANESTHESIOLOGY.
Dennis F. Bandyk, MD, is Professor of Surgery and Director of the Division of Vascular and Endovascular Surgery at the University of South Florida. He is
experienced in the condition of CRPS and has performed surgical sympathectomies for intractable CRPS found to be sympathetically-maintained based on a series of diagnostic/therapeutic sympathetic blocks.
Dr. Bandyk reviewed the above research protocol and made several recommendations to minimize risk to volunteers. He recommended a bed that is available at TGH that rotates automatically from side to side and head up to down to prevent pneumonia.
In addition, for DVT prophylaxis:
He recommended a pre-therapy duplex ultrasound test to verify a normal deep venous system.
Use of pneumatic compression device placed on the calves - bilaterally
A venous duplex scan at the end of the 5-day ketamine treatment procedure to exclude development of DVT.
Dr. Bandyk wrote, “I believe this is an important clinical study for a rare medical condition in patients who are completely disabled by the CRPS condition”.
Patricia Schuster, R.N., has served patients in the ICU at Tampa General Hospital for many years. She has a special interest in addressing the needs of patients in the ICU. Ms. Schuster has designed and implemented a case cart that addresses the comfort needs of patients in the ICU.
DATA SAFETY MONITORING BOARD
Oscar A. de Leon-Casasola, MD
Chief, Pain Medicine Department of Anesthesiology and Pain Medicine Roswell Park Cancer Institute, Buffalo, New York
716 845-3240
Professor of Anesthesiology, University at Buffalo School of Medicine and Biomedical Sciences
Dr. de Leon-Casasola is licensed in New York State and is board-certified in Anesthesiology, Critical Care Medicine and Pain Medicine.
Dr. de Leon-Casasola’s research interests include advances in analgesic therapy; physiology and pharmacology of epidural opioids, perioperative surgical outcomes, thoracic and cardiac anesthesia, acute pain control and chronic cancer pain.
Dr. de Leon-Casasola has authored or co-authored 115 journal articles, abstracts and book chapters. He serves as an Associate Editor for the Latin American Journal of Pain, Argentinian Journal of Anesthesiology, The Journal of the Spanish Society of Pain, and the Clinical Journal of Pain. He also is Editor-in-Chief of Techniques in Regional Anesthesia and Pain Management.
Giancarlo Barolat, MD
Director of the Barolat Institute, Denver, Colorado
(303) 865-7800 (Office)
(720) 220-9761 (Cell)
Dr. Barolat was President of the International Neuromodulation Society and is on the Board of the American Neuromodulation Society and on the Editorial Board of the Journal, Neuromodulation. He is currently Director at large of the International Neuromodulation Society.
Dr. Barolat practiced at Thomas Jefferson University Hospital from 1985 to 2004 as Professor of Neurosurgery and Director of the Division of Functional Neurosurgery. Dr. Barolat has extensive experience with surgical spine procedures. As such, he has performed hundreds of complex spine operations. He has also been involved in the surgical management of intractable seizures through implantation of vagus nerve stimulator devices.
Dr. Barolat is also one of the world leaders in the area of neuro-implantable technologies for the management of pain and motor disorders. He is one of the pioneers of spinal cord stimulation for spasticity and pain management. His practice is one of the largest in the country, with national and international referrals. He has authored of over 60 medical articles and book chapters. He has lectured extensively nationally and internationally.
Timothy R. Lubenow, M.D. Professor, Department of Anesthesiology, Rush Medical College Medical Director, Rush Pain Center Director, Section of Pain Management, Rush University Medical Center, Chicago, Illinois
Dr. Lubenow’s special interests include: Complex Regional Pain Syndrome (CRPS) Continuous Epidural Narcotic-Anesthetic Solutions for Postoperative Analgesia Epidural infusion of Bupivacaine Clonidine Solution for the Management of CRPS Cancer Pain Implantable Drug Infusion Pumps Spinal Cord Stimulation
(312) 942-2043
(630) 234-4938
Robert Walker, MD,
Associate Professor, Department of Internal Medicine
Director of Division of Ethics and Humanities
University of South Florida, Tampa, Florida
Dr. Walker’s current duties include directing the first and third-year medical school courses in medical ethics, chairing the ethics committee at Tampa General Hospital, staffing the ethics consultation service at Tampa General and directing a clinical team at Hospice of Hillsbourough. Dr. Walker’s articles have appeared in the Journal of the American Medical Association, the Journal of General Internal Medicine, the Archives of Internal Medicine, and Academic Medicine.
HOSPITAL EXPENSES
Dr. Hans Schweiger has summarized the basic costs that will be involved for a five (5) day admittance to the Intensive Care Unit and subsequent care at TGH. These charges will include but may not be limited to the following:
Per Diem charge for ICU Admittance
TGH Pulmonary service: ICU ventilator and daily respiratory consults
IV medications:
Ketamine infusion
Midazolam infusion
Antibiotics
Bronchodilators
Vaso-active agents for the treatment of hyper/hypotension
Anesthesia service for intubation, placement of IV lines, extubation and
critical care
Enteral feeding
IV fluids and electrolyte infusions
Labs:
Liver enzymes and creatinine phosphokinase (CPK): Days 1, 3 and 5
Arterial blood gases: Every morning
Arterial blood for drug concentrations
Labs will be drawn daily to monitor the subject.
Chest X-ray: Daily
Initial KUB X-ray to confirm enteral tube placement
Baseline ECG and Cardiology interpretation
Tampa General Hospital has outlined the following financial obligations;
Prior to scheduling for hospital admission, an appointment will be made by the subject with a TGH Financial Counselor to arrange for payment of fees. This person can be reached at: 813 844-4738
The subject must be prepared to pay TGH $27,000. In the event that study related services exceed gross charges of $70,000, the subject will be required to pay TGH at a rate of 35% of gross charges exceeding $70,000.
Payment of $27,000 must be received in the form of cash, certified check or electronic funds transfer prior to scheduling hospital admission.
If the subject changes their mind after paying the $27,000, but prior to admission to the hospital, the subject will receive a full refund of any amounts paid in advance except for a processing fee of $50.
If treatment is stopped before $27,000 in charges have been incurred, the subject will be eligible to receive a refund of the initial payment less the gross charges that have been incurred.
All necessary supplies and drugs associated with these procedures will be included in study charges
Payments made to TGH are for only hospital expenses. Physician(s) services/fees will be billed by and separately payable to those physician(s). These could include Ruffalo, Hooper & Associates, Radiology Associates, etc.)
During the scheduling process, standard hospital admission processes will be completed.
Additional study related visits may incur travel and inconvenience costs.
The Department of Anesthesiology will cover costs related to research data management and publication costs.
While the IRB and others assess whether the study should be approved, parallel efforts will continue concerning ways to avoid, control, minimize, cover, etc. the various costs of the study. Co-investigators will be asked to waive their professional fees for clinical services.
The Principal Investigator plans to provide documentation to the patient’s commercial insurer in an effort to obtain financial assistance for the subjects.
There is no animal model of CRPS on which to apply for funding in the clinical domain. There is insufficient clinical data to apply for funding clinically. The real ethical question is: is it more ethical to charge patients or to not do the study (i.e. not even offer them the chance to participate?). At this stage of development of this particular study, the focus is on providing all the information available to assist IRB members and others to fully assess the risks and benefits of the study, and to assess whether all reasonable steps have been taken to minimize risks to participants consistent with sound research design and to protect participants from possible vulnerabilities.
APPENDIX
Proposed Experimental Revision Of CRPS Diagnostic Criteria.
Riker Sedation-Agitation Scale (SAS).
Descriptions of the Neuropsychological Tests.
Reference Articles.
Internet Material.
DVD Production : Ketamine Research From A Volunteer’s Perspective.
Video Information Release Agreement
Neuropsychological Data on Nine Subjects
APPENDIX 1
Proposed Experimental Revision
Of CRPS Diagnostic Criteria
Proposed New CRPS Research Criteria [Bruehl, Harden, Galer, et al. Pain 1999;81 :147-154]
(1) Continuing pain which is disproportionate to any inciting event
(2) Must report at least one symptom in each of the four following categories
Sensory: reports of hyperesthesia
Vasomotor: reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry
Sudomotor/edema: reports of edema and/or sweating changes and/or sweating asymmetry
Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
(3) Must display at least one sign in two or more of the following categories:
Vasomotor: evidence of temperature asymmetry and/or skin color changes and/or. asymmetry
Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating asymmetry
Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
APPENDIX 2
Riker Sedation-Agitation Scale (SAS)
Score and Descriptor
7 Dangerous Agitation: Pulling at IT tube, trying to remove catheters, climbing over bedrail, striking at staff, thrashing side-to-side
6 Very Agitated: Requiring restraint and frequent verbal reminding of limits, biting ETT
5 Agitated: Anxious or physically agitated, calms to verbal instructions
4 Calm and Cooperative: Calm, easily arousable, follows commands
3 Sedated: Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands but drifts off again
2 Very Sedated: Arouses to physical stimuli but does not communicate or follow commands, may move spontaneously
1 Unarousable: Minimal or no response to noxious stimuli, does not communicate or follow commands
Guidelines for SAS Assessment
1. Agitated subjects are scored by their most severe degree of agitation as described
2. If patient is awake or awakens easily to voice ("awaken" means responds with voice or head shaking to a question or follows commands), that's a SAS 4 (same as calm and appropriate might even be napping).
3. If more stimuli such as shaking are required but patient eventually does awaken, that's SAS 3.
4. If patient arouses to stronger physical stimuli (may be noxious) but never awakens to the point of responding yes/no or following commands, that's a SAS 2.
5. Little or no response to noxious physical stimuli represents a SAS 1.
This helps separate sedated subjects into those you can eventually wake up (SAS 3), those you can't awaken but can arouse (SAS 2), and those you can't arouse (SAS 1).
References
1. Prospective evaluation of the sedation-agitation scale in adult ICU patients. Crit Care Med 1999; 27:1325-1329.
2. Assessing sedation in ventilated ICU patients with the bispectral index and the sedation-agitation scale. Crit Care Med 1999; 27:1499-1504.
3. Confirming the reliability of the Sedation-Agitation-Scale in ICU nurses without prior experience in its use. Pharmacotherapy 2001; 21:431-436.
4. Validating the Sedation-Agitation Scale with the bispectral index and visual analog scale in adult ICU patients after cardiac surgery. Intensive Care Med 2001; 27:853-858.
APPENDIX 3
Descriptions of the Neuropsychological Tests
NOTE: The Florida Board of Psychology prohibits distribution of test materials to a non-psychologist. However, any or all of the test materials may be forwarded to the psychologist of the IRB’s choosing. All tests selected are standard and well accepted, frequently used assessment indices.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
The RBANS is a brief, individually administered test that helps determine the neuropsychological status of adults’ ages 20-89 years who have neuropsychological injury or disease such as dementia, head injury, or stroke. The test is a timed exercise of “connecting the dots” that helps assess psychomotor skills. The test is designed for use in research studies by non-psychiatric personnel that assesses patient performance in five domains: Immediate Memory, Delayed Memory, Visuospatial Ability, Attention and Language.
Rey Auditory Verbal Learning Test (RAVLT)
The Rey Auditory Verbal Learning Test (RAVLT) is a very widely used neuropsychological assessment instrument. It is a brief, easily administered test of verbal learning that uses a fixed order word list. The RAVLT was among the first word list learning tests that were available and it has gained broad acceptance. Its development originated with Andre Rey (1941, 1958), Studies have been done with versions in English, Hebrew, German, Italian, Dutch, and, of course, the original French. Recently researchers have expanded the test’s utility, providing parallel forms, improved and expanded norms, and additional information about the test’s validity.
A list is read to the patient at the rate of one word per second. The patient is then asked to recall the words. The examiner writes down the words in the order they are given. After the patient indicates that he or she can recall no more words the examiner says he is going to read the list again. When he stops the patient is to tell the examiner as many words he or she can remember, including words that were said the first time.
Repeat the instructions as needed for Trials III through V. After Trial V, present List B after giving appropriate instructions indicating the examiner is going to read a second list of words with the patient then saying back as many of the words on the second list that he or she can remember. The order of the words does not matter.
After recall for this list is completed, Trial VI is administered. For this trial, the patient is asked to again recall List A, but the list is not read again. The patient is instructed to tell the examiner all the words that he or she can remember from the first list
Rey Complex Figure Test
The Rey Complex Figure Test and Recognition Trial (RCFT) involves an abstract two dimensional geometric shape and includes a copy trial, a three minute immediate recall trial, a thirty minute delayed recall trial, and a recognition trial with this last aspect administered immediately after the delayed recall trial. The recognition trial presents twelve of the eighteen scoring elements of the complex figure stimulus along with twelve designed to serve as foils. The respondent simply indicates which items are recognized from the earlier copy trial.
FAS and Category Fluency Test
The Letter and Category Fluency Tests are done as measures of executive function. Here the patient is asked to name as many words as he or she can that begin with the letter F but are not proper names of people and places and not simply the same word with different endings. Scoring is based on appropriate responses in sixty seconds. The same procedure is used for the letters A and S. The category fluency measure is similar but this time the patient gives the names of animals, independent of the letter they start with. This measure is aimed at assessing inductive divergent thought processes and is alleged to be particularly sensitive to left frontal lobe function.
Ruff Figural Fluency Test
The Ruff Figural Fluency Test consists of five parts with each presenting a different stimulus pattern of dots. The task is to draw as many unique designs as possible within a sixty-second time period so long as at least two lines are used.
Stroop Color and Word Test
This test presents three pages with each structured in five twenty “word” columns with the words red, green, and blue printed down the page in a random order. This is then followed by a second and similar page except x’s colored in red, green, and blue comprise the columns. The third page is similar but this time the words are printed down each column with this being complicated by the fact that the word is never printed in the color that it describes.
Trail Making A and B Tests
The Trail Making Test is composed of two Parts, A and B. Part A consists of 25 circles printed on a white sheet of paper. Each circle contains a number from 1 to 25. The subject’s task is to connect the circles with a pencil line as quickly as possible, beginning with the number 1 and proceeding in numerical sequence. Part B consists of 25 circles numbered from 1 to 13 and lettered from A to L. The task in Part B is to connect the circles, in sequence, alternating between numbers and letters. The score represents the number of seconds required to complete each part.
Finger Oscillation Test
This test, which uses a specially adapted manual tapper, is a measure of finger-tapping speed. The precise characteristics of this apparatus (tension and angle of the arm, position of the board, etc.) have been maintained to ensure comparability of data between subjects and between investigators.
Measurements are made first with the subject using the index finger of the dominant hand. Next, a comparable set of measurements is obtained for the non-dominant hand. Five consecutive 10-second trials are given to each hand with the hand held in a constant position in order to elicit movements of only the finger rather than the whole hand and arm.
Hand Dynamometer
The subject’s grip strength is evaluated by obtaining two measurements from each upper extremity, in alternating sequence beginning with the preferred hand. The standard procedure requires the subject to extend his/her arm with the dynoamometer pointed toward the floor and to squeeze the handle of the dynamometer as hard as possible.
Grooved Pegboard Test
The unit consists of 25 holes with randomly positioned slots. Pegs, which have a key along one side, must be rotated to match the hole before they can be inserted. This is done first with the dominant hand, then the non-dominant hand. The subject is told to complete the task as quickly as possible. The pegs must be put in the board in the exact order and in the correct direction as demonstrated by the examiner.
Personality Assessment Inventory
This objective inventory of adult personality assesses psychopathological syndromes and provides information relevant for clinical diagnosis, treatment planning, and screening for pathology. The PAI’s 344 items form 22 scales that cover the constructs most relevant to a broad-based assessment of mental disorders; 4 validity scales, 11 clinical scales, 5 treatment scales, and 2 interpersonal scales.
Mutliaxial Pain Inventory (MPI)
The MPI is comprised of three sections and contains a total of 52 questions (61 in the revised version) that are used to create scores on 13 separate scales that were empirically derived from factor analytic studies (Kerns et. al., 1985).
It contains five particularly important dimensions which are 1) pain severity and suffering, 2) pain related life interference including interference with family and marital function, work, and work related activities and social-recreational activities, 3) perceived life control, incorporating conceived ability to solve problems and feelings of personal mastery and confidence, 4) dimension of affective distress, and 5) appraisal of support received from spouse, family, and significant others.
P-3
The P-3 is a 44 item, self-report, multiple-choice instrument designed to identify patients who are experiencing emotional distress associated with primary complaints of pain. The P-3 is appropriate for patients suffering pain as a result of disease, illness, or physical trauma (e.g., motor vehicle accidents and work-related injuries).
