August 2010: CRPS Clinical Trials, Part One

I'm going to steal a moment away from ManorFest activities to update the blog on CRPS clinical trials that are currently accepting new volunteers.

I could use the rest.  We opened ManorMaze to the public this year and, let me tell you, if you have the bad luck to draw Rescue Duty, your dogs are gonna bark.

Written records testify that Marlinspike Hall's Manor Maze dates back as far as 1067.  Cretan Manor Jardinier Ajax Mimnermus transplanted the first thousand English Boxwood in a highly original serpentine pattern that twisted and turned over a particularly hilly, 25-acres bit of Haddock ancestral land.  Twenty-two generations later, the Mimnermus Family still holds the prestigious position of JardinierOfficiel  to the Marlinspike Manor Maze.  A proud and loyal clan, they guard our horticultural secrets with ferocity.  Both little red-headed, freckled Xenophon and his more swarthy third cousin Clinias are currently in training:  One will assume the mantle of Jardinier Officiel;  The other will be offered a lifetime position on the Landscape Crew.  Everyone wins!

Anyway, you can imagine how huge and complex this labyrinth is today, as one Mimnermus after another has judiciously added plantings, making the maze both more elegant and more challenging to exit.  (Though sometimes, I'd swear that it has a life all its own, its paths shifting in the night like sand in a storm -- but I can't prove anything.)

CRPS renders ManorMaze Rescue Duty very tiring, and my wheelchair has lost its charge more than once, over the years, leaving me to call for my own rescue. It's a restful place in which to be trapped, though, as our Illustrious Gardeners have created little enclaves of delight within -- squares dedicated to aromatherapy, curlicued paths lined with delicious mint and sweet clovers! 

[Thank the Good Lord, however, that my chair has never lost power in The Marsh installed by Xenophon's paternal grandmother, Nausicaa, who loved the dramatic tension of taming a wild landscape.  For The Marsh, she took as her inspiration Tolkien's Dead Marshes of Middle Earth.  Being a patriotic soul, Tête-de-Hergéenne through and through, she wanted to memorialize those lands that served as battlefield during the Sixth Uprising, and modeled her marsh on his Mere of Dead Faces that border one of the entrances to Mordor.  Years ahead of her time, she achieved the underwater lighting effect by solar cells and advanced the field of horticultural photovoltaics by decades.  Captain Haddock's great uncle had the forsight to underwrite her studies in Moscow with Aleksandr Stoletov -- where it is our good fortune that she witnessed the creation of the very first solar cell and was able to make such an apt application of the invention!]

Yes, I remember my promise to run down those CRPS Clinical Trials currently open -- I've not forgotten.  I've taken the liberty, as well, of excluding some studies well past their Estimated Primary Completion Date.

You will notice that some of the trials proceed from dated information. Hard science is working hard to catch up after years of studied neglect.  A wonderful resource for all of us is the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA). A good place to start your research, it is a rock of stability on the internet -- which is my way of saying that you need to take care and be very frugal with your trust when dealing with CRPS information online.  There is no lack of people who want to make easy money off of people who are in pain and sleep-deprived, who are sometimes desperate for a "cure" or treatment of any kind.

The International Research Foundation for RSD / CRPS is another dependable site, but not necessarily where beginning researchers may want to start.  I do recommend familiarity with the Clinical Practice Guidelines for Reflex Sympathetic Dystrophy (Third Edition) which are available there.  If your doctors are unfamiliar with them, consider providing them with the link, or print out a copy.

Dr. Anthony Kirkpatrick opened the RSD / CRPS Treatment Center and Research Institute in Tampa just a few years ago -- the only such dedicated institute in the world.  3-day IV Ketamine treatments are available there, as well as being a site that coordinates with ongoing Ketamine Coma research in Mexico.  (Dr. Robert Schwartzman, professor and chairman of neurology at the MCP Hahnemann School of Medicine in Philadelphia helps to coordinate Ketamine Coma research in Germany.)

Dr. Schwartzman has an enlightened grasp of what day-to-day CRPS is like, and is famous for exhortations to stay involved with life -- which reminds me, I'm back on ManorMaze Rescue Duty tonight, so I'd better rest up.  I'm in charge of kerosene-soaked torches, a plum assignment.


**  Graded Exposure (GEXP) in Vivo Versus Physiotherapy in Complex Regional Pain Syndrome Type I (CRPS-I)
This study is not yet open for participant recruitment.

Brief Summary Background:  Research on the treatment of CRPS-I, as described in the Dutch evidence based treatment guidelines (Richtlijn Complex Regional Pain Syndrome type I, 2006), mainly showed improvement at the level of pain and coping with pain. Only little improvement in functional restoration was found. Research in other pain populations such al neck- and back-pain patients has shown that pain related fear contributes to the development of functional disability. GEXP in vivo which aims on systematically reducing fear of movement, shows promising results in CRPS-I patients (de Jong et al., 2005).

Objective:  The objective of the proposed project is to compare the effectivity of GEXP in vivo with that of standardized physiotherapy in CRPS-I patients with pain related fear.

Design:  The study concerns a single blinded, single center, randomized clinical trial. The treatment will be preceded by two pre-measures. After treatment there will be one post-measurement and 3, 6 and 12 month follow-up measurements.

Population:  The study population will consist of chronic CRPS-I patients between 18 and 65, with pain related fear (PHODA-LE-score ≥ 35 and PHODA-UE-score ≥ 32).

Intervention:  The two interventions that will be compared are GEXP in vivo (de Jong et al., 2005) and standardized physiotherapy according to the protocol of Oerlemans, Oostendorp, de Boo en Goris (1999). The GEXP in vivo comprises 17 sessions of one hour, the physiotherapy treatment of 34 sessions of 30 minutes. Both treatments will be given over a period of 17 weeks.

Inclusion Criteria:

1.Diagnosis CRPS-I according to IASP criteria.
2.Pain related (PHODA-LE-score ≥ 35 and PHODA-UE-score ≥ 32)
3.Age between 18 and 65.
4.Rehabilitation treatment has been indicated.

Exclusion Criteria:
1.Pregnancy.
2.Insufficient fluency in Dutch.
3.Generalized pain syndrome.
4.Dystonia.
5.Sympathectomy of the affected extremity.
6.Psychopathology
7.Involvement in a claim regarding the disease.
8.Substance abuse.
9.Symptoms on both upper or both lower extremities.
Principal Investigator: Dr. M. Goossens, Maastricht University
Contacts:
ICMJE Contacts:
Tim Gard, M.Sc. +31 43 3881594 T.Gard@dmkep.unimaas.nl
Marielle Goossens, Dr. +31 43 3881477 M.Goossens@dep.unimaas.nl


**  Study of Proteins Associated With Complex Regional Pain Syndrome

The etiology of Complex Regional Pain Syndrome (CRPS) is unknown but a patient typically presents with a triad of clinical findings: sensory abnormalities, perfusion abnormalities and alterations in motor function. Since some of these findings are seen in the other disease states, the diagnosis is often not clear. A response to a sympathetic ganglion block (stellate or lumbar) is also suggestive of the disorder. However, there is no definitive diagnostic test for CRPS. Experience has shown that early aggressive treatment improves the prognosis. Therefore, tests that facilitate the early diagnosis would have important clinical implications.

Advances in laboratory techniques allow analysis of clinical samples to identify protein or patterns of protein changes associated with a disease state. Patients suffering with CRPS who are currently seen in a pain clinic will be asked to participate in this study. The subjects will complete a brief symptom survey, be examined by a co-investigator to document sensory, temperature and trophic changes, and have a blood sample collected for protein and gene expression (RNA) analysis. Blood samples from age-matched controls will be collected from non-CRPS patients. Fifty patient samples collected from each group will be analyzed and used to teach the diagnostic software and an additional 20 samples (10 controls, 10 CRPS patients) will be used to validate diagnostic accuracy.

Brief Summary: This study will try to learn more about complex regional pain syndrome, or CRPS (previously known as reflex sympathetic dystrophy, spreading neuralgia, and sympathalgia), by examining the release of small proteins in the blood of patients with this condition. Patients with CRPS usually have three types of symptoms:

•Sensory abnormalities - increased sensitivity to pain or a painful reaction to a harmless stimulus
•Perfusion abnormalities - alterations in blood flow, temperature abnormality, swelling, decrease or increased nail growth, and hair and skin changes
•Motor abnormalities - weakness, guarding (Holding the limb in such a fashion that it minimizes accidental or intentional contact from possible sources of pain), and atrophy (wasting)

The cause of CRPS is unknown, and there are no definitive diagnostic tests for the condition. Because early treatment improves the prognosis of CRPS, a test that enables early diagnosis would be important for optimal medical management. The findings of this study may contribute to the development of such a test and possibly new drug treatments.

Additional Reading/Publications:
Cancer proteomics: from biomarker discovery to signal pathway profiling.
Molecular classification of cutaneous malignant melanoma by gene expression profiling.
Value of autonomic testing in reflex sympathetic dystrophy.

Study Sponsor: National Institute of Nursing Research (NINR)
Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Contact: TTY 1-866-411-1010

Original Primary Outcome Measures: To determine the hepatic progression free survival of pts with melanoma metastatic to liver in pts treated with percutaneous hepatic perfusion of melphalan with subsequent venous hemofiltraion (PCP) versus best alternative therapy. 
HISTORICAL VERSIONS OF THIS STUDY


** The Effect of Transcranial Direct Current Stimulation (t-DCS) On the P300 Component of Event-Related Potentials in Patients With Chronic Neuropathic Pain Due To CRPS or Diabetic Neuropathy
This study is not yet open for participant recruitment.'
Intervention:  Device: TDCS/sham procedure on five consecutive days  

The latency and amplitude of P300, subjective pain intensity, and pain thresholds for tactile and thermal stimuli will be determined at before and 15 min and 120 min after the 1st and 5th tDCS/sham procedure, To receive tDCS/sham treatment, two electrodes will be placed on the patient´s skull (for details see section Methods) and the patient will rest for 5 min. After that, the patient will receive 20 minutes of 2 mA tDCS/sham. Subjective pain intensity, and pain thresholds for tactile and thermal stimuli will be determined before-, 15 min after and 120 min after each tDCS/Sham procedure. At the 1st and 5th tDCS/Sham session, the latency and amplitude of P300 will be determined before-, 15 min after and 120 min after the tDCS/sham procedure.

Inclusion Criteria:
•Affected an upper limb or lower limb
•CRPS-related neuropathic pain with a score for "worst pain in the last 24 hours" ≥4 on a numeric scale 0-10
•Must meet CRPS diagnostic criteria (Sandroni et al., 2003) with the application of the IASP criteria as adapted by Bruehl et al (1999):
1.Continuing pain which is disproportionate to any inciting event,
2.Must report at least one symptom (symptoms here are reports by subject) in each of the four following categories: sensory, vasomotor, sudomotor/edema, motor/trophic;
3.Must display at least one sign (signs here refer to objective observation/testing) in in each of the four following categories: sensory, vasomotor, sudomotor/edema, motor/trophic;
•tDCS naïve
•OR
•Affected an upper limb or lower limb
•Diabetes-related neuropathic pain with a score for "worst pain in the last 24 hours" ≥4 on a numeric scale 0-10
Exclusion Criteria:

•Serious health problems other than CRPS or Diabetic Neuropathy (e.g. uncontrolled hypertension, uncontrolled diabetes)
•Pain/painful conditions unrelated to CRPS or Diabetic Neuropathy
•Pregnancy
•History of seizures/epilepsy
•Implanted device (e.g. pacemaker)
•Active illegal drug/alcohol abuse
•Unable to follow directions or complete tools in English
•Previous exposure to tDCS stimulation

Contact: Pesach Shvartzman, MD 972-8-6477429 spesah@bgu.ac.il  [ISRAEL]
Prof Pesach Shvartzman, Ben-gurion Univeraity of the Negev
Soroka University Medical Center


** Intravenous Immunoglobulins in Complex-regional Pain Syndrome
This study is not yet open for participant recruitment.
The purpose of this study is to determine whether intravenous immunoglobulins are effective in the treatment of complex-regional pain syndrome.



CRPS, a chronic pain syndrome associated with trophic disturbances is a frequent complication after limb trauma. More than one third of the CRPS will continue to chronic disease including loss of function in one limb. Some reports implicate an autoimmune pathogenesis of CRPS. Especially the finding of autoantibodies against peripheral neurons and successful treatment in single cases provide evidence for a possible successful treatment of CRPS with intravenous immunoglobulins (IvIg). Therefore IvIg may be an important anti-inflammatory treatment to prevent severe chronification of CRPS. Since IvIg is mainly effective in B-cell-mediated autoimmune diseases, autoantibodies against autonomic neurons and the concentration of B-cell activating factors BAFF and APRIL will be measured in the course of the study.

Intervention: intravenous immunoglobulins

0.36-0.44g/Kg IvIg intravenous, 3x, every 4 weeks
Other Name: Gamunex 10%

Inclusion Criteria:
•CRPS 1 (according to the IASP criteria) between 6 weeks and 6 months after diagnosis

•skin temperature of the affected side equal or higher than on non-affected side
•no change of the analgetic or co-analgetic medication within the last 10 days

Exclusion Criteria:
•Immunosuppressive or immunomodulatory treatment within the last three months
•CRPS previously treated with sympathetic block, lidocaine patch, local DMSO, spinal cord stimulation, intrathecal drug administration
•Known immune-mediated neuropathy (CIDP, MMN, MADSAM)
•Selective IgA-deficiency
•Severe heart disease
•Tumour disease in the last 5 years
•Allergy against Gamunex 10%
•Chronic renal disease Vaccination with live vaccine within the last three months
•Member of another clinical trial within the last 3 months

Responsible party:  Franz Blaes, MD, Dept. of Neurology, Justus-Liebig-University, Am Steg 14, 35392 Giessen, Germany -- University of Giessen
Contact: Franz Blaes, MD +49-641-99(0) ext 45357 franz.blaes@neuro.med.uni-giessen.de
Contact: Marlene Tschernatsch, MD +49-641-99(0) ext 45400 marlene.tschernatsch@neuro.med.uni-giessen.de

Related publications:
Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen.
Intravenous immunoglobulin response and evidence for pathogenic antibodies in a case of complex regional pain syndrome 1.

**  Neurotropin to Treat Chronic Neuropathic Pain
Brief Summary: This study will examine the effectiveness of the drug neurotropin in treating chronic pain after injury to a limb or a large nerve.


Two groups of patients will participate in this study: patients with complex regional pain syndrome type 1, or CRPS-I (also called reflex sympathetic dystrophy) and patients with complex regional pain syndrome type 2, or CRPS-II. CRPS-I is pain that develops after relatively minor injury to an arm or leg, but lasts much longer and is much more severe than would normally be expected. CRPS-II is pain resulting from injury to a large nerve. Candidates will have a history and physical examination, blood tests, and electrocardiogram. Participants will undergo the following tests and procedures:

Patients with CRPS I and II will receive an individualized regimen of physical therapy and standard treatment to control their pain. In addition, they will receive neurotropin or placebo tablets for 5 weeks, then no trial medicine for at least 1 week, and then the other trial drug for the next 5 weeks. That is, patients who took placebo the first 5 weeks will take neurotropin the second 5 weeks and vice versa. Neither the patients nor the doctors will know who received which drug during the two intervals until the study is over. Patients will complete questionnaires about their pain, quality of life, and ability to perform daily living activities. They will have various tests to measure pain (such as sensitivity to heat and cold, to an electric current, to a mild pin prick, etc.); to provide information about changes in their condition (such as tests of range of motion of joints and limb size); to measure blood circulation and sweating in the arm or leg (such as measurements of blood flow to the limb, skin temperature, and sweat production), and other procedures.

Detailed Description:  Patients with Reflex Sympathetic Dystrophy (RSD), re-named Complex Regional Pain Syndrome, type I (CRPS-I), have chronic, post-traumatic pain that spreads beyond the distribution of any single peripheral nerve without evidence of major peripheral nerve damage. A similar disorder, Causalgia, re-named CRPS-II, presents with clear evidence of nerve injury. No successful drug treatment exists for these disorders. Neurotropin is a non-protein extract of cutaneous tissue from rabbits inoculated with vaccinia virus. Neurotropin has been used extensively in Japan to treat RSD and other painful conditions; however, the drug has not undergone clinical therapeutic testing in the United States. This protocol is to carry out double-blind, placebo-controlled, crossover studies about clinical efficacy of Neurotropin for acute pain in dental outpatients and for chronic pain in outpatients with CRPS-I or II.

Related publications:
Reflex sympathetic dystrophy: changing concepts and taxonomy
IASP diagnostic criteria for complex regional pain syndrome: a preliminary empirical validation study. International Association for the Study of Pain.
External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain
 
Responsible Party: Raymond A. Dionne Jr., D.D.S./National Institute of Nursing Research, National Institutes of Health

Study Sponsor: National Institute of Nursing Research (NINR)
Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

**  Pregabalin Versus Placebo as an Add on for Complex Regional Pain Syndrome (CPRS) of the Upper Limb Managed by Stellate Ganglion Block (The PREGA Study)

Intervention:
•Drug: Pregabalin

Dose of 150mg/day divided in two doses. Increased to 300mg/day then to 600mg/day, always divided in two doses for the day.
Other Name: Lyrica
•Other: Placebo

Study Arms / Comparison Groups
•1: Experimental
Pregabalin group is made up of 20 patients. Patients will receive 150mg/day in two divided does. The patients will be assessed weekly and the dose can be increased to 300mg/day, if the patient does not report any decrease in pain. The following week the dose may be increased to 600mg/day if once again the patient reports no decrease in pain. This is also the maximum permissible does that will be given to the patient. If patient reports any side effects then the dose can be decreased once. The time period of 2 to 5 weeks will be the dose adjustment period. After which the drug maintenance period extends from week 5 to 12. All doses will be given in two divided doses/day.
Intervention: Drug: Pregabalin

•2: Placebo Comparator
Ten patients will be be in the placebo group.

Related publication:  Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.

Responsible Party: Dr. Norman Buckley, MD, McMaster University/Hamilton Health Sciences

Study Sponsor:  Hamilton Health Sciences
Collaborators: Pfizer

**  Use of Compression Glove to Prevent Complications After Distal Radius Fractures: a Randomized Controlled Trial

Brief description:  Distal radius fractures (DRF) are the most common type of fracture in the human body, and a large proportion of DRFs result in complications. Previously proposed preventive strategies have questionable efficacy and may impose additional risks on the patient. Because many complications secondary to DRFs are associated with excessive swelling, a prophylactic means for edema reduction could dramatically reduce morbidity among this population. A compression glove is a non-invasive, non-pharmacological way to reduce edema. Previous studies have confirmed its utility in edema reduction after hand trauma and among patients with chronic inflammatory conditions, but none have sufficiently investigated the application to patients with DRF, a population in which this intervention could have a large impact. The investigators propose a RCT to evaluate use of a compression glove during recovery among patients who have sustained an unstable DRF. The investigators hypothesize that patients who wear a compression glove after a DRF:

•Will experience less edema
•Will demonstrate greater functionality
•Will recover more quickly
•Will have lower incidence rates of carpal tunnel syndrome
•Will have lower incidence rates of complex regional pain syndrome
Study arms:
•Compression glove: Experimental

Patients in this group have a compression glove incorporated into their splint for 2 weeks post-op, and wear a glove underneath their cast for 3 weeks. The patient then wears the glove at night after cast removal.
Intervention: Device: Compression glove
•Control: No Intervention
Patients in this group undergo standard recovery procedures. This includes a splint worn for 2 weeks post-op, followed by a short arm cast worn for the next 3 weeks
Inclusion Criteria:

•Male or female
•Between the ages of 18-85
•Patients with unstable unilateral distal radius fractures (requiring surgical stabilization)

Exclusion Criteria:
•Pre-existing cases of carpal tunnel syndrome and/or CRPS
•Nerve or tendon laceration
•Decompression of carpal tunnel concomitant with surgical stabilization
•Additional fractures, including carpal fractures, more proximal fractures of the radius, and finger injuries will be excluded from the study (Ulnar styloid and ulnar head and neck fractures will be included)
•Uncontrolled rheumatoid arthritis patients
•Bilateral fractures
•Unable or unwilling to provide written informed consent.

Responsible Party: Michael Shuler, MD, J&M Shuler, Inc.

Study Sponsor: J&M Shuler
Contact: Michael S Shuler, MD 706-424-8438 msimmss@hotmail.com



(TO BE CONTINUED...)