Translational Research: Gene therapy for chronic pain enters first human trial

University of Michigan Health System Newsroom

ANN ARBOR, Mich. —This week, University of Michigan scientists will begin a phase 1 clinical trial for the treatment of cancer-related pain, using a novel gene transfer vector injected into the skin to deliver a pain-relieving gene to the nervous system.

A gene transfer vector is an agent used to carry genes into cells. In this groundbreaking clinical trial, the investigators will use a vector created from herpes simplex virus (HSV) – the virus that causes cold sores – to deliver the gene for enkephalin, one of the body’s own natural pain relievers.

“In pre-clinical studies, we have found that HSV-mediated transfer of enkephalin can reduce chronic pain,” says David Fink, M.D., Robert Brear Professor and chair of the department of neurology at the U-M Medical School. Fink developed the vector with collaborators and will direct the study.

“After almost two decades of development and more than eight years of studies in animal models of pain, we have reached the point where we are ready to find out whether this approach will be effective in treating patients,” Fink says. The investigators are recruiting 12 patients with intractable pain from cancer to examine whether the vector can be used safely to deliver its cargo to sensory nerves.

The trial represents two firsts, says Fink: It is the first human trial of gene therapy for pain, and the first study to test a nonreplicating HSV-based vector to deliver a therapeutic gene to humans. Fink says the technique may hold promise for treating other types of chronic pain, including pain from nerve damage that occurs in many people with diabetes.

The HSV vector, genetically altered so it cannot reproduce, has a distinct advantage, Fink says: “Because HSV naturally travels to nerve cells from the skin, the HSV-based vector can be injected in the skin to target pain pathways in the nervous system.”

Gene therapy for pain

Chronic pain is an important clinical problem that, despite a wide array of therapeutic options, cannot be effectively treated in a substantial number of patients. Fink notes that one key problem in treating pain is that the targets of conventional pain-relieving medications tend to be widely distributed in the nervous system, so that “off target” side effects of the drugs often preclude the use of those drugs at fully effective doses.

“This provides the rationale for using gene transfer to treat pain,” Fink says. “We use the vector to deliver and express a chemical that breaks down very quickly in the body. The targeted delivery allows us to selectively interrupt the transmission of pain-related signals and thus reduce the perception of pain.”

Enkephalin is one member of the family of opioid peptides that are naturally produced in the body. Opioid peptides exert their pain-relieving effects by acting at the same receptor through which morphine and related opiate drugs achieve their pain-relieving effects. In this trial the enkephalin peptide, produced as a result of the gene transfer, will be released selectively in the spinal cord at a site involved in transmitting pain from the affected body part to the brain.

“We hope that this selective targeting will result in pain-relieving effects that cannot be achieved by systemic administration of opiate drugs, “ Fink says. “This trial is the first step in bringing the therapy into clinical use. A treatment is at least several years off.”

Preclinical studies led to human trial

The phase I clinical trial represents the culmination of studies performed by investigators working in the U-M laboratory co-directed by Fink and his wife, Marina Mata, M.D., also a professor of neurology at U-M, along with colleagues at the University of Pittsburgh led by Joseph Glorioso, Ph.D. In published studies, the researchers have demonstrated that HSV-mediated gene transfer is effective in rats with pain resulting from inflammation, nerve damage or spinal cord injury, and in mice with pain caused by cancer. The extensive preclinical data in animal models were reviewed by the Recombinant DNA Advisory Committee at the National Institutes of Health. The Food and Drug Administration approved an investigational new drug application for the therapy in February.

Funding for the preclinical studies was provided by the NIH, and related studies of the vector were funded by grants from the Department of Veterans Affairs and the Juvenile Diabetes Research Foundation. The human trial is supported by a research grant from Diamyd, Inc., a subsidiary of Diamyd Medical (DIAMB.ST), a publicly traded Swedish biotechnology company. Fink has no financial interest in or consulting relationship with Diamyd. He is an inventor on patents related to this work that are owned by the University of Pittsburgh and licensed to Diamyd. Susan Urba, M.D. and Frank Worden, M.D., medical oncologists at the U-M Comprehensive Cancer Center will serve as principal clinicians for the study, assisted by Suzette Walker, N.P., who will serve as study coordinator, and Heidi L’Esperance, who will serve as data manager.

Trial details

The investigators are seeking patients with intractable pain related to cancer that is unresponsive to maximally tolerated doses of conventional analgesic drugs. The vector will be delivered in 10 small injections into the skin, and will require an overnight stay in the Michigan Clinical Research Unit at U-M Hospital. For more information, contact the U-M Cancer AnswerLine, 800-865-1125, or visit:
www.med.umich.edu/engage/
www.cancer.med.umich.edu/research/clinical_trials.shtml
www.med.umich.edu/neurology

Experimental Treatment CRPS-1

Forwarded from Jim Broatch, Reflex Sympathetic Dystrophy Syndrome Association (RSDSA): Clinical trial for experimental new treatment for CRPS-I at McGill University Health Centre

Clinical trial for experimental new treatment for CRPS-I at McGill University Health Centre
Investigator:Dr. Mark Ware
MUHC Pain Centre
Montreal General Hospital
Candidate profile:· Over 18 years of age· No kidney or liver disease· No diabetes
Length of trial: 10 weeks maximum
For more information: Please contact the Research Nurse, Sylvie Toupin at (514) 934-1934, ext: 44348

http://rs6.net/tn.jsp?e=001jEj1hqYmc_-tpdQk65GWBWAkHnL5UgPORxCXsPaIbHSPuEFWQswP7BKnuU6Wxa9jZCW0RXD5Lftv7BDk9AsZ0jkSNp-S_vCzSw0P1A53iXuARO0AN1RgC4C3lefrjleFNK825kaLYF7tVEjAPnAnDN6EyHeEcTaF


This E-alert was made possible by the contribution of the members of the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA). To learn more about becoming a member of RSDSA, please click here.

RSDSA Home Page

Intravenous IVIG in CRPS

From Lost and Tired

Of course, the banner at the top of the PubMed page reads:

PubMed is open, however it is being maintained with minimal staffing due to the lapse in government funding. Information will be updated to the extent possible, and the agency will attempt to respond to urgent operational inquiries.

Part of the reason I've not yet posted Part Two of the latest Clinical Trials updates for CRPS is precisely because they are shut down, though the staff there is also operating on a "compassionate" basis, helping people with end stage cancers find trials to try.  There are angels everywhere.  Yes, yes, I am sure there are even some GOP members who sport halos.

Maybe.

Anyway, I'm posting the abstract for this case study about immunoglobulin infusions in treating CRPS because some wider (and much older) research studies have claimed success in reducing pain -- significantly -- with as high a success rate as 30-40%.  The usual caveat seems to hold true -- that the likelihood of IVIG being effective is greatest in that magic initial 3 to 6 month period after onset.  So many people face huge battles in getting a correct diagnosis, often for years, so hearing that "3-6 month" mantra again is a bit of a downer. But as groups like RSDSA.org continue the battle for awareness and research, maybe these promising treatments will start reaching that target demographic and there will be fewer and fewer "intractable" cases of CRPS.

I took my optimism pill this morning.  That said, please do remember that this is a case study.  But heck, it was a case study that caught someone's attention about ketamine.  And from ketamine has been extrapolated experimental uses of other drugs blocking NMDA receptors -- she said, hopefully, taking her Namenda (memantine)!

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 Clin J Pain.2013 Nov;29(11):e33-e34.
Favorable Outcome of an Acute Complex Regional Pain Syndrome With Immunoglobulin Infusions.

Medlin F, Zekeridou A, Renaud S, Kuntzer T.

Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.

Abstract

OBJECTIVE::
To emphasize that complex regional pain syndrome (CRPS), a disabling disorder with the implication of aberrant inflammation, vasomotor dysfunction, and maladaptive neuroplasticity, might be treated with a high dose of intravenous immunoglobulin infusions (IVIG).

METHODS::
We describe a patient who presented with CRPS in the acute phase of the disease.

RESULTS::
The CRPS developed secondary to sciatic compression in a young patient and was treated within 10 days by high-dose IVIG (2 g/kg). It resolved completely within days after infusions.

DISCUSSION::
This observational study emphasizes that high-dose IVIG may be a treatment option in the acute phase of CRPS.

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Here is a slightly older study with a resounding cohort of participants -- all TWELVE of them -- who were past the "acute phase" of CRPS onset.  There was evidence of some pain reduction, but again, there were also methodological problems with the research.  I don't know that researchers will ever be able to establish "statistical relevancy" given the unlikelihood of ever achieving a decent number of subjects.  That's why we must sometimes give the hairy eyeball to those who mock CRPSers for our excitement over a case study of one patient -- we deal with what we have and try our darnedest to establish good science behind it.

Please excuse the funky layout below.  Blogger is punking me.

Ann Intern Med. 2010 Feb 2;152(3):152-8. doi: 10.7326/0003-4819-152-3-201002020-00006.

Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial.

Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G.

Source

University of Liverpool, Clinical Sciences Building, University Hospital Aintree, Liverpool L9 7AL, United Kingdom.

Abstract

BACKGROUND:

Treatment of long-standing complex regional pain syndrome (CRPS) is empirical and often of limited efficacy. Preliminary data suggest that the immune system is involved in sustaining this condition and that treatment with low-dose intravenous immunoglobulin (IVIG) may substantially reduce pain in some patients.

OBJECTIVE:

To evaluate the efficacy of IVIG in patients with longstanding CRPS under randomized, controlled conditions.

DESIGN:

A randomized, double-blind, placebo-controlled crossover trial. (National Research Registry number: N0263177713; International Standard Randomised Controlled Trial Number Registry: 63918259)

SETTING:

University College London Hospitals Pain Management Centre.

PATIENTS:

Persons who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment.

INTERVENTION:

IVIG, 0.5 g/kg, and normal saline in separate treatments, divided by a washout period of at least 28 days.

MEASUREMENTS:

The primary outcome was pain intensity 6 to 19 days after the initial treatment and the crossover treatment.

RESULTS:

13 eligible participants were randomly assigned between November 2005 and May 2008; 12 completed the trial. The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95% CI, 1.29 to 1.82; P < 0.001). In 3 patients, pain intensity after IVIG was less than after saline by 50% or more. No serious adverse reactions were reported.

LIMITATION:

The trial was small, and recruitment bias and chance variation could have influenced results and their interpretation.

CONCLUSION:

IVIG, 0.5 g/kg, can reduce pain in refractory CRPS. Studies are required to determine the best immunoglobulin dose, the duration of effect, and when repeated treatments are needed.

PRIMARY FUNDING SOURCE:

Association of Anaesthetists of Great Britain and Ireland, University College London Hospitals Charity, and CSL-Behring.

Comment in

• Intravenous immunoglobulin to fight complex regional pain syndromes: hopes and doubts. [Ann Intern Med. 2010]

Summary for patients in

• Ann Intern Med. 2010 Feb 2;152(3):I48.

Potential Conflicts of Interest: Disclosures can be viewed atwww.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1292.

Requests for Single Reprints: Andreas Goebel, MD, PhD, Pain Research Institute, University of Liverpool, Clinical Sciences Building, University Hospital Aintree, Liverpool L9 7AL, United Kingdom; e-mail,andreasgoebel@rocketmail.com.

Current Author Addresses: Dr. Goebel: Pain Research Institute, University of Liverpool, Clinical Sciences Building, University Hospital Aintree, Liverpool L9 7AL, United Kingdom.

Dr. Baranowski and Mrs. Ghiai: Pain Management Centre, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom.

Dr. Maurer: Institute of Anesthesiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.

Dr. McCabe: The National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, United Kingdom.

Dr. Ambler: Joint University College London Hospitals/University College London Biomedical Research Unit, Ground Floor, Rosenheim Wing, 25 Grafton Way, London WC1E 6DB, United Kingdom.

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But what would a post be without a measure of balancing skepticism?  Here is a taste of some of the immediate reaction to this 2010 study in the form of an editorial, even -- you'll have to use your "zoom" function to enlarge it, sorry!

© 2013 L. Ryan

Topical Rubs

One of my CRPS MedWorm RSS feeds delivered the following non-news news to my inbox this morning -- an announcement that the targeted enrollment number for a Phase 2b trial of a topical cream has been reached. Yes, I know. Kind of a meh-moment.

The meh-moments have been accumulating around here.

The Internet's medical router -- "over 6000 authoritative RSS feeds go in, hundreds of new RSS feeds by category come out" -- MedWorm is a terrific tool for the lazy researcher. Check it out if you try to stay on top of breaking medical news. You know, like for topical creams...

Before addressing that pressing news, though, I must report that Ivan Ljubicic, now in a tied fifth set with American (and ultra-cool dresser) Mardy Fish, needs emergency fashion advice.

Actually, the situation is not an emergent one, as Looby has long defied dictates of color, fit, and the remotely chic. He is a tall, pale man sporting a shaved head (almost always adorned with a *white* headband). His height is undeniably 6'4" but I refuse to believe that he weighs in at the reported 200 pounds.

I further deduce that the sun did not shine in the Serbian-dominated part of Bosnia of his childhood -- nor, apparently, are there opportunities for tanning in his current home of cloudy-dowdy Monaco. He looks positively jaundiced in a bright yellow shirt that fades rapidly to white, ballooning over white shorts, white socks, white shoes. Badly stained white, of course, as this is the terre battue of Roland Garros, after all.

My eyes! My eyes! Ljubo just treated the viewing audience to an around-the-world hip rock, hoping, I think, to approximate Elvis, but... well, failing. Next up for The Lube-Meister? Brazil's Bellucci, and more bad white clothing. I mean, at least wear *bright* white in lieu of the dirty-white, dishwater look.

Ljubicic is actually signed with designer Li Ning... a fact which begs more questions than it answers. Li Ning is one of the leading sports brand enterprises in the PRC. I know when I think of tennis fashion, the PRC fairly leaps to mind. Jelena Jankovic is also sporting their clothing/shoe line.

In the interests of full disclosure, let it be known that I'm a fan of "the war child." Only a fan would care about the nefarious effect of red clay on His Whiteness.

What am I wearing? An oversized, longitudinally-striped night shirt and dark grey chinos. My stripes are pastels, my fabrics all very worn, soft cotton. Turquoise earrings. [No bra, no underwear of any sort, no socks, no shoes -- I cannot tolerate any of them against my skin, or pulling on my shoulders. That's a bit of trivia I bet you wish you had not read.]

In other meh-news, when did Baghdatis achieve a 25th ranking? No offense, but he's basically a country club sort of player. I enjoy watching him, and root for him because he has always seemed to represent the good local player whose level of game rises against better players, making for some exciting points before he eventually winds down to his actual level of proficiency.

He tends to respond in kind... that is, if he is given a fast, flat ball, his return will be faster and flatter. He is a counterpuncher but lacks the speed and placement capabilities required to win majors.

I might feel differently were I sporting undies or red stilletos.

Maybe if I get ahold of some of EpiCept Corporation's analgesic topical cream, I would be able to once again wear proper foundational garments. How's that for a segue?!

Targeted Patient Enrollment Reached In Phase IIb Clinical Trial For Epicept™ NP-1 In Chemotherapy-Induced Peripheral Neuropathy

EpiCept Corporation (Nasdaq and Nasdaq OMX Stockholm Exchange: EPCT) today announced that the targeted enrollment in a Phase IIb trial for EpiCept™ NP-1 in chemotherapy-induced peripheral neuropathy (CPN) has been attained. The trial is being conducted by National Cancer Institute (NCI)-funded Community Clinical Oncology Program. EpiCept™ NP-1 is a patented topical cream formulation of two FDA- approved drugs, 4% amitriptyline and 2% ketamine, and is intended to provide long-term relief from the pain of peripheral neuropathies. CPN may affect 50% of women undergoing treatment for breast cancer.

The double-blind, randomized placebo-controlled study has enrolled more than 400 patients suffering from painful CPN for at least 28 days following the conclusion of chemotherapy. The primary endpoint of the 6-week trial is change in average daily neuropathy intensity scores from baseline to the endpoint. Secondary endpoints include the percentage of patients whose neuropathy intensity decreases at least 30% from baseline as well as various other measures. Topline data is expected to become available by year end.

About EpiCept™ NP-1

EpiCept™ NP-1 is a prescription topical analgesic cream designed to provide effective, long-term relief from the pain of peripheral neuropathies. Peripheral neuropathies are medical conditions caused by damage to the nerves in the peripheral nervous system. The peripheral nervous system includes nerves that run from the brain and spinal cord to the rest of the body. Peripheral neuropathies are associated with conditions that injure peripheral nerves, including herpes zoster, or shingles, diabetes, chemotherapy, HIV and other diseases. Peripheral neuropathies can also be caused by trauma or may result from surgical procedures. EpiCept™ NP-1 Cream is a patented formulation containing two FDA-approved drugs, amitriptyline (a widely-used antidepressant) and ketamine (an NMDA antagonist that is used as an anesthetic).

I shouldn't make fun -- EpiCept's idea of compounding amitriptyline and ketamine for relief of neuropathic pain is well-founded, logically, and I am glad to see it in the pipeline. I don't know enough about the various types of neuropathic pain to say whether the CRPS incarnation is truly comparable to this focus group of chemotherapy patients, but I would imagine some applicable correlation. Besides, it is virtually impossible to have meaningful test results if the cohort is limited to CRPS patients -- I tire of reading about results involving all of 4 or 13 subjects, 3 or 12 of whom have dropped out due to side effects...

In the Supportive Care in Cancer journal (ISSN: 0941-4355 Print; 1433-7339 Online), a similar study announced its results on 24 May 2010. The topical gel used here has the addition of baclofen in its compounded form: baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel.

Again, from a lay point of view, the combination makes beaucoup sense. It's ironic that I can't use topical meds -- I cannot tolerate lotions, creams, gels. Still, it sure sounds like a good idea!

Abstract

Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem.

Methods
Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks.

Results
Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity.

Conclusion
Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

In the women's draw, Serena is looking very good, Venus, also. As I've consistently noted, I am not a fan of the Williams sisters. It's a snooty attitude and I try to revise it every year.

First impressions do endure: I was a non-fan from the beginning. Initially, they seemed to be cobbling together victories with novelty shots and spurts-and-bursts of brilliant power that alternated with amateurish errors.

Venus can thrill me at times, when she moves well to the ball, and executes once she gets there. I am frustrated on her behalf when she hustles to get there, then seems unable to convert the hustle into a point. Another hold-over of my hypercritical past (I am downright magnanimous now) because she is, of course, awesome in her court presence.

The sisters sometimes smother my potential enthusiasm by their attitude -- conveyed as much by a lazy overhead as by a blistering verbal outburst. Then, too, I think they've both sometimes made excuses for poor play that was inexcusable, and have failed to adequately respect their opponents off court.

Okay, okay, none of that is true. It all comes down, really, to fashion sense, to The Togs. They are both accredited designers but who can forget Serena's Klingon industrial black affair from that long ago U. S. Open? One piece, of oh-so-breathable spandex, it is the iconic image conjured whenever I hear her name. Ridiculous and unfair, as it has been eight years now, but that's the way it goes.

It must have been meant to convey the trend toward unrepentant female strength and power, but as Robin Givhan noted back then, it came off as "trash talk," and was a "disservice" to Serena. There was a brief attempt to make it a "teachable moment," during which White America was to confess its discomfort with the Black Female Butt. Clearly, there is truth to the notion that eurocentric white standards continue to dominate, and clearly, Serena and Venus have both enjoyed providing an in-your-face response. I promise, though, if Anna Kournikova were to sport the rubbery unitard? I would have been equally disapproving. Less disappointed, perhaps, because I've not the visceral connection with Kournikova that I share with the American Williams, but no less turned off by it.

It is late-coming, but I might turn the corner as a Serena fan. I like that she is now so fit and that her form is consistent. I'm sure she's very relieved that I am coming around...

I may have to let the catsuit issue die a natural death.

As for Venus, whose heart didn't stall when her skirt flew up to reveal... flesh colored tennis underpants? Actually, my heart didn't skip a beat but I understand much of Paris required resusscitation. I even like the corsetted red "bustier," and if she can tolerate the feel of all that lace, well... cool.

I will never forget the frilly, white, totally retarded looking tennis undies that my stepmother so wanted me to wear. There was no way not to feel stupid, no way not to be totally focused on one's own ass. They were as kryptonite to my forehand crosscourt passing shot and my blistering backhand.

Millions of women are reveling in her diss of the white ruffled bloomer and the attitude and times represented by that infantilizing bit of elastic and polyester.

As many again are thrilled by her incredible and unapologetic behind.

CNN has put together the obligatory long view of the Williams' sisters various fashion statements.

The woman I hope to see win is Justine Henin, someone who also sometimes suffers in the vagaries of body types and sexual tensions. I remember totally losing it a few years ago -- she had just won one of her four French Open titles and I was whooping it up online with fellow enthusiasts when there came a barrage of comments about the size of her breasts. She had just finished schooling the world on pristine clay court play, only to be assessed by her bra cup measurement. It was infuriating, frustrating.

Witness this "Mister Poll" and its enlightened stance:

What do you think of Justine Henin's looks?

She is so ugly I want to vomit!
She looks like a man!
She is just an average girl - not my type
She is ok I've seen better
She is nice
She is so hot she makes me hot thinkig about her!

What do you think of Justine's breasts?

She is a titless wonder - yuck!!
She has got really tiny breasts - I'm turned off..
Her breasts are really tiny and I love them!!!
I never noticed her breasts
They are just an average size pair

How would you feel if you were Justine henin and had her breasts?

My shame would be so great I would never go out
I'd be straight into surgery. Boob job please!
Padded push up bras with extra padding please!
I'd be so embarressed but I would cope somehow.
It would be ok I'd just be fine.
I would love it I'd be out topless bathing!!

Should Justine be punished for her public display of small breasts?

Yes - make her play topless and laugh at her!
Yes - bend her over and spank her bare bottom!
Yes - ban her from tennis she is ugly!
No - as long as she has a boob job!
No - She is ok.
No - She makes me hot.
No - But I still want to see her play topless!!!

Would you have sex with Justine Henin?

No way - She is an ugly dog!
No way - She is probably half man!
No way - with that titless wonder! ha!
No thanks she is not my type.
Yes - but I need lots of alcohol first!
Yes - She is so hot.
Yes - I've got to have her now!!!

It boggles the mind.

Well, I am in a shitload of discomfort and am now off to find an opiate. Maybe I will exchange my oversized, longitudinally-striped night shirt for something more appropriate to day wear. Maybe, like Venus, I can titillate the boys of The Manor by mere illusion and suggestion... because, unlike Venus, I don't have the goods to pull off a flirtation based on anything else.

Postscript: Fred and I just butt heads over... Well, over Venus' butt. I confess to having hit Shrill Tones pretty quickly. Poor Fred. He saw nothing problematic about the black-lace-over-red-corset design but became apopleptic about the tennis undies. What sent me into Shrill Land was his insistance that it was not the flesh-colored aspect of it... No! It was the "fit"! I think my eyes were bugging out. We were watching Venus play Dominika Cibulkova. Now, Dominika's tennis attire bothered me more than Venus' playful dress, mostly because it just looked so damned uncomfortable. I tire of women being uncomfortable on purpose. It's a pet peeve. Most every time I have seen her play, Cibulkova wears the same approximate thing -- a tight, bunched up sheath-type dress that is very short, over shorts that appear equally tight and bunched. I kept asking Fred if the "fit" of Cibulkova's tennis undies did not bother him, as they appeared as form-fitting (that was our chosen euphemism) as all get-out to moi! He kept muttering something about them being fine and "more like shorts." Jesus H. Christ, we do not want to tell our truthes, do we?

He dusted off his usual mumblemumble example -- doyourememberonetimewhenwehaddinneratredlobster? A large [black] woman came into the restaurant wearing see-through leggings without benefit of sufficient tunic to cover her nether regions. He apparently hasn't gotten over it. It was pretty disgusting. We were and are in total agreement on that point. What it had to do with anything, though? I dunno.

Am I NOT supposed to challenge that? Am I NOT supposed to ask what in hell that has to do with Venus Williams, a professional athlete wearing tournament-approved clothing? Am I REALLY supposed to believe that Fred's issue is with the fit of her undergarment and not the fact that she has a beautiful black butt that makes him... nervous?


To summarize: No problem with the coquettish lace and bustier... No problem with the undies virtually disappearing due to their flesh-coloration. BIG PROBLEM because they were clearly too... tight.

Well, hell.

Let's get out of this mess with something we can all be comfortable with. If you appreciate Andy Roddick like I appreciate Andy Roddick, you will appreciate this insightful analysis of his game. View it many times in succession to allow the tennis tips to meld with your Inner Athlete. If his unclad upper body bothers you? Take it up with someone else, as I am fresh out of Shrill:

Coded Message to a Pilgrim

A good Friday evening to you, Dear Readers. This post is written in code, so those of you not privy to elle est belle la seine la seine elle est belle top secret ways, first, I scoff in your general much too hopeful direction, and, B: Lots of luck!

My beloved pilgrim,

I just left a rambling telephone message on your answering machine.  You're likely out earning a living -- what a notion!

It just occurred to moi that, given your proclivity for working ridiculous hours -- entirely by choice and love of the pursuit of green, snort! -- you may not have been rabidly checking your incoming emails.  Having a life and all.

So I wanted you to know that our favorite professor encountered big changes and may have brushed shoulders with a bit of luck and a person of optimism this past Wednesday.  As I am becoming a basket case every Tuesday evening, and something resembling an Orca-sized New York street vendor pretzel during Wednesday's official time stamp... only to dissolve like an Orca-sized New York City street vendor pretzel left out in LA's Macarthur's Park and its famous rain.

Are you still there?  Good, because I'm pretty sure I was able to shake off any doped-up readers who decided to read on, after being so thoroughly discouraged from that endeavor -- my Beloved Freaks!

MacArthur's Park is melting in the darkAll the sweet green icing flowing downSomeone left the cake out in the rainI don't think that I can take it'Cause it took so long to bake itAnd I'll never have the recipe againOh, no

One day, when we meet to discuss all of the many things over which we've been mutually blessed to marvel, we can discuss Jimmy Webb's (and Richard Harris') contribution to the culture.*

Honest to Goodness, though, I hope we can hoist something cold and frothy, first, and examine our mutual navel lint before diving into such depths.  Two fools in a pool...

The Good Prof, weak and limping along in a fog of pain and confusion, was released from the care of the Bone Dood, and handed over to a hematologist oncologist.  Unfortunately, and this sums up the charm of the Bone Dood and his massive "Institute" quite well -- not a criticism; just what we all know is true at large, excellent medical joints -- GB was given no clue as to why he was now being sent to a frigging Blood Cancer Doc, but resigned that the tumor in his shoulder, the tumors in his lungs, and the as yet unidentified LUMPS in his pedagogical ass all logically added up to a burning need for a Blood Doctor.  Oy!

When last we left GB, he was being led down the corridor to a Radiation Oncologist who was gonna "debulk" -- a new verb favorite -- the shoulder tumor to provide him with pain relief.

Odd, but Bone Dood's dawdling in making that step happen proved to be, well, something a smart musculoskeletal oncologist might do, as hurtful as it seemed to moi.

Because Blood Cancer Doc deals often, and well, with persons diagnosed with [don't click on this next link without a cat in the lap and whiskey in a glass] metastatic renal cell carcinoma -- which, despite being located in spots far afield from the kidneys, are still "renal cell carcinomas."

Wanting a euphemism for "kidney(s)" -- and who does not? -- I discovered that "the biblical Hebrew equivalent of the English idiom heart and mind, is כּליות ולב --  i.e. kidneys." This will prove useful in future coded messages, eh?

Blood Cancer Doc was warm, thorough, optimistic, and ready with a plan.  No radiation, no surgeries, but an immediate, time-sensitive (duh!) application to a clinical trial.  Forty pages of information for this pained, tired jokester of an Educator to cull through, decipher, and to which he will dedicate 14 months of his life, IF accepted.

Turns out that had our Intrepid Teacher undergone *any* radiation, or treatment, really, of any kind, he would have been ineligible for the clinical trial, or would have had to delay starting. IF he's accepted.

That news should be had around next... you guessed it!  Wednesday!  Regardless of the response, the friendly, warm, optimistic Blood Cancer Doc is prepared to begin chemotherapy next week.  Either way, he promises it will reduce the pain.

In the interim, he will be kept busy as a bee with testing.  The application and attendant clinical reports also require that the pathology/histology report not be older than 21 days, else our underemployed-overworked loved one will have to undergo another deep biopsy under general anesthesia.

True to form, his major complaint remains... the famed ASS (good luck decoding that acronym, my Intrepid Readership!).

I love him so.  You love him so.  And all three of us still love bad jokes, excellent thought, the sound of rushing rivers, and wild, wild beauty. No code needed.

Smooches Galore.  I love you so...

The old grey donkey, 

Eeyore, stood by himself 

in a thistly corner of the Forest, 

his front feet well apart, 

his head on one side, 

and thought about things. 

Sometimes he thought 

sadly to himself, Why? 

and sometimes he thought,Wherefore? 

and sometimes he thought, 

Inasmuch as which? 

and sometimes 

he didn't quite know 

what he was thinking about. 

--A.A. Milne

Winnie-the-Pooh

Hebrew text from the Dead Sea Scrolls,
from Psalm 145

* "MacArthur Park" is a song by Jimmy Webb, originally composed as part of an intended cantata. Webb initially brought the entire cantata to The Association, but the group rejected it.^[1] Richard Harris was the first to record the song, in 1968; it was subsequentlycovered by numerous artists. Among the best-known covers are Donna Summer's disco arrangement from 1978 and Waylon Jennings's version recorded in 1969 and his recording of the song from 1976. Maynard Ferguson,^[2] Stan Kenton^[3] and Woody Herman all performed big-band jazz arrangements.

While it was a commercially successful song multiple times after it was released, "MacArthur Park" used flowery lyrics and metaphors (most famously, love being likened to a cake left out in the rain) that were considered by media such as the Los Angeles Times to be "polarizing" and "loopy".^[4]

Since its original release, the song became associated with the NBC, most notably with the late Johnny Carson. Harris sang the song in the final episode of The Tonight Show with Johnny Carson in 1992.

 © 2013 L. Ryan

Have you seen Scott Reuben?

Another bit of housekeeping, this related to a promise to keep half-an-eye on ex-con physician Scott Reuben.  To read my previous posts on "doctor" Reuben, click HERE.  While we wait for him to make [up] the news again, here's the obvious question on many peoples' minds:

Big Pharma's Ghostwriters
Why Are These Fraudulent Papers Unretracted?
by MARTHA ROSENBERG

According to Science Times, the Tuesday science section in the New York Times, scientific retractions are on the rise because of a “dysfunctional scientific climate” that has created a “winner-take-all game with perverse incentives that lead scientists to cut corners and, in some cases, commit acts of misconduct.”

But elsewhere, audacious, falsified research stands unretracted–including the work of authors who actually went to prison for fraud!

Richard Borison, MD, former psychiatry chief at the Augusta Veterans Affairs medical center and Medical College of Georgia, was sentenced to 15 years in prison for a $10 million clinical trial fraud[2] but his 1996 US Seroquel® Study Group research is unretracted.[3] In fact, it is cited in 173 works and medical textbooks, misleading future medical professionals.[4]


Scott Reuben, MD, the “Bernie Madoff” of medicine who published research on clinical trials that never existed, was sentenced to six months in prison in 2010.[5] But his "research" on popular pain killers like Celebrex and Lyrica is unretracted.[6] If going to prison for research fraud is not enough reason for retraction, what is? [Please read the rest of the article HERE.]



[1] http://www.nytimes.com/2012/04/17/science/rise-in-scientific-journal-retractions-prompts-calls-for-reform.html?_r=1&pagewanted=all

[2]  Steve Stecklow and Laura Johannes, “Test Case: Drug Makers Relied on Two Researchers Who Now Await Trial,” Wall Street Journal, August 8, 1997

[3] Richard Borison et al., “ICI 204,636, an Atypical Antipsychotic: Efficacy and Safety in a Multicenter, Placebo-Controlled Trial in Patients with Schizophrenia,” Journal of Clinical Psychopharmacology 16, no. 2 (April 1996): 158–69

[4] Alan F. Schatzberg and Charles B. Nemeroff, Textbook of Psychopharmacology (New York: American Psychiatric Publishing, 2009) p. 609

[5] http://www.scientificamerican.com/article.cfm?id=a-medical-madoff-anesthestesiologist-faked-data

[6] Scott Reuben et al., “The Analgesic Efficacy of Celecoxib, Pregabalin, and Their Combination for Spinal Fusion Surgery,” Anesthesia & Analgesia 103, no. 5 (November 2006): 1271–77.

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...)