Procustean Science: Re-Gifting IVIG

Part of me doesn't even want to post this, as it is recycled material from the famous or infamous -- I cannot decide, discern -- Andreas Goebel, forever presenting IVIG as a silver bullet for CRPS.  That's okay, I have seen good things come from focused scientists.

But it seems to me, the layperson with a dangerous small bit of knowledge, that repackaging a theory every few years in the pretty wrapping paper of a new context eventually makes the re-gifting exercise less one of diverse generosity and more one of desperately searching for a respectable vehicle.

In his most recent reincarnation of IVIG as cure all, Dr.Goebel blithely tosses on the rubbish heap the notion of trauma/injury/physical insult as an inciting event in CRPS.  There has always been a caveat to that observation -- that many cannot recall an inciting event, that many cases of "spread" (Dear God, please give us a better and more accurate word!) occur without trauma, large or small, and so on.

Still, I'd wager that most of "us"experience onset, instances of "spread," and, according to most reports I've read of people in remission coming out of that remission, after some sort of inciting injury/insult/trauma.  Call me crazy... (I'll give you a few moments.) -- Call me crazy, but trimming a disease profile so it better fits in the box you're wrapping this year... doesn't make me all a-dither about what's under the Christmas tree.

It makes me want to gift you with "Procrustes" as a middle name.  Andreas Procrustes Goebel.

Dr. Goebel presents himself in the following way on various websites that deal with disease and (all) encompassing theories of immunology and auto-immune scenarios

I am a senior lecturer in pain medicine at the University of Liverpool, and an honorary consultant in pain medicine at the Walton Centre NHS Trust, both in Liverpool in the United Kingdom. After receiving my medical and doctoral degrees from the University of Würzburg in Germany, I trained in anaesthesia and pain medicine first in Germany, then at the Oxford School of Anaesthesia in the United Kingdom.  This was followed by further specialized pain training at University College London Hospitals, and interventional training in Notwill, Switzerland.  I completed a 2-year fellowship in post-trauma immunology at Harvard Medical School in Boston. My main professional interest is with the role of the immune system in chronic pain, and immune modulating drug treatments for unexplained chronic pain conditions. I have a particular interest in a condition called ‘Complex Regional Pain Syndrome’ (CRPS).

I am a fellow of the Royal College of Anesthaesthetists, a member of the British and German Pain Societies and the International Association for the Study of Pain, and founding member of the CRPS network UK.

All of my bitchiness about the window dressing aside, Dr. Goebel was kind enough to answer an email inquiring about any IVIG/immunotherapy ("immune modulating drug treatments for UNEXPLAINED chronic pain conditions"/CAPS mine, all mine) research being done in the U.S., as he is centered in the UK:

This is all experimental at the moment. The only US group which I am aware of, who is trying immune treatments relatively systematically, is the Philadelphia group. You might wish to inquire with Dr. Lopez: Enrique.AradillasLopez@DrexelMed.edu and inquire. 

I have not inquired, as my experience with the staff at Drexel University's Neurology Department has been abysmal, and that's adding a dose of "sweetness and light" to the assessment.*

Well, time to rein myself in and give you the latest Dr. Andreas Procrustes Goebel's  Bento Box for a treatment that may well have tremendous merit, despite how it may be overblown in its marketing hype. This is much easier to take than past incarnations, being constrained by the format of a clinical trial.

Low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS): study protocol for a randomized controlled trial

Longstanding complex regional pain syndrome (CRPS) is refractory to treatment with established analgesic drugs in most cases, and for many patients, alternative pain treatment approaches, such as with neuromodulation devices or rehabilitation methods, also do not work. The development of novel, effective treatment technologies is, therefore, important.

There are preliminary data suggesting that low-dose immunoglobulin treatment may significantly reduce pain from longstanding CRPS. 

Methods: LIPS is a multicentre (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. Participants with moderate or severeCRPS of between 1 and 5 years duration will be randomly allocated to receive IVIg 0.5 g/kg (IntratectTM 50 g/l solution for infusion) or matching placebo administered day 1 and day 22 after randomisation, followed by two optional doses of open-label medication on day 43 after randomisation and on day 64 after randomisation.

The primary outcome is the patients'pain intensity in the IVIG group compared with the placebo group, between 6 and 42 days after randomisation. The primary trial objective is to confirm the efficacy and confidently determine the effect size of the IVIG treatment technology in this group of patients.Trial registration: ISRCTN42179756 (Registered 28 June 13).

Author: Andreas Goebel, Nicholas Shenker, Nick Padfield, Karim Shoukrey, Candida McCabe, Mick Serpell, Mark Sanders, Caroline Murphy, Amaka Ejibe, Holly Milligan, Joanna Kelly, Gareth Ambler



* LIFTED FROM A POST PUBLISHED OCT. 3, 2011:
Remember Dr. Schwartzman of Drexel University fame?  I was so excited at the thought of being Philly bound, and getting to see one of the world's best in the field of CRPS.  It did not work out, mostly because the rarefied air around experts makes them incapable of understanding the limitations of their own impossible schedules!  That's why they have experienced gate-keepers, usually older women with cigarette-ravaged voices and an attitude.  The gate-keepers get to tell all the patients to whom the expert has offered the moon that the moon is made of cheese. 

© 2013 L. Ryan

Low Dose Naltrexone (LDN) in Recalcitrant CRPS

If you've heard of the drug Naltrexone, it's likely to have been according to its most known context, as explained by the good Wikipedia:

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade. In some countries including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol.

Yet, there is a movement calling for low dose Naltrexone clinical trials, as anecdotal evidence accrues that it is improving the quality of life for people with Parkinson's Disease, Crohn's, Multiple Sclerosis, and several cases of pancreatic cancer.

I tend toward skepticism but try to remember that Ketamine, which has proven useful to many CRPS patients, and others with unrelenting pain from things as diverse as advanced cancers to phantom limb pain, also came on the scene as the result of a single case study.

If you -- like me -- would like to read up on LDN therapies, a sort of clearinghouse of information is available through the efforts of doctors and researchers calling themselves "The LDNscience™ Team" HERE.

**********************************************************

This is the first article I've seen dealing specifically with CRPS and low dose Naltrexone.
Full text available online courtesy of SpringerLink

Journal of Neuroimmune Pharmacology
© The Author(s) 2013
Received: 7 November 2012
Accepted: 4 March 2013

Published online: 2 April 2013
10.1007/s11481-013-9451-y


Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Pradeep Chopra (1)  and Mark S. Cooper (2)
(1)Department of Medicine, Alpert Medical School of Brown University, 102 Smithfield Ave, Pawtucket, RI 02860, USA
(2)Department of Biology, Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195-1800, USA

Pradeep Chopra (Corresponding author)
Email: painri@yahoo.com

Mark S. Cooper
Email: mscooper@u.washington.edu

Abstract
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.
Keywords Chronic pain Complex regional pain syndrome CRPS Reflex sympathetic dystrophy RSD Neuropathic pain Naltrexone Fixed dystonia Allodynia Vasomotor Ulceration Dystonic spasms Conversion disorder Functional movement disorder LDN

Introduction
Complex Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic Dystrophy (RSD) is a neuroinflammatory condition that is characterized by a combination of sensory, autonomic, vasomotor, and motors dysfunctions. One of the characteristic symptoms of this condition is that the pain is out of proportion to the initial injury. Diagnoses of CRPS are often delayed because it is under recognized (Binkley 2012). If effective treatments are given early enough in progression of the disease, there is reduced chance for the spread of regional pain, autonomic dysfunction, motor changes, and negative sensory symptoms, such as hypoalgesia (Marinus et al. 2011). As CRPS progresses, it becomes refractory to sympathetic nerve blocks, conventional analgesics, anticonvulsants and antidepressants.

During neuroimmune activation, TLR4 (Toll-Like Receptor 4) is upregulated in microglia, resident immune cells of the central nervous system (Watkins et al. 2009). After transection of the L5 spinal nerve in the rat, TLR4 expression is increased in spinal microglia. This correlates with the rodent developing neuropathic pain (Tanga et al. 2005). From a post-mortem analysis of a CRPS patient, activated microglia and astroglia in the central nervous system (CNS) have been implicated in the generation of CRPS symptoms (Del Valle et al. 2009).

Activation of TLR4 in both microglia and CNS neurons augments the production of pro-inflammatory cytokines via the NF-κB pathway (Milligan and Watkins 2009; Leow-Dyke et al. 2012). NF-kB is a multi-functional transcription factor that is activated by c-Jun-N-terminal kinase (JNK), extracellular signal-related kinase (ERK), or p38 (Milligan and Watkins 2009). In activated glia and neurons, NF-κB activity promotes the production of pro-inflammatory cytokines and neurotoxic superoxides (Milligan and Watkins 2009; Leow-Dyke et al. 2012; Fellner et al. 2013), which act as mediators for neuropathic pain, as well as other neurological dysfunctions (Liu et al. 2000; Barbosa et al. 2012; Besedovsky and del Rey 2011). Pro-inflammatory cytokines, as well as the neurotrophin BNDF (brain-derived neurotrophic factor), induce enhanced excitatory tone and diminished inhibitory tone in nociceptive neural networks, leading to hyperalgesia or allodynia (von Hehn et al. 2012). Sustained TLR4 stimulation in microglial populations can also lead to neuronal injury and death (Fellner et al. 2013).

In rodents, the TLR4 antagonist, naltrexone, is able to suppress allodynia arising from bone cancer (Mao-Ying et al. 2012). In rodents, naltrexone is able to cross the blood–brain barrier, suppress glial cell activation, and reverse neuropathic pain arising from chronic constriction nerve injury (Hutchinson et al. 2008).

A recent study reports that low-dose oral naltrexone reduces pain in fibromyalgia patients (Younger and Mackey 2009). Low-dose naltrexone (LDN) refers to doses approximately 50-fold lower than doses of naltrexone typically given to patients addicted to opioids (Rea et al. 2004; Younger and Mackey 2009).
Opiate antagonists differ from opioids through a replacement of the characteristic N-methyl group with a N-cyclopropyl, N-allyl group. At low concentrations, naltrexone is able to antagonize TLR4 on activated glial cells, without inhibiting other opioid receptors in the CNS (Hutchinson et al. 2008). This allows endogenous anti-nociceptive pathways involving μ-receptors to continue operating.

A recent paper has reported positive benefit of ibudilast, an oral glial attenuator, for the treatment of neuropathic pain in several CRPS patients (Rolan et al. 2009). Below, we describe positive outcomes of two CRPS patients treated with low-dose naltrexone, in combination with other CRPS therapies. Low-dose naltrexone was utilized in these patients after more conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms. Each patient met IASP criteria for the diagnosis of CRPS.

Here are two sets of photos from the article of the first case study, before and after treatment with LDN:

Fig. 1

Advanced CRPS symptoms in Case 1. 4.5 years after onset of the disorder. a Allodynia and pronounced vasomotor dysfunction are present in the lower right extremity (photo taken 9/18/2008). b One week later, the leg has developed numerous ulcerations.

Fig. 2

Case 1. Certain symptoms are attenuated following treatment with low-dose naltrexone (LDN) in a long-standing case of CRPS (6 years after onset). a Allodynia is greatly reduced in both legs after LDN. However, bilateral trophic changes remain in the lower extremities. Slight swelling is present in the distal portion of the right foot. Within 2 months of treatment with LDN, the patient was able to bear full body weight, and walk without assistance. Before LDN, the patient utilized a cane for 6 years. b One year after LDN treatment, the patient still has persistent long-term trophic changes in the skin of both lower extremities (taken 1/16/2013)

DISCUSSION

Causalgia, which is often a salient feature of CRPS, has long been viewed as having a neuroinflammatory etiology (Mitchell 1872; Sudeck 1901). Although centralized neuropathic pain has been connected to activated glia in rodents (Milligan and Watkins 2009), it is an open question whether the symptoms in CRPS in humans are linked to activated glia in the CNS. The positive responses of the two patients discussed above to LDN are among the first reported benefits of glial attenuators for CRPS symptoms. A prior study described moderate pain benefit to several CRPS patients enrolled in a clinical trial of ibudilast, another glial attenuator that is unrelated to LDN in its molecular action (Rolan et al. 2009).

The second case study addressed in this work is based on a teen who suffered from several other disorders, including  Ehlers-Danlos Syndrome. It's unfortunate (and, on a personal note, infuriating) but her instance, in particular, the evidence of "fixed dystonia" was glossed over as a probable conversion disorder.  That seems to be the state of things in areas of study that are a bit removed from clinical experience.

It's also important to recognize the limitations of all case study reports, and in these cases, there not being, for example, the exclusions and protocols of a clinical trial, both patients received a variety of concomitant treatments, and the methods of evaluation were diverse, and sometimes, lacking.

That said, it's something else for those of us with advanced CRPS non-responsive to treatment to check out. There is a large amount of anecdotal evidence/support among MS patients for use of Low Dose Naltrexone, but no sufficiently rigorous clinical trials to date.  It has also gained much support in the treatment of Crohn's disease, but again, more in popular media than scientific.

There have been accusations that LDN may fall into the frustrating category of "an unprofitable cure."

To read about both case studies and further discussion, click HERE.

Engineered Toxin in the Pipeline as Treatment for Chronic Neuopathic Pain

Synthetic Self-Assembling Clostridial Chimera for Modulation of Sensory Functions

Enrico Ferrari †‡, Chunjing Gu †, Dhevahi Niranjan†, Laura Restani §, Christine Rasetti-Escargueil ,Ilona Obara #, Sandrine M. Geranton , Jason Arsenault †, Tom A. Goetze ¶, Callista B. Harper □,Tam H. Nguyen □, Elizabeth Maywood †, John O’Brien †, Giampietro Schiavo ●, Daniel W. Wheeler, Frederic A. Meunier □, Michael Hastings †, J. Michael Edwardson ¶, Dorothea Sesardic , Matteo Caleo §, Stephen P. Hunt , and Bazbek Davletov *†

† MRC Laboratory of Molecular Biology, Cambridge,United Kingdom

‡ School of Life Sciences, University of Lincoln, Lincoln, United Kingdom

§ Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Pisa, Italy

 National Institute for Biological Standard and Control, Health Protection Agency, Potters Bar, United Kingdom

 Department of Cell and Developmental Biology,University College London, London, United Kingdom

# School of Medicine, Pharmacy and Health, University of Durham, Stockton on Tees, United Kingdom

¶ Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom

□ The Queensland Brain Institute, University of Queensland, St Lucia, Australia

● London Research Institute, Cancer Research U.K., London, United Kingdom

 Department of Anaesthesia, Addenbrooke’s Hospital, Cambridge, United Kingdom

 Department of Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom

Bioconjugate Chem., 2013, 24 (10), pp 1750–1759

DOI: 10.1021/bc4003103

Publication Date (Web): September 6, 2013

Copyright © 2013 American Chemical Society

*E-Mail: b.davletov@sheffield.ac.uk; Tel.: +44-114-2225111.

ABSTRACTClostridial neurotoxins reversibly block neuronal communication for weeks and months. While these proteolytic neurotoxins hold great promise for clinical applications and the investigation of brain function, their paralytic activity at neuromuscular junctions is a stumbling block. To redirect the clostridial activity to neuronal populations other than motor neurons, we used a new self-assembling method to combine the botulinum type A protease with the tetanus binding domain, which natively targets central neurons. The two parts were produced separately and then assembled in a site-specific way using a newly introduced ‘protein stapling’ technology. Atomic force microscopy imaging revealed dumbbell shaped particles which measure 23 nm. The stapled chimera inhibited mechanical hypersensitivity in a rat model of inflammatory pain without causing either flaccid or spastic paralysis. Moreover, the synthetic clostridial molecule was able to block neuronal activity in a defined area of visual cortex. Overall, we provide the first evidence that the protein stapling technology allows assembly of distinct proteins yielding new biomedical properties.

PRESS RELEASE FROM THE UNIVERSITY OF LINCOLN, October 2013

Scientists have manufactured a new bio-therapeutic molecule that could be used to treat neurological disorders such as chronic pain and epilepsy.

A team of 22 scientists from 11 research institutes, including Dr Enrico Ferrari from the University of Lincoln, UK, created and characterised a new molecule that was able to alleviate hypersensitivity to inflammatory pain. 

The work is featured on the cover of the October 2013 issue of the scientific journal Bioconjugate Chemistry.

Dr Ferrari joined the School of Life Sciences in October last year from the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, where he took part in the development of a new way of joining and rebuilding molecules in the research group of Professor Bazbek Davletov - now at the University of Sheffield.

Now, by separating elements of clostridium botulinum and clostridium tetani neurotoxins, commonly known as Botox and tetanus toxin respectively, the scientists were able to develop a model to re-join the molecule proteins yielding new biomedical properties, without unwanted toxic effects. 

While the Botox element is able to block neuronal communication – and therefore pain signals - for months, the tetanus component targets the engineered toxin to the central nervous system, rather than stopping at exterior neurons that are the normal target of Botox. The combination of the two effects is of great interest for neuroscience and can be applied to the treatment of several neurological disorders, particularly chronic pain conditions.

Botox and tetanus neurotoxins hold great promise for clinical applications, but since they are the most lethal proteins known to man, their paralytic activity was a stumbling block until now.

Dr Ferrari, who is one of the lead authors of the study, said: “The toxins were split into parts so they were unable to function. Then later they were reassembled using a ‘zipping’ system so they can operate in a safe way. The re-engineered chimera toxin has very similar characteristics to Botox and is still able to block neurotransmission release, but the paralytic effect is a lot less. We then added a tetanus molecule which targets the chimera to where the pain signals travel towards the central nervous system.”

Preliminary data on animal models has now been collated at University College London and future clinical trials are expected to fully characterise the new bio-therapeutic.

Dr Ferrari added: “Many painkillers relieve the pain temporarily and have various side effects. The selling point of this molecule is that the pain relief could last up to seven months, in a similar way that Botox injections for removing wrinkles last for several months. Engineering this kind of toxin has many uses and would be a major improvement in the quality of life for those people who suffer from chronic pain. It is very exciting to know that a protein you made could be one of the future drug treatments.”

The crux of Dr Ferrari’s research is now aimed at creating a method where more than two protein elements can be combined together and their exact order dictated, which will open up further avenues to explore possible medical uses in the future.

Synthetic Self-Assembling Clostridial Chimera for Modulation of Sensory Functions in Bioconjugate Chemistry, DOI: 10.1021/bc4003103


© 2013 L. Ryan

Open Access CRPS Article: Pain Treatment Topics

Pain-Topics.org News/Research UPDATES

These UPDATES are a component of Pain Treatment Topics . Our mission is to serve as a noncommercial resource for healthcare professionals & their patients, providing open access to clinical news, information, research, and education for a better understanding of evidence-based pain-management practices.

Monday, September 9, 2013
Are Opioids Ineffective for Neuropathic Pain?

Neuropathic Pain
Neuropathic pain associated with various types of nerve involvement can be difficult to diagnose and treat. The use of opioid analgesic therapy is controversial due to concerns that this type of pain does not always respond well to these agents and there is potential for adverse effects. An updated systematic review examined 31 studies, involving 1,237 patients with neuropathic pain, and found intermediate-term effectiveness of opioids, but longer-term benefits for chronic conditions seem uncertain.

In this present study, Ewan D McNicol — of the Tufts Medical Center, Boston — and colleagues updated their original Cochrane systematic review first published in 2006 [McNicol et al. 2013]. As before, their assessment included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Research trials were excluded if nonopioid drugs were combined with opioids or if opioids were administered epidurally or intrathecally.

This new review included 31 trials meeting inclusion criteria, studying 10 different opioids: 23 studies were from the original 2006 review and 8 additional studies were discovered for the update. Of the total, 17 studies — 392 participants with neuropathic pain, average 22 participants per study — provided efficacy data for acute exposure to opioids during less than 24 hours.

Most of these short-term studies (16) reported pain outcomes, and with contradictory results: 8 studies reported less pain with opioids than placebo; 2 reported that some but not all participants benefited; 5 reported no differences; and, 1 reported equivocal results. Six studies, with about 170 participants, found that mean pain scores with opioid were only about 15/100 points less than with placebo.
[....] [two large paragraphs are refusing to copy, please consult the original article by clicking on the title.]

COMMENTARY:
Trials included in the systematic review by McNicol and colleagues examined various painful neuropathies, but predominantly postherpetic neuralgia and peripheral diabetic neuropathy. Few trials included patients with back pain primarily of neuropathic origin, which may be common in some patient populations.
This could be important, since it often is difficult to diagnose back pain as being purely neuropathic in origin, without also including a nociceptive component that might be amenable to opioid therapy. Along with that, in the current review, there were insufficient numbers of participants diagnosed with each type of neuropathy to perform subanalysis of efficacy or safety, which lessens the precision and clinical usefulness of the conclusions.
McNicol et al. suggest several other points of some importance….

• The lack of efficacy found with short-term opioid administration should not be interpreted as predictive of whether administration of opioid analgesics could be helpful longer-term for neuropathic pain in individual patients.
• Despite study limitations and possible sources of bias, the NNT outcomes (as noted above) do suggest that opioids may reduce various forms of neuropathic pain. Therefore, McNicol and colleagues suggest that “opioids at low-to-moderate doses are suitable for use over periods of weeks to months in the treatment of neuropathic pain.”
• The use of a single dimension (eg, pain scales) for efficacy assessment in the available studies is problematic, since neuropathic pain is a multidimensional phenomenon that varies from one patient to the next. Also, it is important to demonstrate improvements in specific features of neuropathic pain (eg, evoked or burning pain, etc), in emotional or physical aspects of functioning, and/or in health-related quality of life that might be expected of truly effective analgesic therapy.
• The meta-analyses conducted in this review showed similar opioid responsiveness for neuropathic pain of central and peripheral etiologies, but data were insufficient to resolve any debate regarding the differential efficacy of opioids for these two types of pain.
• A dose-dependent analgesic effect was found in 2 studies examined in the review; however, the dose ranges tested were still in the low-to-intermediate range and may not necessarily reflect clinical practice in some countries. McNicol et al. state, “This, along with increasing concerns about opioid toxicity, especially at higher dose ranges (greater than the daily equivalent of 200 mg of oral morphine), does not support the use of high doses of opioids for the relief of neuropathic pain.”

It is always amazing, yet important, that so many persons with pain are willing to participate in placebo-controlled trials, knowing (due to informed consent) that there is a chance they will not be administered active-drug therapy. Despite this, only 12% of participants receiving placebo withdrew due to a lack of analgesic efficacy, which suggests a considerable placebo effect in such trials. At the same time, NcNicol et al. concede that participants willing to enter these trials may not always be typical of those in everyday clinical practice.
Furthermore, the researchers observe, “intermediate-term studies are more clinically relevant than short-term studies because they assess the benefits and risks associated with opioid treatments for weeks to months; that is, they reflect how opioids are administered for neuropathic pain in clinical practice.” They conclude that intermediate-term opioid treatment has a beneficial effect over placebo for spontaneous neuropathic pain as measured by both number of participants with at least 33% and at least 50% pain relief and in mean differences in post-intervention pain intensity.
At present, however, there are inadequate data to demonstrate improvements in many aspects of emotional or physical functioning afforded by opioids in treating neuropathic pain. And, despite the favorable intermediate-term outcomes regrading pain relief, research data are lacking to verify whether opioids may provide relief of chronic neuropathic pain during administration periods longer than 6 to 12 weeks.
REFERENCE: McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews. 2013, Issue 8, Art. No. CD006146 [abstract here].

BCBS/Regence Medical Policy Manual on CALMARE / Scrambler / TENS for Neuropathic Pain

                                                                               

Medical Policy Manual 
Topic: Transcutaneous Electrical Modulation Pain Reprocessing
Date of Origin: November 2011
Section: Medicine
Last Reviewed Date: November 2012
Policy No: 143
Effective Date: January 1, 2013

IMPORTANT REMINDER
Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

DESCRIPTION
Transcutaneous electrical modulation pain reprocessing (TEMPR), also called scrambler therapy, is intended to interrupt transmission of pain signals by delivering electrical stimulation that is interpreted by the nervous system as “no pain”. Scrambler therapy is performed using a type of transcutaneous electrical stimulation (TENS) device that is specifically designed for this therapy. Cutaneous nerves are stimulated using 5 surface electrode pairs (i.e., channels) that are placed in the dermatomes above and below the pain area.
Unlike conventional TENS, scrambler therapy is administered in the office setting under physician supervision. According to Competitive Technologies, Inc., the makers of Calmare® Pain Therapy device, “the physician provides the initial consultation to discern the most effective path for electrode placement. Treatment applications are interactive between the patient and the provider, with the provider attending and making adjustments approximately every 10 minutes throughout the treatment session, which typically lasts an hour.”

Regulatory Status
The Calmare® Pain Therapy device (Competitive Technologies, Inc.) has 510k approval (K081258) from the U.S. Food and Drug Administration (FDA) under the name Scrambler Therapy MC-5A TENS


MEDICAL POLICY CRITERIA
Transcutaneous electrical modulation pain reprocessing (e.g., scrambler therapy) is considered investigational for the treatment of acute or chronic pain, including but not limited to the following:
A.
Arthritis (any type)
B.
Back and neck pain, chronic or acute
C.
Cancer pain
D.
Chemotherapy-related pain
E.
Musculoskeletal pain
F.
Neuropathic pain
G.
Pain syndromes [e.g., complex regional pain syndrome (CRPS); reflex sympathetic dystrophy (RSD)]
H.
Post-operative pain
I.
Traumatic injury
J.
Visceral pain

SCIENTIFIC EVIDENCE

Background
The most clinically relevant outcomes of therapy for intractable pain are improvements in pain and/or function. Both of these outcomes can be influenced by nonspecific effects, placebo response, natural history of the disease, and regression to the mean; therefore, these therapies need to be evaluated in randomized, controlled trials that maintain satisfactory blinding of the treatment assignment. The appropriate control for electrical stimulation devices for treatment of pain is sham treatment. Pain outcomes require quantifiable pre- and post-treatment measures, which are most commonly measured with a visual analogue scale (VAS). Collectively, the pain measurement literature cautions against using only statistical significance of difference in mean change in scores to determine clinical significance. More meaningful to patients and clinicians is the correlation of improvement in pain scores with improvement in function and quality of life. Thus, quantifiable pre- and post-treatment measures of functional status are also necessary.


Literature Review

Randomized controlled trials (RCTs)
There are no randomized trials that compare active with sham scrambler therapy. The only published RCT is a small, short-term pilot study that compared scrambler therapy with pain medication in 55 patients matched for type of pain which included postoperative neuropathic pain, postherpetic neuralgia, or spinal canal stenosis.[1,2] The authors reported significantly greater pain reduction in the scrambler therapy group compared with the medication control group at 1-, 2-, and 3-month follow-up. While this RCT is useful in informing hypothesis formation, it does not permit conclusions on efficacy and safety due to small size, lack of a sham control group, and short-term followup period.

Nonrandomized trials
The remaining published trials are limited to nonrandomized trials.[3-6] Evidence from these studies is unreliable due to methodological limitations, such as non-random allocation of treatment, non-blinded study design, and lack of comparison groups.

Clinical Practice Guidelines
There are no clinical practice guidelines from professional associations that recommend scrambler therapy.

Summary
The evidence is not sufficient to permit conclusions about the benefits of transcutaneous electrical modulation pain reprocessing (scrambler therapy) as a treatment for pain from any etiology; therefore this therapy is considered investigational.

REFERENCES
1. Marineo, G, Iorno, V, Gandini, C, Moschini, V, Smith, TJ. Scrambler Therapy May Relieve Chronic Neuropathic Pain More Effectively Than Guideline-Based Drug Management: Results of a Pilot, Randomized, Controlled Trial. J Pain Symptom Manage. 2011 Jul 13. PMID: 21763099
2. Marineo, G, Iorno, V, Gandini, C, Moschini, V, Smith, TJ. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J Pain Symptom Manage. 2012 Jan;43(1):87-95. PMID: 21763099
3. Sabato, AF, Marineo, G, Gatti, A. Scrambler therapy. Minerva Anestesiol. 2005 Jul-Aug;71(7-8):479-82. PMID: 16012423
4. Marineo, G. Untreatable pain resulting from abdominal cancer: new hope from biophysics? JOP. 2003 Jan;4(1):1-10. PMID: 12555009
5. Smith, TJ, Coyne, PJ, Parker, GL, Dodson, P, Ramakrishnan, V. Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare(R)) for chemotherapy-induced peripheral neuropathy. J Pain Symptom Manage. 2010 Dec;40(6):883-91. PMID: 20813492
6. Ricci, M, Pirotti, S, Scarpi, E, et al. Managing chronic pain: results from an open-label study using MC5-A Calmare(R) device. Support Care Cancer. 2012 Feb;20(2):405-12. PMID: 21394458

CROSS REFERENCES
Functional Neuromuscular Electrical Stimulation, Regence Medical Policy Manual, Durable Medical Equipment, Policy No. 83.04
Interferential Stimulation for the Treatment of Pain, Regence Medical Policy Manual, Durable Medical Equipment, Policy No. 83.07
Sympathetic Electrical Stimulation Therapy, Regence Medical Policy Manual, DME, Policy No. 83.08
Pulsed Electrical Stimulation for the Treatment of Arthritis, Regence Medical Policy Manual, DME, Policy No. 83.10
Percutaneous Neuromodulation Therapy (PNT), Regence Medical Policy Manual, Surgery, Policy No. 44



© 2013 L. Ryan

CTTC: Ask not for whom the Trolls Troll...

From InvestorsHub June 4, 2013, CTTC Chart

Too late to protect the itty-bitty minded investors in CTTC,  and all the real (non-testimonial inclined, but REAL) sufferers of severe and unrelenting neuropathic pain who were still stupid enough to pay for "treatments" with a super-duper TENS unit with extra gadgetry and a cool sounding fictive Italian provenance, treatments "personally overseen" by chiropractors and obstetricians, President Obama has announced that he's going after "patent trolls."

Upon the briefest of bleary-eyed inspection, all the CALMARE claims of "FDA approval" and "VA administration vendorship" go *poof* and turn into multicolored dried fairy turds that drift down upon us all, midst squeals of "Ew, what is that crap?"

But whatever else they've done, they've reaped the profits of their soul-sucking patents, knowing how to fill out those forms!

I'm no longer a participant in the earth-shattering dialogues taking place over at Investors Hub Competitive Technologies Inc (CTTC) Stock Message Board, where the crap flies without benefit of multi-colored, sparkly, fresh baked muffin scented fairy large intestine beautifications.  But I continue to read it, marveling at the right wing tactic adopted by the losers still defending this "company."  Lie, lie, lie, and lie again!  Fellatio in fellowship, sucking every last drop, never allowing the thought of real people, suffering, to get between the suction of their deep throats and the possibility of a few more bucks off of... not CALMARE, not "Scramber Therapy" or any other made up curative for the most difficult to treat pain dysfunctions known to medicine, from diabetic neuropathy to chemo-induced addlepating allodynia, to my personal favorite, CRPS -- no, none of that trivia.  They're sucking up the goodness of the coming dollars and euros made in strange contracts over... patent rights.  (What I don't get is why a good lawyer couldn't tear those contracts and deals apart by claiming false representation, because hasn't it been made clear, even to the most deftly daft, that Guido Marinara has misrepresented himself and his qualifications so many times that it's now a running joke?  But... Guido Marinara is something of a genius in these schemes, so he's probably avoided signing anything with his personal DNA smeared on it.  Sigh.)

French in Uproar....

I'd like to share with the evil people still supporting CTTC that I am now screaming in my sleep.  Okay, truth be told (they may need to look it up -- that's T as in Testimonial, R as in Rigmarole, U as in Unsubstantiated, and so on, ending with the big H of Hypocrisy) -- Truth be told, I've been screaming in my sleep for years, but there is a difference, qualitative and quantitative.  Now, I wake myself up as well as everyone else in The Manor, and I also require assistance to straighten my legs, turn a bit, and adjust matters so that there might be a modicum of relief.  I am unable to help myself now that my screaming has turned so bitter.  The pain tablets have to be placed in my mouth and my "Hillary for President" water bottle has to be brought to my lips.  It's humiliating, and it's scary terrifying to the people who love me.  The cats, also, are not amused, as they wish to be sole patent-holders of middle of the night caterwauling.

Anyway, from President Obama's lips and signatory pens to your investment "strategies," CTTC-ers and all your loathesome ilk:

Oh, I should say this.  It's only my theory that "patent trolling" is behind CTTC's bizarre business model.  I think it may actually have taken place -- but more in the Old Country than here in the New One.  That Italian pseudo-professor, pseudo-engineer may have out pseudo-ed a good many good old boys with a very simple scheme.

But some sort of benefit from what is essentially frivolous patenting, legal patent fraud, has to be behind CALMARE and CTTC... it cannot all be pure evil, a plot to cause those of us who scream in our sleep from pain to fork over the bucks for extra wires and knobs, chiropractors and baby-catchers.  Can it?

Is it a fluke that in the first paragraph in their forthcoming "About us" section on the CTTC website, the Founding Fathers state, clearly enough for me:

Working across a broad spectrum of disciplines and industries, CTTC provides distribution, patent and technology transfer, sales and licensing services to intellectual property owners seeking to commercialize their innovative products and technologies.

Oh, I forgot!  The company released its fascinating 2012 SEC Form10-K.  I don't know how to decipher these documents but I do recognize old-fashioned silly bullshit when it wafts before moi -- as in... compare some of these claims with the company actually doing the production of this hot product in Seoul, Korea. I did reasonably well in math, and even better in reading comprehension, back in second grade, at least, and I spotted the source of the stink unaided.  Anyway.  I am just hoping there will be some sort of prosecution here on Earth and that the FDA and the SEC don't defer everything to the Heavenly District Courts.  Nothing much approaches the level of gratuitous relief of a Balm of Gilead like indictments and public excoriation...

This article from CNNMoney was written by David Goldman [@DavidGoldmanCNN]  on June 4, 2013: 12:19 PM ET.

Obama cracks down on patent trolls

The Obama administration issued a stern rebuke of so-called "patent trolls" Tuesday, in an attempt to stop those whom the White House says manipulate the patent system for undue financial gain.

The White House directed the United States Patent and Trade Office to take five new actions that would help stem the rising tide of patent-related lawsuits tying up the court system. Many patent-holding companies with no intention of ever releasing products have made an entire business model out of suing other companies for patent infringement.

The USPTO will now require that patent-holding companies disclose who really stands to benefit from a lawsuit and identify the ultimate patent holder for each application and assigned patent. In many cases, patent-holding entities will create shell companies that allow them to hide their identities, the scope of their portfolios, and connections with other patent-holders.

The White House also wants the USPTO to train examiners to cut down on overly broad patent claims, educate small inventors about how to deal with patent trolls, and expand its outreach to inventors to help develop policies and laws.

In addition, the administration ordered a review of the U.S. International Trade Commission, which has the ability to ban imports of goods deemed to infringe on patents. Patent-holding companies are increasingly taking their claims to the ITC, and the White House would like their enforcement decisions to be made more transparent and efficient.

The Obama administration has made patent reform a priority, passing the first major overhaul of the patent system since 1952. That 2011 bill allowed the USPTO to set its own fees, gave patents to the first inventor to file a claim, and aimed to help keep some cases out of the courts. But the president clearly wants more to be done.

On a Google (GOOG, Fortune 500) Hangout in February, Obama said patent trolls abuse a system that was designed to protect inventions and foster innovation.

"They don't actually produce anything themselves," Obama said. "They're just trying to essentially leverage and hijack somebody else's idea and see if they can extort some money out of them."

Intellectual Ventures is a notorious example of a "patent troll" company. The research firm, based around the corner from Microsoft's headquarters in the Seattle area, acquires thousands of patents and has a research lab to develop its own. Yet it has no products to speak of. The company engages in constant patent litigation, and many tech companies have accused Intellectual Ventures of stifling innovation.

Intellectual Ventures said it is reviewing the administration's actions but declined comment for this story. 

The White House also asked Congress to pass laws that would have an even greater impact to curb "abusive" lawsuits. 

Among the recommendations are protections for consumers sued by patent trolls, ensuring that the ITC has flexibility to hire qualified judges, and awarding attorney's fees for court filings deemed to be "abusive."

Many technology giants have supported the administration's actions on patent reform. Tech companies are among the most-sued firms by patent trolls, and many have annual legal fees that outweigh their yearly spending on research and development. Patent lawsuits involving Apple (AAPL, Fortune 500), Samsung, Google, Oracle (ORCL, Fortune 500), Nokia (NOK), Microsoft (MSFT, Fortune 500) make daily headlines, often resulting in payouts totaling billions of dollars.

Google, whose chairman Eric Schmidt is an outspoken friend of the Obama administration, has stated that it will no longer proactively sue other companies for abuse of open-source software patents. A Google spokesman said the company welcomes the White House's actions on Tuesday.

The Association for Competitive Technology industry association, of which Microsoft, Apple, Intel (INTC, Fortune 500) and Facebook (FB) are sponsors, praised the executive actions.

"The patent system is critical to the innovation economy, but patent trolls are endangering startups around the world," said Morgan Reed, ACT's executive director, in a statement.  

Are you an entrepreneur or small business that has dealt with possible bad-faith claims of patent infringement? Email parija.bhatnagar@turner.com and you may be included in an upcoming story on CNNMoney.com.

CRPS: Spatial Perception (Where are my hand?)

Spatially defined modulation of skin temperature and hand ownership of both hands in patients with unilateral complex regional pain syndrome

1. G. Lorimer Moseley¹,², 
2. Alberto Gallace³ and 
3. Gian Domenico Iannetti⁴

+Author Affiliations

1. 1 The Sansom Institute for Health Research, University of South Australia, Adelaide 5000, Australia
2. 2 Neuroscience Research Australia, Sydney, Australia
3. 3 Faculty of Psychology, University of Milano-Bicocca, Milan 20126, Italy
4. 4 Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK

1. Correspondence to: Lorimer Moseley, Sansom Institute for Health Research, University of South Australia, GPO Box 2471, Adelaide 5001, Australia E-mail: lorimer.moseley@gmail.com

Received March 21, 2012.
Revision received August 16, 2012.
Accepted September 19, 2012.

Summary

Numerous clinical conditions, including complex regional pain syndrome, are characterized by autonomic dysfunctions (e.g. altered thermoregulation, sometimes confined to a single limb), and disrupted cortical representation of the body and the surrounding space. The presence, in patients with complex regional pain syndrome, of a disruption in spatial perception, bodily ownership and thermoregulation led us to hypothesize that impaired spatial perception might result in a spatial-dependent modulation of thermoregulation and bodily ownership over the affected limb. In five experiments involving a total of 23 patients with complex regional pain syndrome of one arm and 10 healthy control subjects, we measured skin temperature of the hand with infrared thermal imaging, before and after experimental periods of either 9 or 10 min each, during which the hand was held on one or the other side of the body midline. Tactile processing was assessed by temporal order judgements of pairs of vibrotactile stimuli, delivered one to each hand. Pain and sense of ownership over the hand were assessed by self-report scales. Across experiments, when kept on its usual side of the body midline, the affected hand was 0.5 ± 0.3°C cooler than the healthy hand (P < 0.02 for all, a common finding in cold-type complex regional pain syndrome), and tactile stimuli delivered to the healthy hand were prioritized over those delivered to the affected hand. Simply crossing both hands over the midline resulted in (i) warming of the affected hand (the affected hand became 0.4 ± 0.3°C warmer than when it was in the uncrossed position; P = 0.01); (ii) cooling of the healthy hand (by 0.3 ± 0.3°C; P = 0.02); and (iii) reversal of the prioritization of tactile processing. When only the affected hand was crossed over the midline, it became warmer (by 0.5 ± 0.3°C; P = 0.01). When only the healthy hand was crossed over the midline, it became cooler (by 0.3 ± 0.3°C; P = 0.01). The temperature change of either hand was positively related to its distance from the body midline (pooled data: r = 0.76, P < 0.001). Crossing the affected hand over the body midline had small but significant effects on both spontaneous pain (which was reduced) and the sense of ownership over the hand (which was increased) (P < 0.04 for both). We conclude that impaired spatial perception modulated temperature of the limbs, tactile processing, spontaneous pain and the sense of ownership over the hands. These results show that complex regional pain syndrome involves more complex neurological dysfunction than has previously been considered.*


*over-used punchline!

Graphic from CRPS UK

       

Useful adjunct article published in same journal, September 14, 2009, available in entirety (pdf)

Space-based, but not arm-based, shift in tactile
processing in complex regional pain syndrome
and its relationship to cooling of the affected limb


G. Lorimer Moseley [1]

Alberto Gallace [2,3]

and Charles Spence [3]

1 PaiN Group & Department of Physiology, Anatomy & Genetics, University of Oxford, UK and Prince of Wales Medical Research Institute &
School of Medical Sciences, University of New South Wales, Sydney, Australia
2 Department of Psychology, University of Milano-Bicocca, P.zza dell’Ateneo Nuovo 1, 20126 Milano, Italy
3 Department of Experimental Psychology, Oxford University, South Parks Road, Oxford OX1 3UD, UK

Correspondence to: G. Lorimer Moseley,
Prince of Wales Medical Research Institute,
Cnr Easy & Barker Streets,
Randwick, 2031,
Australia
E-mail: lorimer.moseley@gmail.com


Complex regional pain syndrome (CRPS) occurs after stroke, but most cases develop after peripheral trauma and without evidence of brain trauma. However, CRPS is associated with symptoms that appear similar to those observed in patients suffering from hemispatial neglect. Ten participants (four males) with CRPS of one arm performed temporal order judgements
of pairs of vibrotactile stimuli, one delivered to each hand, at one of 10 possible stimulus onset asynchronies, under two conditions: arms held each side of the midline and arms crossed over the midline. Participants released a foot switch to indicate which hand had been stimulated first. The order of conditions was randomized and the foot under which the switch was
positioned was counterbalanced. There were two blocks of 150 trials in each condition. The stimulus onset asynchronicity at which the participants were equally likely to select either hand, the point of subjective simultaneity (PSS), was compared between conditions and between those with left or right-sided symptoms. When arms were not crossed, the participants prioritized stimuli from the unaffected limb over those from the affected limb (mean SD PSS = 25 7.5 ms) and the magnitude of the PSS strongly related to the degree to which the affected hand was cooler than the unaffected hand (r = 0.942, P50.001). When the arms were crossed, the effect was reversed: the participants prioritized stimuli from the affected limb over those from the unaffected limb [PSS = –18 13 ms; main effect of condition F (1, 9) = 98.6, P50.001]. There was no effect of the side of
symptoms. These results show that CRPS is associated with a deficit in tactile processing that is defined by the space in which the affected limb normally resides, not by the affected limb itself, and which relates to the relative cooling of the affected limb. This pattern is consistent with data from those with hemispatial neglect after stroke and raises the possibility that chronic CRPS
involves a type of spatial neglect.

Abbreviations: CRPS = complex regional pain syndrome; JND = just noticeable difference; PSS = point of subjective simultan



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