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

I cannot help it, I am full of hope...

One of the numerous feeds to which I subscribe channels news about CRPS -- that's not likely a shock to you!

What probably is news is that whenever I prepare to click on the summarizing email, my lungs, my mind, my heart, all fill with hope. Once I see what news awaits, that hope normally fizzles and fades, losing all its precious buoyancy.

I have an appointment with Dr. PainDude in a little under two hours. It has been a long while since I showed up with papers in hand, with hope. I just printed the following article, and almost miss the days of toner smell, mimeograph fumes. Today, the paper gives nothing away.

It blurs my eyes, these words: The team at the Pain Research Institute discovered that a single, low dose infusion of intravenous immunoglobin (IVIG) significantly reduced pain in just under 50 per cent of patients treated, with few adverse effects. The pain relief lasted on average 5 weeks.

O Christ, O God Almighty: Let it be true.

The text in its entirety below. I will do further research this afternoon.


Scientists at the University of Liverpool have discovered that treating the immune system of patients with Complex Regional Pain Syndrome (CPRS) leads to a significant reduction in pain.

CRPS is an unexplained chronic pain condition that usually develops after an injury or trauma to a limb, and continues after the injury has healed. CPRS I - formerly called Reflex Sympathetic Dystrophy - can arise after any type of injury. CRPS II, previously called causalgia (a term coined in the American Civil War when it was first diagnosed), follows partial damage to a nerve. In some cases the pain can be so severe that patients request amputation, only to find that the pain returns in the stump.

CRPS pain can improve within one year after the injury, but if it is still unchanged after 12 months (longstanding CRPS), then it will often not improve at all. Longstanding CRPS affects about 1 in 5,000 people in the UK.

The team at the Pain Research Institute discovered that a single, low dose infusion of intravenous immunoglobin (IVIG) significantly reduced pain in just under 50 per cent of patients treated, with few adverse effects. The pain relief lasted on average 5 weeks. The results of this study may change the future treatment of patients with CRPS, and have an impact on research in other severe chronic pain areas. Intravenous immunoglobulin treatment for CRPS is currently not available on the NHS.

Although the cause of the syndrome is unknown, precipitating factors include injury or damage to the body's tissue. Changes in the way nerves send messages to the brain about pain may occur at the injury site. These changes may then lead to more changes in the nerves of the spinal chord and brain. All these changes are thought to play a role in causing and prolonging the condition. Conventional pain drugs either don't work, or have considerable side effects.

Dr Goebel, Senior Lecturer in Pain Medicine, explains: "In CRPS, the real effect of this treatment in clinic may turn out to be even greater than what we have already seen, because IVIG can be given in higher doses, and repeated treatment may have additional effects. IVIG is normally repeated every four weeks and we are working to develop ways which would allow patients to administer the treatment in their own home."

"The discovery is expected to have a real impact on the treatment of other unexplained chronic pain conditions; if one pain condition can be effectively treated with an immune drug, then it is possible that other types will also respond."

The research is published in the journal Annals of Internal Medicine.

Notes: [....]
The research was carried out in collaboration with University College London.
Research activities on the role of the immune system in chronic pain are the focus of the newly created 'Centre for Immune Studies in Pain' (CISP) at the University of Liverpool, led by Dr. Goebel. For further details visit www.liv.ac.ukpricisp. Support for these and other research activities aimed at relieving chronic pain comes from the Pain Relief Foundation in Liverpool.

Source:
Sarah Stamper
University of Liverpool

Aha! A better article,* of course, is available at RSDSA.org -- from The Annals of Internal Medicine (cutting to the chase, "results... limitation... conclusion"):

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.

*yes, it is a bit of cold water... damn it.

**************************************************************************************************
later... in an email to my sister-in-law, this brief but exciting episode was summarized thusly:

i got all excited this morning by a news report that i.v. immunoglobulin had been found to "significantly" reduce pain in CRPS. an hour later, i found out that the big study had all of 13 people in it, one of whom dropped out. "just under 50%" of the participants had positive results. let's see. putting on my thinking cap. half of 12, six. okay, "just under" must mean... FIVE. then hank did his "statistics" speech: there must be at least a cohort of 30 to be statistically relevant... sometimes, i wish he would keep all that book learnin' to himself. i should have known that when something sounds too good to be true, it probably is.

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


Friday, 5 February 2010:

Further tidbits keep popping up. An editorial accompanied the published research. It sought to temper impulsive enthusiasm as a response to this study, emphasizing caution and the tremendous need for more work. In case you've not kept up with the exciting times in CRPS/RSD research, the authors give a quick gloss at the beginning of their editorial -- and I am resolved to place my hope in that steady progress. It's just that when severe chronic pain and disability roll on unabated for eight years? Well, it can be difficult to be positive. So I tend to grab and latch on to any research that makes sense. I don't mean to mislead anyone by these occasional bursts of unwarranted optimism; Please pardon me if I inadvertently played upon your heartstrings. Also, my case of CRPS is pretty awful and I sometimes forget that most cases are not this bad. I shouldn't be dragging you into my freak show!

Editorial: Intravenous Immunoglobulin to Fight Complex Regional Pain Syndromes: Hopes and Doubts
Frank Birklein, MD, PhD; and Claudia Sommer, MD, PhD

From University of Mainz, Mainz 55131, Germany; and University of Würzburg, Würzburg 97080, Germany.

Chronic pain is multifaceted. It involves changes in somatosensory processing from the primary afferent neurons to the brain; it induces negative emotions, such as fear and depression; and it often entails serious consequences for working ability and personal life. Long-standing complex regional pain syndrome (CRPS) has all of these features and may be associated with substantial reduction of limb function, leading to physical impairment.

In recent years, we have made progress in understanding CRPS. Studies of the acute phase of posttraumatic CRPS show the importance of cytokines and growth factors for pain and hyperalgesia; the involvement of peptides in changes in skin perfusion, edema, and sweating; and the effect of sympathetic neurotransmission on pain in selected patients. We have learned that in long-standing CRPS, cortical reorganization of sensory, motor, and autonomic function might underlie the profound disturbances of the body reference scheme. Although acute CRPS can be challenging to treat, the outcome is often favorable. Treatment of chronic CRPS, when central neuroplastic changes are fully established, is especially difficult.

And so concludes a pretty accurate, if embarrassing, example of my emotional ups-and-downs as I follow the thread of medical news, in real time [as real as it gets at Marlinspike Hall, deep, deep in the Tête de Hergé (très décédé, d'ailleurs)]. Despite my initial over-reaction, all the subsequent information did not cause too much grief -- it simply served as a reminder that this is serious business, for serious people, and that one mustn't let hope get out of hand.

Right?


2/15/2010: I was definitively told, via bullhorn, to "step away from the study... toss your hope on the ground and step away from ridiculous hope." Yes, the Hope Police came down on me like the proverbial ton of bricks. My case is extreme; My case is refractory; My course is "complicated." And then there was this surprise statement from Dr. Go-To Guy: "Bianca, ma belle, this is old news."

As soon as I get my breath back, lobbying will begin for a little offlabel use of immunoglobulin. Shhhhh!


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