Evidence-based Review of Neuromodulaton Treatments in CRPS: A Crisis of Data, A Crisis of Faith

This is an odd and interesting article.  It's honest and, to my understanding of things, a fair assessment of where we are at in available, actual CRPS neuromodulation treatments, of which I am not a fan, awaiting, like many, some evidence.  This is a kind of rubber-meets-the-road piece, beginning and ending with the usual lament of LACK OF EVIDENCE.  Clearly, it's going to be a long while before evidence-based practices will be scientifically established for this God-forsaken disease.  The full text is available in RSDSA.org's excellent research library, and you can access it (and download it) HERE.

Neuromodulation: Technology at the Neural Interface
(onlinelibrary.wiley.com) DOI: 10.1111/j.1525-1403.2012.00531.x

FROM THE EDITOR-IN-CHIEF -- Robert M. Levy, MD, PhD
Evidence-Based Review of
Neuromodulation for Complex
Regional Pain Syndrome:
A Conflict Between Faith
and Science?

While it was more than 20 years ago, I remember well the face of
a 19-year-old woman who presented to me with what was then
called reflex sympathetic dystrophy (RSD). Having sustained an
innocuous injury during gymnastics practice four years earlier,
Susan developed discoloration, swelling, and severe burning pain in
her foot and leg. Aggressive rehabilitation therapy, pharmacotherapy,
and even sympathectomy had failed to improve her symptoms.
A trial of spinal cord stimulation (SCS) was highly successful
and a permanent system was implanted with complete relief of her
pain and resolution of her symptoms. Most memorable to me was
that she returned seven years later, symptom free, requesting that
her stimulator be removed prior to her planned pregnancy. The
smile on her face as she held her newborn child was the only testament
that I needed to convincemyself of the efficacy of SCS for RSD.
Since that time, I have had many successes and more than a few
failures of SCS for what is now known as complex regional pain
syndrome (CRPS). We have developed new stimulation techniques,
including high-frequency and intraspinal nerve root stimulation, to
rescue the therapy in patients who were no longer obtaining relief.
Nonetheless, I remained a strong believer in the value of SCS for
CRPS, both due to my personal anecdotal experience and the
support of at least one randomized, controlled clinical trial (1).
CRPS is characterized by continuous, intense pain out of proportion
to the severity of an injury, if any has been identified, which
tends to get worse over time. Typical features include changes in
color and temperature of the affected limb(s) accompanied by
intense burning pain, skin sensitivity, sweating, and swelling (2).
CRPS type I occurs in the setting of a soft tissue injury, while CRPS
type II develops following nerve injury. Of particular note is that
neuromodulation therapies are widely considered to be valuable
therapies for medically refractory CRPS. In fact, the website of the
National Institute of Neurologic Diseases and Stroke states that
“Spinal cord stimulation. . .appears to help many patients with their
pain” and that “Intrathecal drug pump. . .decreases side effects and
increases drug effectiveness” (Figs. 1 and 2) (2).
It was with this mindset that I approached a recent satellite conference
of the International Association of the Study of Pain (IASP)
Meeting in Milan, Italy. Organized by Drs. Joshua Prager, Michael
Stanton-Hicks, and Candy McCabe, “A Comprehensive Analysis of
CRPS Treatment: The New, The Old,WhatWorks and What Doesn’t—
Updating the Treatment Algorithm” was an IASP Pain and Sympathetic
Nervous System Special Interest Group symposium and CRPS
guidelines update meeting (Figs. 3–5).
With the participation of such august clinicians and neuroscientists
as Ralf Baron, Frank Huygen, Srinivasa Raja, and J.J. Van Hilten,
to name a few, this conference promised to be critically important
for the direction of CRPS research and therapy for many years to
come. I was honored to have been invited to critically review and
present the data supporting neuromodulation therapies for CRPS.
In performing a formal, evidence-based review of the literature, I
expected that an objective and impartial evaluation would fully
support my strongly held personal beliefs of the efficacy of neuromodulation
therapies for CRPS. Suffice it to say that my faith was

seriously challenged.

[He goes on to do an evidence-based review of neuromodulation modalities in treating CRPS, in each case coming up with insufficient, or no, satisfactory studies to support evidence-based conclusions]

PERIPHERAL NERVE FIELD

STIMULATION (PNfS)

PERIPHERAL NERVE STIMULATION (PNS)

SPINAL COLUMN

STIMULATION (SCS)

DEEP BRAIN STIMULATION (DBS)

MOTOR CORTEXT

STIMULATION (MCS)

INTRATHECAL DRUG DELIVERY (ITDD)

NON-NEUROMODULATION THERAPIES

FOR CRPS

CONCLUSIONS
I come back to the subtitle of this article: a conflict between faith
and science. I have great personal faith that in carefully selected
patients, neurostimulation and ITDD can be effective treatments for
the pain and spasticity related to CRPS. To be completely honest, I
also have great faith that in some patients, neuromodulation helps
neither of these CRPS symptoms. However, we are left with a gap
between our faith and our science. I routinely recommend that we
assess our therapies with the same critical eye as those who do not
believe in the effectiveness of neuromodulation therapies. Those of
us immersed in the field of neuromodulation often look askance at
the literature supporting sympathectomy for CRPS; however, we
have seen that the literature support for both interventions is seriously
flawed.
While a lack of evidence is not a lack of effectiveness, it remains
a lack of evidence. When our patients, our society, and our reimbursement
systems all demand evidence-based support of our
clinical practice, we cannot ignore the fact that there is inadequate
evidence to highly recommend most neuromodulation therapies
for CRPS. Some issues cannot be scientifically proven, and in those
cases we must rely upon our faith for guidance. The efficacy of
neuromodulation therapies for CRPS is, however, something that
can be proven or disproven. We have come a long way toward this
goal over the past decade, but we have much more to do. External
funding agencies, including the National Institutes of Health, have
expressed a renewed interest in supporting comparative outcomes
and cost-effectiveness research. By taking advantage of
these opportunities and supporting properly designed, carefully
executed studies, we can finally answer these questions and
improve the effectiveness of chronic pain therapy.
Robert M. Levy, MD, PhD

Editor-in-Chief

"Above all else, stay in life."

These were my feet, or as I call them "the things at the end of my legs," back
in 2011, which partially explains my reticence to update their current loveliness.  This is just to give
those who are unfamiliar with advanced CRPS an idea of what it can look like.  What it
feels like is in the realm of "difficult to describe without obscenities."  I have it in both arms and legs and
in the lower portion of my face.

If you sometimes feel the not-so-subtle pull of bias as you research articles and studies about CRPS, you may appreciate the work of the Cochrane Collaboration:

The Cochrane Collaboration is named after Archie Cochrane (1909-1988), a British epidemiologist, who advocated the use of randomised controlled trials as a means of reliably informing healthcare practice. We are an independent, not-for-profit organisation, funded by a variety of sources including governments, universities, hospital trusts, charities and personal donations.

In essence, they've assembled teams of researchers, possibly more diverse than most such teams, but no less qualified, that are guided by "what works." They review scholarly publications with effectiveness in mind, based on the evidence before them.

It is the kind of plain speaking that comes from thorough analysis, and that many of us need, especially when we are being offered and counseled all sorts of doom and gloom or wild therapies.  Sadly, some of these well-intentioned offers and counsels are motivated by an underlying greed.  Or so I hear...

So visit Cochrane Reviews --

Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care. They investigate the effects of interventions for prevention, treatment and rehabilitation. They also assess the accuracy of a diagnostic test for a given condition in a specific patient group and setting. They are published online in The Cochrane Library. 

Each systematic review addresses a clearly formulated question; for example: Can antibiotics help in alleviating the symptoms of a sore throat? All the existing primary research on a topic that meets certain criteria is searched for and collated, and then assessed using stringent guidelines, to establish whether or not there is conclusive evidence about a specific treatment. The reviews are updated regularly, ensuring that treatment decisions can be based on the most up-to-date and reliable evidence.

For everyone who already knows that regional or sympathetic blocks are largely ineffective and are still used mainly as a money-maker, this kind of evidence-based review can ease your mind.  And it is something you can cite when the procedure-oriented pain management clinics schedule your 200th block without any evidence of success the first 199 tries!

On the other hand, it is gloomy news, but not unexpected.  There is no magic bullet, no cure, no one therapy that has had overwhelming success, or even what most people would consider any success at all.  We patients with CRPS tend to look at one person who responds well out of a cohort of thirty as phenomenally good news!  There is much that is, as they say, "in the pipeline," but until those treatments come rolling out the medical assembly line and into the arsenal of our own local physicians, we are stuck with the "throw everything at it" approach.  

This is a frustrating way to deal with a horrific disease that not only debilitates the body, but the mind and one's social body, as well.  It empties our pockets and it empties our date books of most everything except medical appointments.  Even my dear Fred says, from time to time, that he cannot stand seeing and hearing about so much pain day in, day out.  (That's where we get our strangely grim smiling faces and gravely laughter from! The effort of suppressing the expression of what we have to feel is also debilitating.)

So take your cues from the "best evidence," rely on "what works" for you, and be vigilant about following research.

I don't mention it often, but think of it daily:  Back in the beginning years of coming to terms with this disorder, about which my doctors only offered confusion and pessimism (two of them cried), I kept running into the name of Drexel University Chair of Neurology, Dr. Schwartzman.  This was years before he offered me an "expedited appointment," which turned out to actually mean "over two years" away.  This was in the days of "What the heck is happening to me?  When will this pain stop?  Where are my legs!? What's wrong with my hands?"  I emailed him in the middle of the night, as the middle of the night is when most CRPSers are up.  In later years, he and his staff would send his research papers, making me break out dictionaries and strain my brain to understand.  Back then, however?  He gave me some summary information, was very kind, but the greatest thing he gave me was this gift of advice --

 "Above all else, stay in life."

-- Dr. Robert Schwartzman
(recently retired, just discovered! a well-deserved rest to him!)

It took me years to peel the layers of that onion... and I am peeling, still.  My appointment will never happen, and would be pointless now, but that bit of wisdom can be salvation in a rough moment.  Use it yourself, if you need it.  I don't think he'd mind...

I return you now to the Cochrane Review!



Which treatments are effective for the treatment of complex regional pain syndrome in adults?

O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL
Published Online: April 30, 2013


Abstract 

Background: 
There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used.

Objectives: 
To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS).

Main results: 
We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.

There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.

There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.

For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn.

Authors' conclusions: 
There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult.

This record should be cited as: O'Connell NE, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD009416. DOI: 10.1002/14651858.CD009416.pub2

Assessed as up to date: March 1, 2013
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