This is in response to Sandy's request the other day that I clarify my post under the heading of "Differential expression patterns of cytokines in complex regional pain syndrome."

To begin with, a "pro-inflammatory cytokine" is any number of protein messengers that trigger an inflammatory response. (And for a more precise definition of cytokine, see the online mondofacto medical dictionary at http://www.mondofacto.com/facts/dict...ion=look+it+up)

One, such pro-inflammatory cytokine that has been identified as, among other things, an independent risk of death from cardiac artery disease (CAD), in some but not all studies, is something called Interleukin-6 or IL-6. Now, in 2005, a paper came out finding relatively high levels of IL-6 in the cerebral spinal fluids of CRPS patients. Changes in Cerebrospinal Fluid Levels of Pro-inflammatory Cytokines in CRPS, Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzmann RJ, Pain, 2005; 116: 213-219, free full text at http://www.rsds.org/2/library/articl.../alexander.pdf

As you might imagine, this got a lot of people excited. On a referral from a rheumatologist I saw a year later that the Mayo Clinic, I went packing to Johns Hopkins in the thirds week of October, 2006 to try to get into a large trial of an anti-IL-6 drug, only to have cold water thrown in my face: first the trial was at that time only open to people with defined rheumatological conditions, and CRPS wasn't one of them, and, more importantly, while it was believed the link between IL-6 and, for instance, CAD was quite high, it's role in CRPS was described to me as "iffy," notwithstanding the 2005 article of Alexander, et al. And, sure enough, a month later out came the epub of a second study by essentially the same group of authors reporting somewhat less robust results:

Changes in immune and glial markers in the CSF of patients with Complex Regional Pain Syndrome, Alexander GM, Perreault MJ, Reichenberger ER, Schwartzman RJ, Brain Behav Immun., 2007 Jul; 21(5): 668-76. Epub 2006 Nov 28.

Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. guillermo.alexander@drexelmed.edu

Complex Regional Pain Syndrome is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. The pain in CRPS is continuous, it worsens over time, and it is usually disproportionate to the severity and duration of the inciting event. This study compares cerebrospinal fluid (CSF) levels of pro- and anti-inflammatory cytokines, chemokines and several biochemical factors (glial fibrillary acidic protein (GFAP), the nitric oxide metabolites (nitrate plus nitrite), the excitatory amino acid neurotransmitter glutamate, calcium, total protein and glucose) in patients afflicted with CRPS to levels found in patients suffering with other non-painful or painful conditions. The aim of the study is to determine the degree of involvement of glial cells and immune system mediators in the pathophysiology of CRPS. There was no elevation or reduction of a CSF marker that was specific for CRPS patients. However, there were several patterns of markers that could be helpful in both elucidating the mechanisms involved in the disease process and supporting the diagnosis of CRPS. The most common pattern was found in 50% (11 out of 22) of the CRPS patients and consisted of; elevated IL-6, low levels of IL-4 or IL-10, increased GFAP or MCP1 and increases in at least two of the following markers NO metabolites, calcium or glutamate. The results from this and other similar studies may aid in elucidating the mechanisms involved in the pathophysiology of CRPS. A better understanding of these mechanisms may lead to novel treatments for this very severe, life-altering illness.

PMID: 17129705 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

(I'm guessing that someone at Johns Hopkins was familiar with follow up study by Alexander et al, before it was posted online.)

It was against this background, and other related studies, that Differential expression patterns of cytokines in complex regional pain syndrome, Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C, Pain, 2007;132:195–205, free full text at http://www.rsds.org/2/library/articl...erle_Rolke.pdf came out, finding in part that:

We found elevated levels of pro-inflammatory cytokines and reduced levels of anti-inflammatory cytokines in patients with CRPS. Specifically, mRNA levels of the pro-inflammatory cytokines TNF and IL-2 and serum IL-2 protein levels were elevated, and mRNA levels of the anti-inflammatory cytokines IL-4 and IL-10 were reduced. TGFb1 protein levels were also lower in patients with CRPS. Taken together, these findings show a pro-inflammatory cytokine profile in our patients with CRPS. [Emphasis added.]

The point I was trying to make when I compared the Uceyler et al study of 2007 with Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups, Schinkel C, Scherens A, Köller M, Roellecke G, Muhr G, Maier C., Eur J Med Res. 2009 Mar 17; 14(3):130-5, was that the latter, and far more ambitious study - which had hoped to find a distinct pattern of change in cytokine expressions, as the disease went from the acute to chronic stage - instead only found a handful of changes in CRPS patient from controls (notably finding no significant change in the levels of either IL-2 or IL-6, in which the Uceyler and Alexander groups, respectively, found significant changes) and concluding instead:

Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I.

Now, at first blush, it looks like the authors as saying "pattern, what pattern?" But having given it some consideration, I'm starting to think that their findings tell a new story altogether.

Now this is not to say that there is no evidence of an inflammatory response in acute cases of CRPS, where the 2009 study by Schinkel et al apparently found statistically significant differences in between acute cases, on the one hand and chronic cases on the other hand, in the levels of IL-12, Substance P (a protein found in the brain and spinal cord that is associated with some inflammatory processes in the joints), and Tumor Necrosis Factor-Alpha, a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction, and is among other things the key mediator of septic shock in response to infection. But the sole statistically significant difference that was found between patients with chronic CRPS and healthy volunteers that Schinkel et al found was with respect to something called calcitonin gene-related peptide (CGRP).

Now, it turns out that CGRP is far from uninteresting. As I posted last night on the "Botox" thread, when I ran a Wikipedia search on CGRP, it noted, among other things, that:

It is the most potent peptide vasodilator and can function in the transmission of pain [fn. 2: Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985), "Calcitonin gene-related peptide is a potent vasodilator," Nature 313 (5997): 54–6] [fn. 3: McCulloch, J., et al. (1986), "Calcitonin gene-related peptide: Functional role in cerebrovascular regulation," Proc Natl Acad Sci USA 83: 5731–5735, abstract at http://www.pnas.org/content/83/15/5731] . . . . CGRP receptors are found throughout the body suggesting that the protein may modulate a variety of physiological functions in all major systems (eg, respiratory, endocrine, gastrointestinal, immune, and cardiovascular). Increased levels of CGRP have been reported in migraine and Temporomandibular joint disorder patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.

Regulation of the calcitonin gene related peptide (CGRP) gene is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway, cytokines such as TNFα and iNOS. 5HT1 agonists such as sumatriptan increase intracellular calcium which cause decreases in CGRP promoter activity. Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein [fn. 15: Durham, P., R. Cady, and R. Cady (2004), "Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy," Headache 44 (1): 35–42, abstract at http://www3.interscience.wiley.com/j...RY=1&SRETRY=0]. Receptor antagonists such as telcagepant, which is in phase III from Merck Pharmaceuticals, also has promise in limiting the effects of CGRP [fn. 16: Tepper, S.J. and M.J. Stillman (2008), "Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine," Headache 48 (8): 1259–68, abstract at http://www3.interscience.wiley.com/j...4225/abstract] [Citations partially omitted; emphasis added.]

http://en.wikipedia.org/wiki/Calcito...elated_peptide

Bottom line: there may well be a single and quite specific inflammatory aspect to chronic CRPS, but there's no reason that I can see in the literature to believe that those agents which tend to reduce most acute inflammation will necessarily have any effect on it.

I hope this clarification is helpful.

Mike

I attended a pain conference recently, and this subject came up:

Opiates actually stimulating pain, thru the reaction of glial cells in the nervous system sending out inflammatory cytokines that induce further pain response.

This is one paper that discusses it:
http://www.nature.com/npp/journal/v2.../1300315a.html

If you Google "morphine glial cells" you can find others.

This is pretty new, and some doctors are unaware of this research at this time. But this finding is explaining why people with chronic head pain, develop MORE pain when using opiates for it.

Other links of interest:
http://www.colorado.edu/honors/Honor...teraction.html

and this is interesting too:
http://www.neurologyreviews.com/09mar/C1.html

This is a pretty complex subject.

Mrs D my pain doctor just told me that too and why he feels long term other then just severe flare ups opiates are not the way to go. I am still confused I guess as what is one supposed do and you do hear of people on here that are benefiting from them on a more regular basis. Thanks for those links.

I don't know Daniella....the research is looking for a way to
block the glial cells responses. The last link I gave explains that.

This information is definitely going to be influencing the FDA and other government actions in the near future. There will be quite a uproar...wait and see.

Mrs. D -

But the papers on morphine glial cells do not explain the vasodilation/edema of CRPS, whereas high levels of CGRP might, don't you think?

From my perspective, any theory of CRPS, not simply one's garden-variety back pain, that can't address vasodialation, can only explain how too high an opioid comsumption can only make our pain worse. And beyond that, may not worth the paper it's printed on, at least as to CRPS per se. Unless it can. Please discuss.

Mike

You are right up to a point.

What I see, is that the glia which holds the spinal cord and
brain together, is an active promoter of inflammatory cytokines. The RSD response is complex. Certainly the vaso effects are obvious. But then there is the PAIN part...some of that IS mediated in the brain centrally. I have been reading here some members who have had tolerance to opiates and also new pain/burning--the Opana posts by Dew. These responses are in addition to the regional damage, IMO. So I put this up because....because use of opiates for all chronic pain is on the table now, and may be very altered in the future. Based on the attitude of the specialist neurologists I heard discuss many chronic pain states, opiates are not going to be popular in the near future. That is unless Big Pharma finds a way to block this glial response, soon.

It just might be that the anti-inflammatory diet, helps with these issues as well as those in the periphery. I know myself that certain foods trigger my PN pain and burning significantly.
It stands to reason that others with chronic pain are also in a similar situation.
(I don't use opiates, BTW)

I've been away for a while.Just dropping in to see whats up with everyone.
I thought I'd repost the RSD Diet for those that may have missed it and still might be interested.
My best to you all. Di


01-14-2009, 03:39 PM #2
DianaA
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Join Date: Jun 2007
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RSD Diet

--------------------------------------------------------------------------------

Quote:
Originally Posted by screwballpookie
Hey you all,
I see everybody talks about the rsd diet and I don't know what it is. Can anyone help me? I would like to know what it is to see if it will help me as well. I am willing to try anything at least once to see if it helps. If it doesn't then I know what not to do. So please help me.

I also have another question. Can anyone explain in short form what HBOT is? If maybe it is something I can try to see if it helps with my pain. Thanks and you all take care.

Sincerely,
Tracy(screwballpookie)

Tracy, I hope this helps. Here's the copy I have. I picked this up on the interent,
All the best! Diana

RSD Diet Guidelines

Dr. Hooshmand states this diet isn't for losing or gaining weight. The purpose of this particular diet of his, is to exclude foods that are harmful to one's health and that aggravates chronic pain such as with RSD.

The Five C's you need to avoid are: cookies, cakes, chocolates, cocktails and Candy. Other foods that should be avoided are internal organ meats like: liver, sauage and hot dogs. There are certain foods that help the inhibitory nerve cells that suppress the pain input, and they are the Four F's: Fresh Fruit, Fresh Veggies, Fish and Fowl.

Four F's-

Fresh Fruit (not canned) Fresh Vegetables(Olive Oil is best to cook with) Fish-DOn't use margarine. Baked or broiled Fowl-Skinned. not fried.(baked, roasted or grilled is fine)

Foods that are allowed rarely or sparingly

Tea, Lamb, Pulp of potato

Foods To Avoid

Coffee, soft drink with sugar crystalline sugar ,Pies, Bologna, Salami, Hot Dogs, Sherbert ,Ice Cream, Enriched Flour(bleached) ,Syrups, Mayonnaise, All fried foods, Canned fruits packed in syrup, Candies, Bacon, or pork, Donuts, Margarine, Nondairy cream substitutes ,Alcohol, Cake Mixes ,Potato Chips, Dips ,Crisco & other shortenings(replace with olive oil), Lard, Sweetrolls and Cakes.

FOODS YOU CAN HAVE

Diet drinks(low to no sodium, no sugar or caffine) ,Nuts-salted & raw, Honey(natural) ,Skim Cheese, Apples, All Fresh Fruits, Unsweetened orange juice, Natural fresh squeezed orange or grapefruit juice ,Apple juice(natural), All Fresh Vegetables, Veal ,Chicken & Fowl(skinned) ,Lobster(no butter), Lean Roast Beef(moderation), Raisins ,Skim Milk, Tuna(packed in water). Drink 6-8 glasses water daily. Fruits(dried), Shrimp ,All Fish Cereals(low sugar , whole grain) Sardines Sweet Potatoe & skin Lowfat plain yogurt(add yoour own fruit), Lowfat cottage cheese, Oatmeal(plan and unflavored) ,Crab

here is the link to Dr Hoosmands Diet

http://www.rsdrx.com/four_f's_diet.htm

Dear Mrs. D -

I think that we are in full agreement that the CRPS patient is at equal risk with any other patient of developing Opioid Induced Hyperalgesia. I particularly enjoyed your posting of "Glial Cells—A New Target for Chronic Pain Treatment," with it's interview with Linda Watkins, Ph.D. For another treatment of the subject, check out, "Opioid Guidelines in the Management of Chronic Non-cancer Pain," Trescot AM, Boswell MV, Atluri SL, et al, Pain Physician, 2006; 9: 1 - 40 at 17, free full text at http://www.rsds.org/2/library/articl...ician2006.pdf:

Hyperalgesia or abnormal pain sensitivity manifests as increased pain from noxious stimuli and as pain from previously non-noxious stimuli. Long-term use of opioids may be associated with the development of hyperalgesia. Experimental and clinical studies describe that cellular mechanisms of neuropathic pain may be similar to opioid-induced hyperalgesia. In an experimental setting, NMDA-receptor-mediated changes that cause abnormal pain sensitivity have been shown to occur in animals in the spinal cord dorsal horn cells of animals after repeated exposure to opioids. Similarly, these changes have been observed in the spinal cord in animal models of neuropathic pain. Consequently, interactions between neural mechanisms of opioid tolerance and neuropathic pain involving spinal and supraspinal neural circuits may have important clinical implications.

Repeated administration of opioids not only results in the development of tolerance but also hyperalgesia. In fact, opioid-induced abnormal pain sensitivity has been observed in patients treated for both pain and addiction. It also has been postulated that there may be correlation between tolerance which is a desensitization process, and hyperalgesia which is a pro-nociceptive process or sensitization. In prolonged opioid therapy, desensitization and sensitization together may contribute to tolerance or an afferent decrease in analgesia, regardless of the progression of the pain. Ballantyne and Mao stated that the need for dose escalation during opioid therapy – that is, the development of “afferent” opioid tolerance – may result from pharmacologic opioid tolerance, opioid-induced abnormal pain sensitivity, or disease progression. The potential use of NMDA antagonists in the treatment of neuropathic pain, opioid tolerance, and opioid-induced hyperalgesia is the subject of multiple investigations. [Citations to references omitted.]

That said, I see no reason, following the results of the 2009 article by Schinkel et al, referred to in my prior post, to assume that chronic CRPS has the same "inflammatory signature" as does - say - PN or back pain, where only a single pro-inflammatory cytokine - calcitonin gene related peptide (CGRP) - was observed to stand out to any level of statistical significance in chronic CRPS patients. If that's the case, I would suggest that we have to consider at least the possibility that a diet with wonderful anti-inflammatory properties in general, might have little or no effect on chronic CRPS unless it happens to effect the regulation of the CGRP gene, which:

. . . is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway, cytokines such as TNFα and iNOS. 5HT1 agonists such as sumatriptan increase intracellular calcium which cause decreases in CGRP promoter activity. Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein. Receptor antagonists such as telcagepant, which is in phase III from Merck Pharmaceuticals, also has promise in limiting the effects of CGRP. [Citations omitted.]

http://en.wikipedia.org/wiki/Calcito...elated_peptide

You have stated that you believe "It stands to reason that others with chronic pain are also in a similar situation." But you have to acknowledge that is only an assumption, which may or may not be correct. All that I am suggesting is that we be prepared to think of this analagously to the manner in which CRPS has been shown to produce patterns of gray brain matter atrophy and white matter structures on structural MRIs that are wholly unlike those observed in patients with either chronic back pain or fibromyalgia. See, "The Brain in Chronic CRPS Pain: Abnormal Gray-White Matter Interactions in Emotional and Autonomic Regions," Paul Y. Geha, Marwan N. Baliki, R. Norman Harden, William R. Bauer, Todd B. Parrish, and A. Vania Apkarian, Neuron 60, 570–581 at 574 - 575 (November 26, 2008), free full text at http://www.apkarianlab.northwestern....S_Neuron08.pdf

As such, I simply submit that if Schinkel et al are correct, the most amazing anti-inflamatory diet in the world may or may not have an effect on chronic CRPS, depending on its effect on the regulation of the CGRP gene. And one of the things that makes me feel that they are are on the right track is if you do a PubMed search under "CRPS calcitonin gene related peptide" you get only 5 articles, but written by some of the best minds in the field, e.g., two by Frank Birklein and one co-authored by Anne Louise Oaklander.

Still, nothing would make me happier to know that if I stuck to Diet X for six weeks, there would be a 50% reduction in my pain and all of my edema would resolve.

Mike

PS It's unfortunate that Merck had to put telcagepant on hold in April of this year, perhaps permanently, due to issues of elevated liver enzymes when migraine patients started taking it on a daily basis - as any CRPS patient would have to - as opposed to the episodic use for which it was planned, but word has it that Merck and perhaps others may be trying to tweak the molecule even in the present moment, so there may be more news yet on that front. http://www.thedailyheadache.com/2009...rmanently.html

I guess when we find out what is unique to RSD patients compared to those who do not develop this, we will have our answers.

This seems similar to Fibromyalgia, which is becoming obvious, as an inherited problem. Once triggered by an injury, trauma, Fibro does not go away either.

The central pain sensitization is similar in Fibro patients and PN patients, as well as RSD patients. PN patients also have demyelination that is now being tested for. The new skin biopsies, are proving this condition. It might be that PN has several subsets, of peripheral degeneration + central pain perceptions.

Right now MS is being looked at as a multiple process. Beginning with an inflammatory phase and followed by a disruption in astrocytes --
http://ms.about.com/b/2009/06/09/cou...sease.htm?nl=1

So we are all in the same boat, waiting for research to point the way, more clearly.

how long have you had rsd,,and what time frame did it spread,,,im 6months out,and getting worse,,,remission would be nice,,if you read my thread,,i had thr 2months ago when the rsd was only in the back of my heel,,,now both legs to the knees,,,,,,,,any encouraging thoughts would ne appreciated thank you ......bobber