[Sandel]

The Biochemical Origin of Pain: The origin of all Pain is Inflammation and the Inflammatory Response. PART 2 of 3 –Inflammatory Profile of Pain Syndromes

http://www.ncbi.nlm.nih.gov/pmc/arti...tool=pmcentrez

S

oops sory about the spelling up top.

[Mslday]

Wow Sandel, this is a great paper!

Hope you and your family are all managing to make it through the flu bug ok. Have your arms calmed down from your shots yet?

Thanks for posting this.

MsL

[fmichael]

Sandra -

No time to read, must run. Don't have a problem with the premise of the paper, emphasis on "origin." What I do know is that if you go to the RSDSA Medical Artical Archieve page under "Research" http://www.rsds.org/2/library/articl....html#Research you'll get a number of articles showing a great drop off in the number of observed pro-inflammatory cytokines as CRSP begins it's transition to the chronic phase, where it is presumable maintained by ingrained permutations in the thamaic-cortical loops.

Is the problem of post-cytokine pain addressed in the paper to your knowledge?

Mike

[Mslday]

Hi Mike,

The paper posted by Sandel “The origin of all Pain is Inflammation and the Inflammatory Response” appropriately addresses the audience for which it was intended.

To answer your question one simply needs to scroll down to the conclusion.

In accordance with our Law of Pain, the origin of all pain is inflammation and the inflammatory response. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. We are proposing a re-classification and treatment of pain syndromes based upon their inflammatory profile.

Treatment of pain syndromes should be based on these principles:
1. Determination of the inflammatory profile of the pain syndrome
2. Inhibition or suppression of production of the appropriate
inflammatory mediators e.g. with inflammatory mediator blockers or
surgical intervention where appropriate
3. Inhibition or suppression of neuronal afferent and efferent (motor)
transmission e.g. with anti-seizure drugs or local anesthetic blocks
4. Modulation of neuronal transmission e.g. with opioid medication.

At the L.A. Pain Clinic, we have successfully treated a variety of pain syndromes by utilizing these principles. This unifying theory of the biochemical origin of pain is compatible with, inclusive of, and unifies existing theories and knowledge of the mechanism of pain including the gate control theory, and theories of pre-emptive analgesia, windup and central sensitization. Our current knowledge is rudimentary and but a beachhead in the vast frontier of inflammation and the inflammatory response. We have medications for only a few of these mediators. More research is needed to understand and develop new drugs and interventions to treat inflammation and the inflammatory response and thus to conquer pain.

As the authors state "Our current knowledge is rudimentary". It has provided some current forward thinking guidelines for treatment based on a set of principles outlined above. It's a broad paper and doesn't address your specific question about the problem of post-cytokine pain with any great depth. I don't believe that is well understood by many practicing doctors let alone many of the researchers.

The problem as I see it is that the science is just now starting to understand chronic pain. Most clinicians still use the surgical pain model to bridge the gap between acute pain and chronic pain. There is little general knowledge among many medical professionals of the fact that it is the persistence of that acute pain that in fact leads to chronic pain although I do believe the tides are changing.

Most people understand acute pain, you break an arm, you set it in a cast give some pain relievers and it heals. It wasn't until most recently that chronic pain began to be accepted by the medical professionals as a disease process in and of itself.

As patients we have all experienced an analgesic gap, a specific time period during pain therapy when our pain is unrelieved. This sets off a whole series of mechanisms, which is where I believe your question is leading.

Unfortunately there is still a huge gap in translating the most recent discoveries of chronic pain research to the bedside and that where most of us wallow in our frustrations.


Hope you are doing well.

MsL

[fmichael]

This was written before I saw MsL's last post:

Two more comments, having read the portion of the article posted.

1. Classifying diseases in terms of their inflammatory profiles may make sense. Don't know. Please note however that this appears in the Journal of Medical Hypothesis, which means that you don't have to prove anything - by definition - it just has to appear plausible. And in that regard, note that the inflammatory profile of CRPS shifts dramatically over time, from a stew of proinflammatory cytokines, Substance P, TNF-[alpha], etc., to basically a single peptide, Calcitonin Gene-Related Peptide (CGRP).

This is significant because it's only been in the last year or so that researchers have focused on the "longitudinal profile" of CRPS. Thus if you go back only a year or two in the literature, you will see no attempt to segregate CRPS patients by stage of disease. See, Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C, Differential expression patterns of cytokines in complex regional pain syndrome, Pain 2007; 132: 195–205 http://www.rsds.org/2/library/articl...erle_Rolke.pdf ; Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzmann RJ, Changes in Cerebrospinal Fluid Levels of Pro-inflammatory Cytokines in CRPS , Pain 2005; 116: 213-219 http://www.rsds.org/2/library/articl.../alexander.pdf

In support of the majority of his thesis regarding the role of inflammation in CRPS, Omogui relies primarily on Birklein F, Schmelz M, Schifter S, Weber M. The important role of neuropeptides in complex regional pain syndrome. Neurology. 2001 Dec 26; 57(12): 2179–2184. Yet the later article of Birklien and Schemlz appears to be the authors’ latest word on the subject. See, Birklein F, Schmelz M, Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS), Neuroscience Letters 2008; 437: 199-202 http://www.rsds.org/2/library/articl...in_Schmelz.pdf at 201:

Inflammation in the classical sense with positive blood markers has not been proven, but any inflammation has a "neurogenic component." As indicated above, peripheral trauma, in particular if it is accompanied by partial peripheral nerve lesion, causes a rapid release of NGF and cytokines. Both are able to activate and sensitize primary afferents, locally at the injury site or proximally in the respective nerve trunk. Accordingly, increased levels of proinflammatory cytokines have been shown in CRPS skin by analysis of suction blisterfluids and in CRPS spinal fluid. Our own group concentrated on cytokines in blood samples. We have been able to demonstrate increased TNF-alpha in plasma samples of two different independent CRPS patients groups. Increase of TNFalpha in that study was correlated to mechanical hyperalgesia. In a very recent more extensive study we confirmed these findings-not only on protein but also RNA level in CRPS blood samples. Different proinflammatory cytokines were upregulated while antiinflammatory cytokines were downregulated in the patients.

Cytokines also increase the neuropeptide content of primary afferent neurons. Activation of sensitized primary afferents then causes an increased release of neuropeptides into the affected body region. Chronic release of neuropeptides might be responsible for the above-mentioned CRPS symptoms. In serum samples from patients with acute CRPS, CGRP, SP and bradykinin were found to be significantly increased, in particular when clinical inflammatory signs were present. Subsequent to these exploratory investigations, neurogenic inflammation was elicited directly in the skin by transcutaneous electrical stimulation via intradermal microdialysis capillaries by our group. We first investigated the flare by Laser-Doppler scanning on the affected and on the unaffected side in our CRPS patients. Neurogenic flare was significantly more intense in patients-on both the affected and the clinically unaffected side. Another characteristic of neurogenic inflammation in rodents is SP-mediated plasma protein extravasation (PPE). In healthy humans, C-fibers usually contain too little SP to induce PPE. In CRPS, however, significant PPE could be shown in almost all patients investigated. In contrast to the flare response, this increased PPE was limited to the affected side. These results suggested two possible pathomechanisms leading to facilitated neurogenic inflammation in CRPS-either increased release or hampered inactivation of neuropeptides, or both. In order to further unravel these mechanisms, we perfused SP in ascending concentrations through dermal microdialysis fibers in CRPS patients and controls. We found SP significantly more effective at inducing PPE in CRPS patients. Similar to the increased flare response,this increased responsiveness to SP was present on both the affected and unaffected limbs. [Footnotes omitted.]

However, when the first reported longitudinal study was done across the length of their disease, a different pattern emerged altogether. See, Schinkel C, Scherens A, Köller M, Roellecke G, Muhr G, Maier C, Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups, Eur J Med Res. 2009 Mar 17; 14(3): 130-5.

Abstract

OBJECTIVES: The Complex Regional Pain Syndrome I (CRPS I) is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet.

METHODS: To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP), White Blood Cell Count (WBC), Interleukins 4, 6, 8, 10, 11, 12 (p70), Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-a) and its soluble Receptors I/II, soluble Selectins (E,L,P), Substance-P (SP), and Calcitonin Gene-Related Peptide (CGRP) at different time points in venous blood from patients with acute (AC) and chronic (CC) CRPS I, patients with forearm fractures (FR), with neuralgia (NE), and from healthy volunteers (C).

RESULTS: No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007), FR/C (CGRP p = 0.048) and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049). High interindividual variations were observed. No intra- or interindividual correlation of parameters with clinical course (e.g. chronification) or outcome was detectable.

CONCLUSION: 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. [Emphasis added for some statistically significant findings, although the authors were apparently hoping for more.]

PMID: 19380284 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=2

Accordingly, the only longitudinal (pilot) study to date of CRPS across the disease cycle among a group of patients - as opposed to sampling CRPS patients as an undifferentiated group vs. controls - found that the "Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I," precisely the opposite result predicted by Omoigui, who maintains that diseases should be classified by their inflammatory profiles.*

Which brings to mind the Riddle of the Sphinx: What walks on four legs in the morning, two at Noon and three in the evening? (Man)

2. I had seen the name of Sota Omoigui, MD before, but I couldn't recall seeing his departmental title: Division of Inflammation and Pain Research, L.A Pain Clinic, 4019 W. Rosecrans Ave, Hawthorne, CA 90250. At that point, I had no choice but to open his web page, but not to pop ups, etc.: http://www.medicinehouse.com/ (Talk about something for everyone.)

That said, the man definitely contributed Chapter 23, "Cholesterol, interleukin-6 inflammation, and atherosclerosis—role of statins, bisphosphonates, and plant polyphenols in atherosclerosis and other diseases of aging," in Ronald Ross Watson (Editor), Douglas Larson (Editor) Immune Dysfunction and Immunotherapy in Heart Disease, Wiley September 2007 http://www.wiley.com/WileyCDA/WileyT...fContents.html and he has 7 hits on Pub Med, so he remained a mystery to me.

That is until I came across the C.V. which he had submitted as a member of The FDA Advisory Committee on Anesthetics and Life Support Devices http://www.fda.gov/downloads/Advisor.../UCM177291.pdf And to tell the truth, a sad read it is. Clearly a sharp guy, and yet . . . . Still, there those seven Pub Med references under his name, three of which, including the first part of the 3-part article Sandra pulled and an article on which his chapter in the Watson and Larson text is based, are available free of charge. (Just run a search in Pub Med under his name.)

I wish everyone a good day.

Mike

* In fairness to Dr. Omoigui, one could take the position that our knowledge of inflammatory processes was still woefully incomplete (as suggested by the conclusion of Schinkel et al). Yet to do so would be to reduce his "Law of Pain" to an article of faith.

[fmichael]

MsL -

As noted, I accept that inflammation initiates all pain, but not that inflammation maintains all pain.

Do I quibble with the notion that inflammation is the origin of all pain? What came first, the chicken or the antibody?

As to where I am on all of this right now (and entirely consistent with the foregoing) as well as to get your opinion on a little editorial - by a pretty important guy - please give a quick look at a thread called The fascination of complex regional pain syndrome, Jänig, W., Exp. Neurol. (2009) I posted a couple of weeks back at http://neurotalk.psychcentral.com/thread106842.html

thanks,
Mike

[fmichael]

Although filed in 2005, it appears to still be pending: http://www.wipo.int/pctdb/en/wo.jsp?...7&DISPLAY=DESC

I wish him all the luck in the world, subject to my underlying misgivings about whether medical procedures should be subject to patent in the first place. But that's not my call. Check out the abstract:

Abstract

This invention relates to a method for prevention and treatment of aging, age-related disorders and/or age-related manifestations including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia and some forms of arthritis and cancer in a subject comprising administering to said subject, separately, sequentially or simultaneously a therapeutically effective dosage of each component or combination of statins, bisphosphonates, cholesterol lowering agents or techniques, interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinases inhibitors/antibodies, serine/threonine kinases inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear factor .kappa.B (NF-.kappa.B) inhibitors/antibodies, I.kappa.B kinase (IKK) inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies, STAT transcription factors inhibitors/antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof, administered separately, in sequence or simultaneously. Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of atherosclerosis, peripheral vascular disease, coronary artery disease, aging, age-related disorders and/or age-related manifestations including osteoporosis, type 2 diabetes, dementia and some forms of arthritis and tumors. Inhibition of Interleukin 6 mediated inflammation may be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or by direct inhibition of the signal transduction pathway utilizing interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinases inhibitors/antibodies, serine/threonine kinases inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear factor .kappa.B (NF-.kappa.B) inhibitors/antibodies, I.kappa.B kinase (IKK) inhibitors/antibodies, activator protein-1 (AP-1) inhibitors/antibodies, STAT transcription factors inhibitors/antibodies, altered IL-6, partial peptides of IL-6 or IL-6 receptor, or SOCS (suppressors of cytokine signaling) protein, or a functional fragment thereof. Said method for prevention and treatment of said disorders is based on inhibition of Interleukin-6 inflammation through regulation of cholesterol metabolism, isoprenoid depletion and/or inhibition of the signal transduction pathway.

Mike

PS And here's the information on what appears to be his still pending US patent application for the same concept: http://appft.uspto.gov/netacgi/nph-P...DN/20060275294