EPIGENETICS AND CHRONIC PAIN

Robert Melashenko MD

Disclaimer

• NONE

Drugs:

Opiates

NSAIDS

Chronic Pain Fuels Boom :in O.pioids Published: Feb 19, 2012

By John Fauber 1 Reporter

1 Milwaukee Journal Sentinel/MedPage

Today

Tlwough From 1999 llvtil"1 UWPalna. posllionsand ~ 2010. got $2.5 Policy Studies h<!lped lilleralcie how mDllon from opioid Group

opods are ptesoibOO ~nles. ¥1dviewed.

In recent ~got Issued an opioid milaons of dollatS AJMrleMI from induslly. ""'"

fritnty p.lboot

1~opaod Foundation gtidl! in 2mi Olmp;!nies.

Lasl~got~ ~ Como!a $1.5 m• )I I from Ac ~ ... ., .,, lheptwmaaubcaf Pain ... ,, : hi

1996

rdJstly. CO t$l!I SS stllemail

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hill diCIW:P'S\.

CX)ll'C>anles. Sccllty

~rabon's foundatlongotan ISSU!d model undisclosed Fed er;atlon of guideflnes/policy on amount from opioid State Mldlclll thB use cl Ol)IOlds 1n

companies tor a 8-ds 1998. =·ted in bocll< on Ol)IOld prescntq.

Federation maintained: "[Our] most recent policy reflects the considerable body

of research and experience accrued since our last series of formal policies related

to opioid prescribing and addiction were adopted in 2004. Our lates

By 2010, the United States, with about five per cent of the world's population,

was consuming ninety-nine per cent of the world's hydrocodone (the narcotic

in Vicodin), along vvith eighty per cent of the oxycodone (in Percocet and

OxyContin), and sixty-five per cent of the hydromorphone (in D ilaudid).

-

~~ T he NEW ENGLAND JOURNAL of MEDICINE

Pere;-

A Flood of O e ioids, a Rising Tide of Deaths

• _ ...... NOVEMBER 18, 2010

n engl j med 363;21 november 18, 2010

Fundamentals of Inflammation, Serhan et al. Cambridge University Press. 2010. p16

Nonsteroidal drugs (inhibitors of cyclooxygenases I and II) will provide symptomatic relief of pain but these drugs, on balance, have very limited effects on inflammation. That is, they poorly suppress the inflammatory response.

Acta Pharmacologica Sinica 2005 Aug; 26 (8) 926- 933

Review

Cheng LU02, Ming-liang HE3

, Lars BOHLIN4

flJ Bla,clkwell Publishing

elective COX-2 inhibitors remain

2Instit11te of 1Wolec11/ar Biology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China; 1Center for Emerging and Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China; 4Department of1Wedicinal Chemist1y, Biomedical Center, Uppsa/a University, Sweden

NATURE MEDICINE • VOLUME 5 • NUMBER 6 • JUNE 1999

NATURE MEDICINE • VOLUME 5 • NUMBER 6 • JUNE 1999

Figure 2

Source: American Journal of Pathology, The 2010; 177:1576-1591 (DOI:10.2353/ajpath.2010.100322 )

Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Y. Adkins, D.S. Kelley / Journal of Nutritional Biochemistry 21 (2010) 781–792

The Journal of Rheumatology Copyright © 2011.

“Doctors end up chasing pain” instead of focusing on treating the underlying

condition, she said. (Claire Trescott MD)

But what is the “underlying” condition?

NYT. Meier. April 8, 2012

Fundamentals of Inflammation, Serhan et al. Cambridge University Press. 2010.

British Journot o( Anoesthesio 111 Cl!: 26- 37 (2013! doi:l 0.1093/bjo/oetl 28

~ euroinflammat1on an A. Ellis1* t and D. L. H. Bennett2t

eneration of neuroQatnic Qain

1 King's College London, Wolfson Wing, Hodgkin Building, Guy's Campus, London SEl lUL, UK 2 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK

• Corresponding author. E-mail: amanda.elli s@kcl.ac.uk

Editor's key points

• There is increasing evidence of t he role of inflammatory processes in neuropathic pa in.

• Peripheral inflammatory mediators can sensit ize the nervous system, both periphera lly, and cent rally.

Fundamentals of Inflammation, Serhan et al. Cambridge University Press. 2010.

Nutrition & Metabolism 2012, 9:32

The major discovery of Serhan´s work is that the conclusion of an inflammation is a controlled process of the immune

system (IS) and not simply the consequence of an extinguished or “exhausted” immune reaction.

Figure 2

Source: American Journal of Pathology, The 2010; 177:1576-1591 (DOI:10.2353/ajpath.2010.100322 )

Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Leading Edge

Nonresolving Inflammation Carl Nathan" 2•• and Aihao Ding" 2

' Department of Microbiology and Immunology, Weill Cornell Medical College 2Program In Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences Cornell University, New York, NY 10065, USA •

Infiltration by myeloid-derived suppressor cells

Failed phenotypic switch In

macrophage and T cell

populations

Inadequate production

of resolution mediators

Prolonged or excessive response

Nonre s olutio n o f INFLAMMATION

I A<horo~"'°''' I/// Chronic

obstructive pulmonary

disease

I \ I Obesity I 1 Cancer I Multipl~

sclerosis

I Asthma

Subnormal response

Persistent stimulation (microbes,

particulates, food antigens, [co)allergens)

Rheumatoid arthritis

Inflammatory bowel disease

tlammation is an inherent """'~ammation Nonethe­ages switch phenotypes, m pro- to anti-inflamma­pids, and gasses. Aside iencies in these mecha-

ubnormally. This greatly lem calls for conceptual,

Figure 3. Mechanisms and Consequences of Nonresolution of Inflammation Cell 140, 871 - 882, March 19, 2010 ©2010 Elsevier Inc.

Arachido c acid-derivea e oxy:eicosatrienoic ci s produced by cytochrome P450 epoxygenases represent yet another class of anti-inflammatory lipids. EETs can inhib"t NE-i.:B and block inauction of COX2 and 5'-lii;ioxygenase (Node et al., 1999).

COX2 :::;ha~s~al~~~~~

=-=."".::~::::::.~o;.:.f ..!:p:.;e::.rs:;i=s.:.:.:tent stim u la ti on of i nfl amm ation arise from the biosynthetic incorporation of a foreign food antige into self-mo ecu es, w tn wnicn anti5odies en react. For example, humans have a loss-of-function mutation in a gene encoding an enz¥me requ1red1or productioo of -glycolyJoeura­minic acid (Neu5GC] which the human immune system can therefore recognize as foreign Hedlund et al., 2008). Dietarv Neu5Gc is taken up from red meat and dairy products, Incorpo­rated into cell surface glycans, and bound by antibody. The resulting inflammation appears to promote angiogenesis and oncogenesis in a COX2-dependent manner (Hedlund et al., 2008).

Cell 140, 871-882, March 19, 2010 ©2010 Elsevier Inc.

Btftish Journal o[Anoesthe~iq 107 (SllJ27 - i4Q(2Ql1l doi:l 0. 1093/bjo/oer358

CLINICAL PRACTICE

A Chondrokonton* and P. S. A. Gloss

Deportment of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY, USA

• Corresponding author. E-mail: arvind.chondrokantan@stonybrook.edu

Although there are multiple definitions of pain, most experts agree that it is primarily a sensory experience.72 There are two major components that contribute to perioperative pain, namely inflammatory and neuropathic pain. Both of these states share multiple common features and can be experienced either jointly or separately.93

PLOS Biology June 2014 | Volume 12 | Issue 6

…observations reveal a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain in response to inflammation.

micro RNA

->RNA --~>~

IEi:ogressJ n.Nemobiology 91 (2010) 275i299

Contents lists available at ScienceDirect

Progress in Neurobiology

ELSEVIER journal homepage: www. elsevier.com/locate/pneurobio

Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression

Richard C. Shelton *, Andrew H. Mille r

Vanderbilt University, 1500 21st Avenue South, Suite 2200, Nashville, TN 37212, United States

Diet & Inflammation

Sialic Acid

PUFA’s

Intestinal Microbiota

A difference in one molecule led physician Ajit Varki to question what sets humantt apart from other apes. Bruce Lieberman meets a man who sees a big picture in the finer points.

Nature, Vol. 454, 3 July 2008

Human uptal<e and incorporation of an immunogenic nonlluman Clietary sialic aciCI Pam Tangvoranuntakul*, Pascal Gagneux*, Sandra Diaz*, Muriel Bardor*, Nissi Varki *, Ajit Varki* t, and Elaine Muchmoret

*Glycobiology Research and Traini ng Center, Departments of Med icine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0687; and *San Diego Veterans Affairs Medical Center, La Joll a, CA 92161

Edited by Sen-itiroh Hakomori, Pacific Northwest Research Institute, Seattle, WA, and approved August 18, 2003 (received for review M arch 18, 2003) . . ,,, ,,, -- ,,, . teins. NeuSGc has never been reported in plants or microbes to our knowledge. We found that NeuSGc is rare in poult~ and fish, common in milk products, anCI enriched in red meats. Furthermore, normal humans have variable amounts of circulating lgA, lgM, and lgG antiliodies against NeuSGc, witll the highest levels comparable to ttlose of the ~reviously k.nown anti-a-galactose xenoreactive antillodies. This finding represents an instance wherein humans absorll anCJ metabolically incorporate a nonhuman dietary com­ponent enriched in fooCls of mammalian origin, even wllile gen­erating xenoreactive, and potentially autoreactive, antibodies against the same mole{ule. Potential implications for human dis­eases are briefly discussed.

www .pnas.org/cgi / doi / 10.1073 / pnas.2131556100 PNAS I Odober 14, 2003 I vol. 100 I no. 21 I 12045-12050

A 1 • 1

• e • c .75

J I .6

• • • -·-.25 • • I I I

I 0 lg A lgM lgG

B a.a

~O.I

JOA 0.2

0.0 ------------............ u 1.0 u 4.0

Fig. 5. ELISA detection of anti-NeuSGc antibodies in normal human sera and demonstration of specificity. (A) Results are plotted as mean background values with PAA-N euSAc subtracted from the signal with P AA-NeuSGc. The mean value for all positivesera in each subclass is represented by the hori zontal bar. (8) Two of th e human sera identified as medium or high positive for anti-NeuSGc lgG antibodies to the target NeuSGc-PAA were tested in the same ELISA with dilu­tions of chimpanzee serum added to inhibit binding. A human serum with undetectable anti-NeuSGc antibodies was used as a control.

18936- 18941 I PNAS I !December 2, 2008 I vol. 105 I no. 48

Evidence for a novel human-specific xeno-auto-antibod~ response against wascular endoiliehum

BLOOD, 10 DECEMBER 2009 • VOLUME 11 4, NUMBER 25 XENO·AUTO·ANTIBODIES AGAINST VASCULAR ENDOTHELIUM 5227

A Chicken Anti-NeuSGc lgY Control lgY

Chicken Anti-NeuSGc lgY

---· --· • · - · - , - --·. -1 -· ··-···- · · -·- - --- --·--····· . by immunohistochemistry with both a secretion monospecific chicken anti-NeuSGc anti· body and w ith affinity-purified human anti· factor-<X . NeuSGc antibodies demonstrates endo- man anti-I thelial expression of NeuSGc, likely NeuSGc < orig inating from NeuSGc-rich foods like human s

Submitted May 6, 2009; accepted September 11 , 2009. Prepublished online as Blood First Edition paper, October 14, 2009; 00110. 1182Jbloocl·2009-05-220400.

0 0 0 ::I

x I\.) 0 0

Probiota

The numbers are staggering.

Human

10 Trillion Cells

~ 21,000 P.C genes

Microbes

100 Trillion Cells

2-3 Million P.C. genes

By these measures, we are 99% bacterial.

At the “Body Board Meeting” who sets policy?

ucosallmmunology

!1~~:1} Im,rr; • ~ r~lJ9) 2,. ~.2.

:IC . :! ": !:~/ ..U.:~i-9 .-; 2.

2010 British Society for Immunology, Clinical and Experimental Immunology, 160: 85–91

ff~a®ll® O[li) HUMAN NEUROSCIENCE

OPINION ARTICLE pub lished: 15 September 2014

doi: 10.3389/fnhum.2014.00720

Microbiota, the immune S¥Stem, black moods and the 6rain - melancnolia ugoatea

Lesley E. Smythies ' and John R. Smythiesz,3 * 1 Department of Medicine (Gastroenrero/ogyi, University of Alabama at Birmingham, Birmingham, AL, USA ' Department of Psychiatry. University of Alabama at Birmingham. Birmingham. AL. USA 3 Department of Psychology. Center for Brain and Cognition. University of California. San Diego, San Diego, CA. USA •correspondence: vanna.smythies@gmail.com

Polyunsaturated Fatty Acids

(PUFA’s)

Y. Adkins, D.S. Kelley / Journal of Nutritional Biochemistry 21 (2010) 781–792

ELc;EV1ER

Prostaglanclins, l.eukotrienes and Essendal Fatty Acids 00 (2014) 133-138

Contents lists available at ScienceDirect

Prostaglandins, Leukotrienes and Essential Fatty Acids

jo urn al ho mepage : www.elsevier.com/l ocate/p lefa

A low on1ega-6 polyunsaturated fatty acid (n-6 PUFA) diet increases oniega-3 (n-3) long chain PUFA status in plasn1a phospholipids in hun1ans * KE. Wood a.c.l , A. Lau •·1, E. Mantzioris b, R.A. Gibson c. C.E. Ra msden ct. B.S. Muhlhaus ler c.*

.a School of Medicine, Deparflnenr of f\'urrir:ion and Diererict. Rinders Unhel'$iry, Adebide, SA 5042, Aus.rrulia b School of Phannacy and Medical Sciences. Universiry of Sou di Aus.rrulil, Adelaide SA 5001. AtrtD'alio c RX>Dpltrt Res.earth CenD'e, Sd!ool of Agriru!rure, Food and Wl'ne, The Univel'$iry of Adelaide Adebide, SA 5<X54, Aus.rrulil d IDboracory ofMernbtane Biochernis.rry and Biophysia. Narionol Ins.riruce on A fcoho/ Abuse a rid Afcoho/is.rn, Nar:ional Ins.r:irures.ofHea/rh lkd!esda, MD, USA

<I> CrossMark

Neuroscience 241 (2013) 22- 31

SPINAL INJECTION OF DOCOSAHEXAENOIC ACID ATTENUATES CARRAGEENAN-INDUCED INFLAMMATORY PAIN THROUGH INHIBITION OF MICROGLIA-MEDIATED NEUROINFLAMMATION IN THE SPINAL CORD

Y. LU, a.b L.-X. ZHAO, • 0 .-L. CAO • AND Y . .J. GA0°*

;:i Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong UnivelSity, Nantong 226001, China

Key words: inflammatory pain, carrageenan, docosahexaee noic acid, microglia, cytokines, chemokines.

Diet & Healing

Scand J Rheumatol 2000:29:308-13

~egan Cliet alleviates fil>rom algia s mP-toms

K. Kaartinen1. K. Lammi1, M. Hypen2, M. Nenonen3

, 0. Hanninen1. and A.-L. Rauma1

1Department of Physiology, University of Kuopio, 2Rehabilitation Centre for Rheumatic Patients, Kangasala, 3National Research and Development, Centre for Welfare and Health, Helsinki, Finland

SPECIAL TOPIC SERIES

(Clin J Pain 2004;20: 19- 26)

ieta~ Constituents as Novel TheraP-ies for Pain Jill M. Tall, PhD, and Srinivasa JV. Raja, MD

Ageing Research Reviews 17 (2014) 16–24

Pharmacological Research 65 (2012) 565– 576

European Journal of Pharmacology 651 (2011) 1–8

Journal of the American College of Cardiology © 2006 by the American College of Cardiology Foundatio n Published by Elsevier Inc.

STATE-OF-THE-ART PAPER

e Effects o Inflammation lE.m_phasis o Syndr..omeJ Dario Giugliano, MD, PHD,* Antonio Ceriello, MD,t Katherine Esposito, MD, PHD* Naples, Italy; and Coventry, United Kingdom

Vol. 48, No. 4, 2006 ISSN 0735- 1097/06/$32.00

doi: JO. JO 16/j .jacc .2006.03 .052

Reducing the incidence of corona heart disease \Vith diet is possible. The main dietary strategies include aoequate oinega-3 fatt)', acids lnta e, eductio of saturated and trans-fats , and-consumption of a dietlliglLin fruits, :v:egetables,_.nuts ancLw:hole..grains.ancllo1Y~refinecl grmns. Each of these strategies may be associated vvith ovver generation of iiiliainmation. This review examines the e12idemiologic an clinical e · dence concerning diet an in.flm -mation. Dietazy vatterns high in refined starches. sugar. and saturated and trans-fatty acids. poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive roduction of roin.flammator c okines associated vvith a reduced roduction of anti-inflammatory cytokines. he \vhole diet approach seems particularly promising to reduce the inflammation associated \Vith the metabolic syndrome. The choice of healthy sources of carbohydrate, fat, and protein, associated with regular physical activity and avoidance of smoking, is critical to fighting the \Var against chronic disease. Western dietary pattern warm up inflammation, \~hile prudent die_tary .. patterns cool it dcnro. (J Am Coll Cardiol 2006;48: 677- 85) © 2006 by the American College of Cardiology Foundation

R aja, c efd

. p a111

ose (5 ing con ta \:vitl ti on et al .

PAIN Pain 129 (2007) 5- 7

www.elsevier.com/locate/ pain

EditoriaJ

F oocLa11cLpai11: Sl1oulcLwe be n1ore i11tereste · n wha our patients eat?

BMJ editorial coJ.ru11e1iLrevie\ving ai1 article on (o­lic acid noted that doctors are generally inorc co111fort-

le is able \\ritl1 drugs tl1an \\1iti1 food and that this 111a be a11e to 111any octors 1avin )' a li1nited knO\V eage of pes, 11utritio11 f51nitl1, 2004 ). D ietary interve11tio11s are attrac- tory tive due to availabilit ' · O\\r costs ai1d lo\v toxicit . W'e :gas, 110\v 1<110\v 1n11cl1 abo11t tl1e toxicity of NSAID s a11d cox­ibs, but w·l1at do \\re k110\¥ a bout 011r IJai11 patie11t' s diets? Tl1e gro\vi11g body of scientific evide11ce indicates tl1at diet and 1111trition inay be a 1Jro111ising area for f11t11re pai reseaLch an ain treat111e11 .

Pharmaceutical Research, Vol. 25, No. 9, September 2008

Vegan Diet Eases Diabetic Neuropathy Pain

Bunner noted that current treatments for diabetic neuropathy - which occurs in about half of all type 2 diabetes patients -- only treat the pain, and do not treat the underlying cause of that pain.

An earlier observational study by Crane and Sample(] Nutr 1l1ed1994; 4: 431-439) of 21 type 2 diabetics with nerve pain showed that being on a low-fat, high-fiber vegan diet for a month brought complete pain relief to 81°/o of participants, who lost about 11 pounds on average.

IOllCOlOGY Toxicology 155 (2000) 45-53

www .else vier .com/locate/toxicol

Antioxidants in vegan diet and rheumatic disorders

0. Hanninen a,*, K. Kaartinen a, A.-L. Rauma a, M. Nenonen c, R. Torronen a, S. Hakkinen a, H. Adlercreutz b, J. Laakso b

a Department of Physiology, University of Kuopio, P. 0. Box 1627, 70211 Kuopio, Finland b Department of Clinical Chemistry and Department of Clinical Pharmacology, 00014 University of Helsinki, Helsinki, Finland

c National Research and Development Centre for Welfare and Health, Helsinki, Finland

Abstract

Plants are rich natural sources of antioxidants in addition to other nutrients. Interventions and cross sectional studies on subjects consuming uncooked vegan diet called living food (LF) have been carried out. We have clarified the efficacy of LF in rheumatoid diseases as an example of a health problem where inflammation is one of the main concerns. LF is an uncooked vegan diet and consists of berries, fruits, vegetables and roots, nuts, germinated seeds and sprouts, i.e. rich sources of carotenoids, vitamins C and E. The subjects eating LF showed highly increased levels of beta and alfa carotenes, lycopen and lutein in their sera. Also the increases of vitamin C and vitamin E (adjusted to cholesterol) were statistically significant. As the berry intake was 3-fold compared to controls the intake of polyphenolic compounds like q_uercetin, myricetin and kaempherol was much higher than in the omnivorous controls. The LF diet is rich in fibre, substrate of lignan production, and the urinary excretion of polyphenols like enterodiol and enterolactone as well as secoisolaricirecinol were much increased in subjects eating LF. The shift of fibromyalgic subjects to LF resulted in a decrease of their joint stiffness and pain as well as an improvement of their self-experienced health. The rheumatoid arthritis patients eating the LF diet also reported similar positive responses and the objective measures supported this finding. The improvement of rheumatoid arthritis was significantly correlated with the day-to-day fluctuation of subjective symptoms. In conclusion the rheumatoid patients subjectively benefited from the vegan diet rich in antioxidants, lactobacilli and fibre, and this was also seen in objective measures. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Antioxidants; Living food; Lactobacilli and fibre

THE NEW “MULTIMODAL” APPROACHIN TREATING CHRONIC PAIN

1. The goal should be an attempt to decrease and eliminate drugs instead of chasing an elusive therapeutic window.

2. All patients are counseled on decreasing inflammation via diet!

3. Narcotics reserved for acute pain “flare-ups”, not as maintenance drugs.

4. Exercise, sleep, and stress reduction given “equal billing” with drugs and procedures.

“Let food be thy medicine and medicine be thy food.”

- Hippocrates