Dr C Leigh M Arseneau HBSc ND FMP

Medical Director of the Centre for Advanced MedicineChief Naturopathic Doctor for the Canadian Centre for Integrative Therapy

Medical Advisor for the Centre for Restorative Medicine AOR Medical Advisory Council

Clinical Advisor for Fluids IQEditorial Board for the Journal of Restorative Medicine

Integrative Medical Strategies for Chronic Pain

ldquoIt is much more important to know what sort of person has a disease than what sort

of disease a person hasrdquo

Sir William Osler

The DESTINATION is not nearly as important as the JOURNEY

``When I see a patient with arthritis coming in the door I leave by the

back door``

Sir William Osler

The Thumb Tack Rule

Dr Sidney Baker

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

ldquoIt is much more important to know what sort of person has a disease than what sort

of disease a person hasrdquo

Sir William Osler

The DESTINATION is not nearly as important as the JOURNEY

``When I see a patient with arthritis coming in the door I leave by the

back door``

Sir William Osler

The Thumb Tack Rule

Dr Sidney Baker

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

The DESTINATION is not nearly as important as the JOURNEY

``When I see a patient with arthritis coming in the door I leave by the

back door``

Sir William Osler

The Thumb Tack Rule

Dr Sidney Baker

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

``When I see a patient with arthritis coming in the door I leave by the

back door``

Sir William Osler

The Thumb Tack Rule

Dr Sidney Baker

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

The Thumb Tack Rule

Dr Sidney Baker

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

Step BackLook at the Whole Picture

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

The Future of Medicine

bull ldquothe network concept reveals a number of surprising connections amongst diseases forcing us to rethink the way in which we classify and separate themrdquo

N Engl J Med 2007357(4)370-379

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

Learning Objectives

bull The (Humbling) Complexity of Chronic Painbull Pain Perception ndash a Personalized Experiencebull Pain a metaphor for Dysfunctionbull Applying the Biopsychosocial Model bull The Need for an Interdisciplinary Team Approach

ndash Overview of our Integrative Model ndash Our Teamrsquos Philosophy on Chronic Pain ndash the Need for a

Systemrsquos Approach (pain is not simply one pathway gone awry)

bull Case Studybull Health Restoration through Systemrsquos Biologybull Natural Productrsquos for the Treatment of Chronic Complex

Pain Patients

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

What is pain

bull ldquoAn unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damagerdquo

H Merskey and N Bogduk eds IASP Task Force on Taxonomy 1994

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

bull Noxious stimulation always results in

changes in gene expression within the

central nervous system and different

chronic pain states generate unique

neurochemical signatures in the brain and spinal cord

Catherine Willner MD - 2015

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

Pain is a metaphor for dysfunction

How well do we understand it

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

Our Integrative Medical Philosophy

bull Address the underlying cause(s) of Pain

bull Biochemical individuality

bull Physiological network

bull Patient-centered medicine

bull Implement evidence based practices

bull Integrate CAM and conventional treatment

bull Whole system - mind body spirit

Pain Recovery and Health Restoration

bull Optimal Nutrition and Gastrointestinal Functionndash Emphasis on the microbiome

bull Toxin Avoidance and Effective Detoxificationndash Biotransformation

bull Strong Accurate Immunitybull Balanced inflammatory Functionbull Regulated Endocrine Controlbull Ageless Neurological System

ndash Methylation

bull Abundant Energy Productionndash Mitochondria

bull Patent Circulatory Systembull Spirituality

Multi-modal Multidisciplinary Approach

Patient

Comprehensive Lab Testing amp Imaging

Standard Medical Assessment

Injection Work Up

Botox

PRP

Neural Block

Drug Therapy

Additional Referral if warranted

Manual Assessment Physio Chiro Osteo

Complete Assessment

Report

Confirm candidate for Injection Therapy

Initiate Tailored Manual Therapy

Biological Assessment and Systemrsquos Review

Naturopathic Doctor

Environmental ScreenPossible Mold Metals

Solvents etcEnvironmental Consult

Referral

Review Labs

Order Functional Labs

Nutritional Status

Infusion Therapy

Diet Diary

Referral to DieticianNutritionist

Implement Personalized Program

Suspected Relevant SNPrsquosReferral for Lifestyle

GenomicsPersonalized Approach

Custom to Genetic needs

Generate Collaborative Report to Review by Team

ACE QuestionnairePsychologyPsychotherapy

consult with HRV Psychological ampEmotional

Therapy Initiated

Medical Doctor

Comprehensive Laboratory Testing for Chronic Pain

bull CBC

bull Lytes total protein albumin globulin

bull HbA1C fasting glucose fasting insulin

bull Lipid Panel

bull Ferritin uric acid

bull AM Cortisol DHEA

bull TSH T4 T3 RT3

bull Free testosterone Progesterone Estradiol Estrone

bull CK AST

bull ALT GGT ALP total bilirubin

bull Creatinine BUN

bull RBC Cholinesterase serum mercury

bull hs-CRP ESR Fibrinogen

bull ANA

bull B12 homocysteine MMA

bull Zinc copper RBC Se RBC Mg

bull 25-hydroxy vitamin D

bull Amylase lipase urine Indican

bull C3 C4 CD57 CD56 CD4CD8 ratio

Comprehensive Laboratory Testing for Chronic Pain

bull CBC

bull Lytes total protein albumin globulin

bull HbA1C fasting glucose fasting insulin

bull Lipid Panel

bull Ferritin uric acid

bull AM Cortisol DHEA

bull TSH T4 T3 RT3

bull Free testosterone Progesterone Estradiol Estrone

bull CK AST

bull ALT GGT ALP total bilirubin

bull Creatinine BUN

bull RBC Cholinesterase serum mercury

bull hs-CRP ESR Fibrinogen

bull ANA

bull B12 homocysteine MMA

bull Zinc copper RBC Se RBC Mg

bull 25-hydroxy vitamin D

bull Amylase lipase urine Indican

bull C3 C4 CD57 CD56 CD4CD8 ratio

Integrative Medicine

Genetic Influence on Pain Perception

Emerging relevant SNPs related to pain perception

Genetic Influence on Pain Perception

Emerging relevant SNPs related to pain perception

Epigenetics and Nutrigenomics

Genetic Uniqueness and Pain Perception

bull Catechol-O-methyltransferase (COMT) is an important Phase II metabolism enzyme Specifically it is responsible for inactivating catechol neurotransmitters (such as dopamine adrenaline and noradrenaline) via methylation

bull COMT an important enzyme in dopamine catabolism plays a key role in processes associated withhellipreward pain memory and learning

Qual Life Res (2010) 191407ndash1417

PLoS ONE 7(10) e48135 doi101371journalpone0048135

VOLUME 17 | NUMBER 2 | February 2014 nature neuroscience

PLoS ONE 6(3) e18035 doi101371journalpone0018035

Genetic Uniqueness and Pain Perception

bull Catechol-O-methyltransferase (COMT) is an important Phase II metabolism enzyme Specifically it is responsible for inactivating catechol neurotransmitters (such as dopamine adrenaline and noradrenaline) via methylation

bull COMT an important enzyme in dopamine catabolism plays a key role in processes associated withhellipreward pain memory and learning

Qual Life Res (2010) 191407ndash1417

PLoS ONE 7(10) e48135 doi101371journalpone0048135

VOLUME 17 | NUMBER 2 | February 2014 nature neuroscience

PLoS ONE 6(3) e18035 doi101371journalpone0018035

Food Signals and Pain Modulation

Phys Med Rehabil Clin N Am 2015 May26(2)309-20 doi 101016jpmr201412006

Am J Clin Nutr 2011 Aug94(2)479-85 doi 103945ajcn111013540 Epub 2011 Jun 15

Lipids Health Dis 2014 13 195 2014 Dec 16 doi 1011861476-511X-13-195

Diabetes Metab Syndr Obes 20125175-89 doi 102147DMSOS33473 Epub 2012 Jul 6

Nutr Res Rev 2018 Jun31(1)131-151 doi 101017S0954422417000270 Epub 2018 Apr 22

Clin Exp Rheumatol 2015 Jan-Feb33(1 Suppl 88)S117-25 Epub 2015 Mar 18

Swiss Med Wkly 2015 Nov 2145w14190 doi 104414smw201514190 eCollection 2015

ldquoAppropriate nutritional interventions may be one of the most useful tools doctors have to improve overall health outcomes in their

patients and specifically reduce inflammationrsquo

Food pyramid for subjects with chronic pain foods and dietary consituents as anti-inflammatory and anti-oxidant agents

bull Emerging literature suggests that diet constituents may play a modulatory role in chronic pain (CP) through management of inflammationoxidative stress resulting in attenuation of pain

bull A narrative review was performed to evaluate the existing evidence regarding the optimum diet for the management of CP

bull 172 eligible studies

bull Comparable effects to drug management therapy

Olive oil weeklylegumes and fish (four portions) white meat eggs and fresh cheese (two portions)red or processed meats (once per week)sweets can be consumed occasionally

low glycemic index should be consumed every day (three portions)fruits and vegetables (five portions)yogurt (125 ml)red wine (125 ml)

bull Top 5 alkali foodsndash Pumpkin seeds

ndash Sweet Potato

ndash Seaweed

ndash Lime watermelon

bull Top 5 anti-inflammatory foodsndash Ginger and Tumeric

ndash Avocado

ndash Blueberries

ndash Hemp seeds

ndash Brussel sprouts

ndash Cold water fish

bull Top 5 anti-oxidantsndash Goji berries

ndash Kidney beans

ndash Pecans

ndash Artichokes

ndash Dark chocolate ()

bull Low Glycemic ndash Broccoli

ndash Cinnamon

ndash Apples

ndash Lentils

ndash Rolled oats

bull Top 5 alkali foodsndash Pumpkin seeds

ndash Sweet Potato

ndash Seaweed

ndash Lime watermelon

bull Top 5 anti-inflammatory foodsndash Ginger and Tumeric

ndash Avocado

ndash Blueberries

ndash Hemp seeds

ndash Brussel sprouts

ndash Cold water fish

bull Top 5 anti-oxidantsndash Goji berries

ndash Kidney beans

ndash Pecans

ndash Artichokes

ndash Dark chocolate ()

bull Low Glycemic ndash Broccoli

ndash Cinnamon

ndash Apples

ndash Lentils

ndash Rolled oats

Oxidative Stress

Oxidative stress levels in patientrsquos with inflammatory and non-inflammatory back pain are higher than in controls which suggests that oxidative stress may be involvedhelliprdquo

Eur J Gen Med 201310(4)185-190

Fibrom open 2016 Vol 1(1) 105

Oxidative Stressbull Targets

ndash Cell Membranesndash Receptorsndash Enzymesndash DNA

bull Causesndash Low phytochemical rich diet (lack

of fruits and vegetables)ndash Systemic inflammatory cytokines

(inflammation)

ndash Xenobiotic load (chemical toxins)

Diabetic Care 200326770-76Expert Opin Ther Targets 2013 Sep17(9)1081-9Brain Res Bull 2009 Aug 14Biofactors 199910157-67Pain 2009 Sep145(1-2)129-35Med Hypotheses 200157(2)139-45

bull Protective substancesndash Superoxide dismutase (requires zinc copper and selenium)ndash Glutathione peroxidasendash (selenium dependent amp protein)ndash Catalase (Iron dependent)ndash Dietary input

bull Vitamin Cbull Vitamin Ebull CoQ10bull Alpha lipoic acidbull L-Carnitinebull Glutathionebull Quercetinbull Rosemary

Alpha Lipoic Acidbull Free radical scavenger and cytoprotectantbull Readily crosses the Blood-brain-barrierbull Upregulates glutathione synthesis (DHLA) and regenerate anti-

oxidants such as Vitamin E and C bull Improves insulin-mediated glucose uptakebull Metal chelation capacitybull Inhibits NFKBbull Repair oxidatively damaged proteins (DHLA)bull Cofactor for mitochondrial bioenergetic enzymes

Current Medicinal Chemistry Vol 11 No 9 (2004) 1135ndash1146

The Journal of Nutrition Vol 133 No 11 (2003) 3327ndash3330

Diabetes Care Vol 29 No 11 (2006) 2365ndash2370

General Pharmacology Vol 29 No 3 (1997) 315ndash331

J Med Food 2017 Oct 4

Drugs R D 201414(1)1-7

Clin Drug Investig 200828(8)495-500

Alpha Lipoic Acid continuedbull Diabetes (Type 1 and Type 2)

bull Diabetic and Autonomic Neuropathy

bull Insulin Resistance

bull Metabolic Syndrome

bull Liver disease

bull Neurodegenerative disease

bull Alzheimerrsquos Disease

bull Hypertriglyceridemia

Diabet Med 200421(2)114-121

European Journal of Pharmacology Vol 728 5 April 2014 Pages 59-66

PLoSOne 20105(9)

CircRes 10-28-200597(9)880-890

Proc Natl Acad Sci USA 3-6-2007104(10)4077-4082

Life Sci 12-14-200680(2)146-153

Free Radic Biol Med 199722359-78

Mitochondropathies

The final outcome of dysfunction

ldquoProtecting mitochondrial function would be a promising strategy to

alleviate or prevent chronic pain statesrdquo

copy2001 ACEcopy2001 ACE

Mitochondria

Mitochondrial Health

Impacts CP

Postgrad Med J 2013 Dec89(1058)709-14

Alpha Lipoic Acidbull Free radical scavenger and cytoprotectantbull Readily crosses the Blood-brain-barrierbull Upregulates glutathione synthesis (DHLA) and regenerate anti-

oxidants such as Vitamin E and C bull Improves insulin-mediated glucose uptakebull Metal chelation capacitybull Inhibits NFKBbull Repair oxidatively damaged proteins (DHLA)bull Cofactor for mitochondrial bioenergetic enzymes

Current Medicinal Chemistry Vol 11 No 9 (2004) 1135ndash1146

The Journal of Nutrition Vol 133 No 11 (2003) 3327ndash3330

Diabetes Care Vol 29 No 11 (2006) 2365ndash2370

General Pharmacology Vol 29 No 3 (1997) 315ndash331

J Med Food 2017 Oct 4

Drugs R D 201414(1)1-7

Clin Drug Investig 200828(8)495-500

Alpha Lipoic Acid continuedbull Diabetes (Type 1 and Type 2)

bull Diabetic and Autonomic Neuropathy

bull Insulin Resistance

bull Metabolic Syndrome

bull Liver disease

bull Neurodegenerative disease

bull Alzheimerrsquos Disease

bull Hypertriglyceridemia

Diabet Med 200421(2)114-121

European Journal of Pharmacology Vol 728 5 April 2014 Pages 59-66

PLoSOne 20105(9)

CircRes 10-28-200597(9)880-890

Proc Natl Acad Sci USA 3-6-2007104(10)4077-4082

Life Sci 12-14-200680(2)146-153

Free Radic Biol Med 199722359-78

Mitochondropathies

The final outcome of dysfunction

ldquoProtecting mitochondrial function would be a promising strategy to

alleviate or prevent chronic pain statesrdquo

copy2001 ACEcopy2001 ACE

Mitochondria

Mitochondrial Health

Impacts CP

Postgrad Med J 2013 Dec89(1058)709-14

Alpha Lipoic Acid continuedbull Diabetes (Type 1 and Type 2)

bull Diabetic and Autonomic Neuropathy

bull Insulin Resistance

bull Metabolic Syndrome

bull Liver disease

bull Neurodegenerative disease

bull Alzheimerrsquos Disease

bull Hypertriglyceridemia

Diabet Med 200421(2)114-121

European Journal of Pharmacology Vol 728 5 April 2014 Pages 59-66

PLoSOne 20105(9)

CircRes 10-28-200597(9)880-890

Proc Natl Acad Sci USA 3-6-2007104(10)4077-4082

Life Sci 12-14-200680(2)146-153

Free Radic Biol Med 199722359-78

Mitochondropathies

The final outcome of dysfunction

ldquoProtecting mitochondrial function would be a promising strategy to

alleviate or prevent chronic pain statesrdquo

copy2001 ACEcopy2001 ACE

Mitochondria

Mitochondrial Health

Impacts CP

Postgrad Med J 2013 Dec89(1058)709-14

Mitochondropathies

The final outcome of dysfunction

ldquoProtecting mitochondrial function would be a promising strategy to

alleviate or prevent chronic pain statesrdquo

copy2001 ACEcopy2001 ACE

Mitochondria

Mitochondrial Health

Impacts CP

Postgrad Med J 2013 Dec89(1058)709-14

ldquoProtecting mitochondrial function would be a promising strategy to

alleviate or prevent chronic pain statesrdquo

copy2001 ACEcopy2001 ACE

Mitochondria

Mitochondrial Health

Impacts CP

Postgrad Med J 2013 Dec89(1058)709-14

Addressing Mitochondrial Dysfunction

bull Saturate the Mitochondria with Nutrients to Improve ATP Production

bull Stabilize Mitochondrial Membranes with Appropriate Type and Amount of Fatty Acids

bull Reduce Oxidative Stress and Prevent Damage to the Mitochondrial Membranes

Metabolism ATP Production

bull Lipids Carbs and Protein following digestion are processed and trans-ported into the mitochondria

bull Krebrsquos cycle continues the break down to high

energy electrons

bull Electron Transport Chain utilizes oxygen to

produce ATP for cellular energy

bull All cell function and physiology depends on the functioning and efficiency of the

mitochondria

Energy Production

bull Mg plays a key cofactor and structural role in ATP production

ATP(energy)

Mg2+

Cell

Dr Paul Hrkal ND 2017

Mg2+ Malate

bull Malic Acid

ndash Increases cellular energy production

ndash Shown to reduce muscle pain in 2 clinical trials

bull Fibromyalgia

Dr Paul Hrkal ND 2017

Mg2+ Glycinate

bull Glycine

ndash Acts as a central inhibitory neurotransmitter = ldquocalmingrdquo effect

ndash Promotes detoxification

Dr Paul Hrkal ND 2017

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Metabolism ATP Production

bull Lipids Carbs and Protein following digestion are processed and trans-ported into the mitochondria

bull Krebrsquos cycle continues the break down to high

energy electrons

bull Electron Transport Chain utilizes oxygen to

produce ATP for cellular energy

bull All cell function and physiology depends on the functioning and efficiency of the

mitochondria

Energy Production

bull Mg plays a key cofactor and structural role in ATP production

ATP(energy)

Mg2+

Cell

Dr Paul Hrkal ND 2017

Mg2+ Malate

bull Malic Acid

ndash Increases cellular energy production

ndash Shown to reduce muscle pain in 2 clinical trials

bull Fibromyalgia

Dr Paul Hrkal ND 2017

Mg2+ Glycinate

bull Glycine

ndash Acts as a central inhibitory neurotransmitter = ldquocalmingrdquo effect

ndash Promotes detoxification

Dr Paul Hrkal ND 2017

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Energy Production

bull Mg plays a key cofactor and structural role in ATP production

ATP(energy)

Mg2+

Cell

Dr Paul Hrkal ND 2017

Mg2+ Malate

bull Malic Acid

ndash Increases cellular energy production

ndash Shown to reduce muscle pain in 2 clinical trials

bull Fibromyalgia

Dr Paul Hrkal ND 2017

Mg2+ Glycinate

bull Glycine

ndash Acts as a central inhibitory neurotransmitter = ldquocalmingrdquo effect

ndash Promotes detoxification

Dr Paul Hrkal ND 2017

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Mg2+ Malate

bull Malic Acid

ndash Increases cellular energy production

ndash Shown to reduce muscle pain in 2 clinical trials

bull Fibromyalgia

Dr Paul Hrkal ND 2017

Mg2+ Glycinate

bull Glycine

ndash Acts as a central inhibitory neurotransmitter = ldquocalmingrdquo effect

ndash Promotes detoxification

Dr Paul Hrkal ND 2017

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Mg2+ Glycinate

bull Glycine

ndash Acts as a central inhibitory neurotransmitter = ldquocalmingrdquo effect

ndash Promotes detoxification

Dr Paul Hrkal ND 2017

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Magnesium Form Key Clinical Uses Mg

Mg oxide Laxative 58

Mg citrate Laxative general magnesium support 11

Mg Chloride Many - inflammation depression 12

Mg (bis) glycinate Insomnia restless legs anxiety muscle spasm 11-14

Mg malate Fibromyalgia muscle pain 11

Mg aspartate Chronic fatigue 7

Mg taurate Cardiovascular disease Arrhythmia 88

Mg orotate Hypertension Congestive Heart Failure

Mitral valve prolapse Stable angina Blood vessel elasticity

72

Mg L-Theronate Brain injuries cognition memory focus 81

Dr Paul Hrkal ND 2017

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Condition

Asthma Mg has a bronchodilating and anti-inflammatory effect

Brain injury Mg levels could fall by up to 60 after a TBI Research in animals has shown that magnesium improved neurological function such as behavior and cognition

Heart palpitations and irregular heartbeats

Mg is a key electrolyte in regulating nerve and heart conduction Magnesium (along with potassium) supplementation can stabilize and regulate heart contraction

PMS and cramps Mg shown to reduce painful cramps and headaches as well as relieve premenstrual mood swings

Migraines Migraine attacks have been associated with Mg deficiency which may be present in up to half of patients suffering from migraines Mg shown to alleviate the frequency and intensity of migraine

Fibromyalgia Research shows that patients suffering from fibromyalgia have often a deficiency in magnesium

Depression and anxiety Human studies have confirmed that magnesium supplementation has a beneficial effect on mood

Dr Paul Hrkal ND 2017

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Magnesium and Inflammation

bull Anti-inflammatory Recent review study supplementation reduced a marker of inflammation (CRP) among individuals with elevated levels (greater than 3)

Curr Pharm Des 2017 May 25

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Mitochondrial Therapeutics

bull Coenzyme Q10

bull Alpha Lipoic Acid

bull L-Carnitine

bull D-Ribose

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

The Inflammatory Cascade

A Complex Array

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Inflammation ndash A Unifying Law of Pain

bull Determine

bull inflammatory profile

bull 2 Inhibit or suppress

bull inflammatory

bull mediators

bull 3 Inhibit or suppress

bull afferent and efferent

bull motor transmission

bull 4 Modulate neuronal

bull Transmissionbull All should be reclassifiedbull as variants ofbull inflammation-inducedbull pain

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Understanding Inflammation

bull It is a complex highly orchestrated process that relies on signal transduction to activate an interconnected network of recursive self-amplifying cascades

bull Acute inflammation is an adaptive phenomenon that primarily consists of defend and repair functions

bull Chronic inflammation is a destructive maladaptive phenomenon responsible for a wide variety of seemingly disparate diseases

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Multiple Physiological Pathways

bull The inflammatory response can be set in motion by a wide range of exogenous and endogenous triggers

bull Susceptibility to these triggers is influenced by genetic and epigenetic factors

bull The response to inflammatory triggers is amplified or dampened by endogenous mediators

bull It is the ongoing presence of triggers and mediators that fuels the fire and perpetuates the pathology of chronic inflammatory disease

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

A Natural Approach to Controlling

The Inflammatory Cascade

Cytokines

bull Interleukin 1

bull Interleukin 6

bull Tumor Necrosis Factor-Alpha

T Helper Cell

Antigen

Immune cells identify antigen

Immune cells produce cytokines

Cytokines recruit immune cells

More cytokines produced more inflammation

Nutrients That Calm the ImmuneInflammatory Response

I Kappa A

NF Kappa B

Kinase Pathways

Arachadonic Acid

COX-2 COX-2

PGE2

RIAA calms the kinase

pathways

Omega-3 EFAs

PGE1 amp3Curcumin and rosemary

block COX-2 Joints tissues etc

Adequate selenium and zinc

calm the inflammatory response

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Boswellia Serrata

bull Promote and healthy inflammatory response

bull Inhibits 5-lipoxygenase (leukotriene synthesis)

bull Decreases the pro-inflammatory cytokines (IL-6 and TNFalpha)

bull Reduces edema

bull Anti-arthritic and analgesic properties

bull Regulates blood glucose and improves lipid profile

bull Neuroprotection (Post-concussive recovery)

bull Improves lung and immune function (Immunomodulation)

bull Improvement in cognitive function

Journal of Pharmacological and Experimental Therapy Vol 261 No 3 (1992) 1143ndash1146

PLoS One Vol 10 No 5 (2015) e0125375

Phytomedicine Vol 10 No 1 (2003) 3ndash7

Arthritis Research and Therapy Vol 10 No 4 (2008) R85

Brain Injury Vol 27 No 12 (2013) 1454ndash1460

Iran Journal of Pharmaceutical Research Vol 13 No 3 (2014) 1003ndash1009

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Overview Natural Agents for Treating Chronic Inflammation

bull Botanical

ndash Boswellia Rosemary curcumin Skutellaria ginger Oleanolic Acid

bull Proteases (bromelain trypsyn)

bull Phytochemicals and Antioxidants

bull Essential fatty acids

J Ethnopharmacol 199338113-19

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

Gastro-Intestinal Health and Chronic Pain

ldquoA cholinergic anti-inflammatory pathway has been described through Vagus nerve fibers which is able to dampen peripheral inflammationrdquo

Front Neurosci 2018 12 49

LOSS OF INTEGRITY

ldquoTranslocation of bacteria and toxins through leaky gut mucosa may amplify or perpetuate systemic inflammationrsquo

Eur J Surg Suppl 199858332-36

Turk J Gastroenterol 200112(2)141-44

Can J Gastroenterol 199913(Suppl A)S15A-S17A

Acta Neurol Scand 198877(3)187-91

IMAJ 20013755-60

The GI-Immune Connection

Toxins

Liver Stress Kupffer Cell Activation

MALTGALT

Activation

GI inflammation and leaky gut initiate a cascade

of signaling events that can increase inflammation

Scharz B et al Intestinal ischemic reperfusion syndrome pathophysiology clinical significance therapy Wien Klin Wochenschr1999111(14)539-48

Systemic

Inflammation

Antigens

Leaky Gut

(Inflammation)

Localized

Inflammation

The Influence of the Microbiome

bull ldquoIf the GI system is populated with the wrong bacteria there is an increase in pro-inflammatory cytokines and the development of visceral hyperalgesiardquo

bull Probiotic use has been reported to reduce anxiety and stress response and improve moodhellip

bull Consumption of a fermented milk product containing specific probiotics modulates brain activity affecting midbrain connectivity

bull The complexity of the superorganism helps us explain the variety of physical and emotional aspects of pain

Dr Donald C Manning MD PhDAmerican Academy of Pain Management 2014 Annual Clinical Meeting

The GI-Immune Connection

Toxins

Liver Stress Kupffer Cell Activation

MALTGALT

Activation

GI inflammation and leaky gut initiate a cascade

of signaling events that can increase inflammation

Scharz B et al Intestinal ischemic reperfusion syndrome pathophysiology clinical significance therapy Wien Klin Wochenschr1999111(14)539-48

Systemic

Inflammation

Antigens

Leaky Gut

(Inflammation)

Localized

Inflammation

The Influence of the Microbiome

bull ldquoIf the GI system is populated with the wrong bacteria there is an increase in pro-inflammatory cytokines and the development of visceral hyperalgesiardquo

bull Probiotic use has been reported to reduce anxiety and stress response and improve moodhellip

bull Consumption of a fermented milk product containing specific probiotics modulates brain activity affecting midbrain connectivity

bull The complexity of the superorganism helps us explain the variety of physical and emotional aspects of pain

Dr Donald C Manning MD PhDAmerican Academy of Pain Management 2014 Annual Clinical Meeting

The Influence of the Microbiome

bull ldquoIf the GI system is populated with the wrong bacteria there is an increase in pro-inflammatory cytokines and the development of visceral hyperalgesiardquo

bull Probiotic use has been reported to reduce anxiety and stress response and improve moodhellip

bull Consumption of a fermented milk product containing specific probiotics modulates brain activity affecting midbrain connectivity

bull The complexity of the superorganism helps us explain the variety of physical and emotional aspects of pain

Dr Donald C Manning MD PhDAmerican Academy of Pain Management 2014 Annual Clinical Meeting

Toxicants and the Pain Process (Solvents heavy metals pesticides and other toxicants)

bull Solvents ndash ldquoThere is strong evidence that some solvents may cause peripheral neuropathyrdquo

bull Pesticides ndash ldquoNeurologic symptoms are also common with chronic exposure Peripheral neuropathy manifested by paresthesia pain anesthesia paresis and ataxia may be a prominent featurerdquo

bull Heavy metalsndash ldquohellipdirect proportionality between the level of pain the increase of the concentration of

heavy metals in all the examined grouprdquo

ndash ldquoConcentration of heavy metals in serum samples of RA patients and healthy control individuals differ significantlyhelliprdquo

Ann Stomatol (Roma) 2014 Apr-Jun 5(2) 41ndash51

Iran J Public Health 2017 May 46(5) 626ndash633

Occup Environ Med 2006 Mar 63(3) 221ndash226

npicorsteduRMPPrmpp_ch21pdf

CDC 2400 adults and childrens 200 synthetic chemical toxins

To date over 87000 new chemicals

Found in baked goods and pre-packaged foods such as a pizza

box hygiene products such as underarm deodorant and after

shave cosmetics such as eyeliner and lipstick furniture and

carpets clothes cleaned at the dry cleaner pesticides car

exhaust etc

Pain Symptom Manage 200019S2-S6Ann N Y Acad Sci 2001933119-29

Am J Med 1998105(Suppl 3A)74S-82S

Ubiquitous Toxicants and Pain Sensitization

Genetic Variations

bull There are numerous genetic variations in the activity of both phase 1 and phase 2 enzymes

bull This along with nutritional status and total toxic load may help explain why detoxification abilities for a particular substance may vary as much as 100-fold or more between different

individuals

J Clin Pharmacol 199737(7)635-48

Interpatient variability genetic predisposition and other genetic factors

West WL Knight EM Pradhan S Hinds TS

Center for Drug Abuse Research (CDAR) Howard University Department of PharmacologyCenter for Drug Abuse Research College of Medicine Howard University Washington DC 20059 USA

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes Selected are the polymorphic enzymes of cytochromes P-450 (CYP) as examples of phase I enzymes and methyl transferases n-acetyl transferases and glutathione-s-transferases as examples of phase II enzymes The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described Phase I enzymatic reactions are predominantly oxidative whereas phase II reactions often couple with the byproducts of phase I Overall in poor metabolizers whether phase I or phase II there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists

Research identifies significant genetic

variation in CYP450 Phase I enzyme

expression in humans These variations

have a significant impact on the patients

ability to clear toxins

Genetic Variations in Phase I Enzymes Affect

Your Patients Ability to Clear Toxins

Genetic Variations

bull There are numerous genetic variations in the activity of both phase 1 and phase 2 enzymes

bull This along with nutritional status and total toxic load may help explain why detoxification abilities for a particular substance may vary as much as 100-fold or more between different

individuals

J Clin Pharmacol 199737(7)635-48

Interpatient variability genetic predisposition and other genetic factors

West WL Knight EM Pradhan S Hinds TS

Center for Drug Abuse Research (CDAR) Howard University Department of PharmacologyCenter for Drug Abuse Research College of Medicine Howard University Washington DC 20059 USA

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes Selected are the polymorphic enzymes of cytochromes P-450 (CYP) as examples of phase I enzymes and methyl transferases n-acetyl transferases and glutathione-s-transferases as examples of phase II enzymes The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described Phase I enzymatic reactions are predominantly oxidative whereas phase II reactions often couple with the byproducts of phase I Overall in poor metabolizers whether phase I or phase II there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists

Research identifies significant genetic

variation in CYP450 Phase I enzyme

expression in humans These variations

have a significant impact on the patients

ability to clear toxins

Genetic Variations in Phase I Enzymes Affect

Your Patients Ability to Clear Toxins

J Clin Pharmacol 199737(7)635-48

Interpatient variability genetic predisposition and other genetic factors

West WL Knight EM Pradhan S Hinds TS

Center for Drug Abuse Research (CDAR) Howard University Department of PharmacologyCenter for Drug Abuse Research College of Medicine Howard University Washington DC 20059 USA

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes Selected are the polymorphic enzymes of cytochromes P-450 (CYP) as examples of phase I enzymes and methyl transferases n-acetyl transferases and glutathione-s-transferases as examples of phase II enzymes The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described Phase I enzymatic reactions are predominantly oxidative whereas phase II reactions often couple with the byproducts of phase I Overall in poor metabolizers whether phase I or phase II there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists

Research identifies significant genetic

variation in CYP450 Phase I enzyme

expression in humans These variations

have a significant impact on the patients

ability to clear toxins

Genetic Variations in Phase I Enzymes Affect

Your Patients Ability to Clear Toxins

Types of Reactions

Phase I activation

Cytochrome P450 enzymes

Parent

Fat-Soluble

Compound

Water-

Soluble

Compound

Phase II conjugation

Glucuronosyltransferase

Sulfation

Amino Acid Conjugation

Glutathione Conjugation

N-Acetyltransferase

Activated

Intermediate

Enzymes increased by

bull Sulphoraphane (in Broccoli seeds)

bull Carbinols (in Cruciferous vegetables)

bull Polyphenolics (in Green Tea)

bull Selenium (activates Glutathione peroxidase)

bull Glycine Taurine Glutamine Arginine Cysteine and Methionine

Phase II Liver Detoxification

Sulforaphane Glucosinolate(SGS)bull Activates the transcription factor Keap1Nrf2ARE

bull Exhibits indirect antioxidant activity for at least 48 to 72 hours a significantly longer period of time than direct antioxidants such as vitamins C E and beta carotene

bull Supports the bodyrsquos ability to protect cellular DNA from damage

bull Metabolic disposal of xenobiotics carcinogens and other electrophils through selective induction of phase II conjugation

bull Supports the bodyrsquos protective response against age related CNS inflammation (microglial and macrophage activation)

Proc Natl Acad Sci USA 1992 Mar 1589(6)2399-403

Altern Med Rev 2010 Dec15(4)352- 60 Review

Front Genet 201237 Epub 2012 Jan 24

Clin Immunol 2009 Mar130(3)244-51

Proc Natl Acad Sci U S A 2004 May 4101(18)7094-9

Nutr Neurosci 2005 Apr8(2)101-10

Enzymes increased by

bull Sulphoraphane (in Broccoli seeds)

bull Carbinols (in Cruciferous vegetables)

bull Polyphenolics (in Green Tea)

bull Selenium (activates Glutathione peroxidase)

bull Glycine Taurine Glutamine Arginine Cysteine and Methionine

Phase II Liver Detoxification

Sulforaphane Glucosinolate(SGS)bull Activates the transcription factor Keap1Nrf2ARE

bull Exhibits indirect antioxidant activity for at least 48 to 72 hours a significantly longer period of time than direct antioxidants such as vitamins C E and beta carotene

bull Supports the bodyrsquos ability to protect cellular DNA from damage

bull Metabolic disposal of xenobiotics carcinogens and other electrophils through selective induction of phase II conjugation

bull Supports the bodyrsquos protective response against age related CNS inflammation (microglial and macrophage activation)

Proc Natl Acad Sci USA 1992 Mar 1589(6)2399-403

Altern Med Rev 2010 Dec15(4)352- 60 Review

Front Genet 201237 Epub 2012 Jan 24

Clin Immunol 2009 Mar130(3)244-51

Proc Natl Acad Sci U S A 2004 May 4101(18)7094-9

Nutr Neurosci 2005 Apr8(2)101-10

Sulforaphane Glucosinolate(SGS)bull Activates the transcription factor Keap1Nrf2ARE

bull Exhibits indirect antioxidant activity for at least 48 to 72 hours a significantly longer period of time than direct antioxidants such as vitamins C E and beta carotene

bull Supports the bodyrsquos ability to protect cellular DNA from damage

bull Metabolic disposal of xenobiotics carcinogens and other electrophils through selective induction of phase II conjugation

bull Supports the bodyrsquos protective response against age related CNS inflammation (microglial and macrophage activation)

Proc Natl Acad Sci USA 1992 Mar 1589(6)2399-403

Altern Med Rev 2010 Dec15(4)352- 60 Review

Front Genet 201237 Epub 2012 Jan 24

Clin Immunol 2009 Mar130(3)244-51

Proc Natl Acad Sci U S A 2004 May 4101(18)7094-9

Nutr Neurosci 2005 Apr8(2)101-10

Chronic Stress Response and the Pain Process

Addressing the Psychology of Pain

ldquoIt is likely that sustained arousal may facilitate the development of

sensitization in some or many neural circuitsrdquo

Addressing the Psychology of Pain

ldquoIt is likely that sustained arousal may facilitate the development of

sensitization in some or many neural circuitsrdquo

What is Stress

bull A physiologic response to a demand for change

bull ldquoFight or Flightrdquo response

bull General Adaptation Syndrome

bull Sympathetic Nervous System Dominance

StressNot Just An Adrenal ProblemStress triggers psycho-neuroendocrine-immune imbalance

Applied Nutrition Science Reports No 576

Stress induced Dysfunction

Altered HPA axis

BMC Res Notes 2008 Dec 221134

Archives of general psychiatry vol 63 pg 1267

Pain 199983(2)313-19

IMAJ 20013755-60

Z Rheumatol 199857 (Suppl 2)67-71

Cur Rheumatol Rep 20024(4)286-92

Pharm bio and behaviour 2005

Ann N Y Acad Sci 1998840684-97

Conditions Associated With Sympathetic Dominance

Long-term Effects of Elevated Cortisol amp Catecholamines

◼ GI distress IBS ulcers

◼ Cardiovascular symptoms rapid pulse pounding heartweakness dizziness chest pain high BP

◼ Mood changes general irritability floating anxiety depression impulsive behavior nervous laughter increase startle response

◼ Hyper-kinesis or -excitation

◼ Sleep disturbancesnightmares insomnia

◼ Brain architecture changes Lower hippocampal volume ( cortisol)

◼ Cognitive impairmentinability to concentrate poor memory

◼ Neuromusculoskeletal complaints TMJ bruxism tremblingnervous ticks back and muscle ache

◼ Energy level Fatigue of unknown origin

◼ Adrenal architecture changes Adrenal hyperplasia ldquoburnoutrdquo dryness of mouth sweating salt craving

◼ Immune impairmentincreased susceptibility to viral infections autoimmune disorders

Stress impacts inflammation

Health Psychology November

2002 Vol 21 No 6 531ndash541

ldquoThey had flatter diurnal slopes of cortisol secretionhellip There was

also evidence that chronic stress impaired the immune systemrsquos

response to anti-inflammatory signals The capacity of a

synthetic glucocorticoid hormone to suppress in vitro

production of the pro-inflammatory cytokine interleukin-6 was

diminishedhellipFindings suggest a novel pathway by which chronic

stress might alter the course of inflammatory diseaserdquo

ldquoThis study examined whether

chronic stress impairs the immune

systemrsquos capacity to respond to

hormonal signals that terminate

inflammationrdquo

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

StressNot Just An Adrenal ProblemStress triggers psycho-neuroendocrine-immune imbalance

Applied Nutrition Science Reports No 576

Stress induced Dysfunction

Altered HPA axis

BMC Res Notes 2008 Dec 221134

Archives of general psychiatry vol 63 pg 1267

Pain 199983(2)313-19

IMAJ 20013755-60

Z Rheumatol 199857 (Suppl 2)67-71

Cur Rheumatol Rep 20024(4)286-92

Pharm bio and behaviour 2005

Ann N Y Acad Sci 1998840684-97

Conditions Associated With Sympathetic Dominance

Long-term Effects of Elevated Cortisol amp Catecholamines

◼ GI distress IBS ulcers

◼ Cardiovascular symptoms rapid pulse pounding heartweakness dizziness chest pain high BP

◼ Mood changes general irritability floating anxiety depression impulsive behavior nervous laughter increase startle response

◼ Hyper-kinesis or -excitation

◼ Sleep disturbancesnightmares insomnia

◼ Brain architecture changes Lower hippocampal volume ( cortisol)

◼ Cognitive impairmentinability to concentrate poor memory

◼ Neuromusculoskeletal complaints TMJ bruxism tremblingnervous ticks back and muscle ache

◼ Energy level Fatigue of unknown origin

◼ Adrenal architecture changes Adrenal hyperplasia ldquoburnoutrdquo dryness of mouth sweating salt craving

◼ Immune impairmentincreased susceptibility to viral infections autoimmune disorders

Stress impacts inflammation

Health Psychology November

2002 Vol 21 No 6 531ndash541

ldquoThey had flatter diurnal slopes of cortisol secretionhellip There was

also evidence that chronic stress impaired the immune systemrsquos

response to anti-inflammatory signals The capacity of a

synthetic glucocorticoid hormone to suppress in vitro

production of the pro-inflammatory cytokine interleukin-6 was

diminishedhellipFindings suggest a novel pathway by which chronic

stress might alter the course of inflammatory diseaserdquo

ldquoThis study examined whether

chronic stress impairs the immune

systemrsquos capacity to respond to

hormonal signals that terminate

inflammationrdquo

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

Stress induced Dysfunction

Altered HPA axis

BMC Res Notes 2008 Dec 221134

Archives of general psychiatry vol 63 pg 1267

Pain 199983(2)313-19

IMAJ 20013755-60

Z Rheumatol 199857 (Suppl 2)67-71

Cur Rheumatol Rep 20024(4)286-92

Pharm bio and behaviour 2005

Ann N Y Acad Sci 1998840684-97

Conditions Associated With Sympathetic Dominance

Long-term Effects of Elevated Cortisol amp Catecholamines

◼ GI distress IBS ulcers

◼ Cardiovascular symptoms rapid pulse pounding heartweakness dizziness chest pain high BP

◼ Mood changes general irritability floating anxiety depression impulsive behavior nervous laughter increase startle response

◼ Hyper-kinesis or -excitation

◼ Sleep disturbancesnightmares insomnia

◼ Brain architecture changes Lower hippocampal volume ( cortisol)

◼ Cognitive impairmentinability to concentrate poor memory

◼ Neuromusculoskeletal complaints TMJ bruxism tremblingnervous ticks back and muscle ache

◼ Energy level Fatigue of unknown origin

◼ Adrenal architecture changes Adrenal hyperplasia ldquoburnoutrdquo dryness of mouth sweating salt craving

◼ Immune impairmentincreased susceptibility to viral infections autoimmune disorders

Stress impacts inflammation

Health Psychology November

2002 Vol 21 No 6 531ndash541

ldquoThey had flatter diurnal slopes of cortisol secretionhellip There was

also evidence that chronic stress impaired the immune systemrsquos

response to anti-inflammatory signals The capacity of a

synthetic glucocorticoid hormone to suppress in vitro

production of the pro-inflammatory cytokine interleukin-6 was

diminishedhellipFindings suggest a novel pathway by which chronic

stress might alter the course of inflammatory diseaserdquo

ldquoThis study examined whether

chronic stress impairs the immune

systemrsquos capacity to respond to

hormonal signals that terminate

inflammationrdquo

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

Conditions Associated With Sympathetic Dominance

Long-term Effects of Elevated Cortisol amp Catecholamines

◼ GI distress IBS ulcers

◼ Cardiovascular symptoms rapid pulse pounding heartweakness dizziness chest pain high BP

◼ Mood changes general irritability floating anxiety depression impulsive behavior nervous laughter increase startle response

◼ Hyper-kinesis or -excitation

◼ Sleep disturbancesnightmares insomnia

◼ Brain architecture changes Lower hippocampal volume ( cortisol)

◼ Cognitive impairmentinability to concentrate poor memory

◼ Neuromusculoskeletal complaints TMJ bruxism tremblingnervous ticks back and muscle ache

◼ Energy level Fatigue of unknown origin

◼ Adrenal architecture changes Adrenal hyperplasia ldquoburnoutrdquo dryness of mouth sweating salt craving

◼ Immune impairmentincreased susceptibility to viral infections autoimmune disorders

Stress impacts inflammation

Health Psychology November

2002 Vol 21 No 6 531ndash541

ldquoThey had flatter diurnal slopes of cortisol secretionhellip There was

also evidence that chronic stress impaired the immune systemrsquos

response to anti-inflammatory signals The capacity of a

synthetic glucocorticoid hormone to suppress in vitro

production of the pro-inflammatory cytokine interleukin-6 was

diminishedhellipFindings suggest a novel pathway by which chronic

stress might alter the course of inflammatory diseaserdquo

ldquoThis study examined whether

chronic stress impairs the immune

systemrsquos capacity to respond to

hormonal signals that terminate

inflammationrdquo

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

Stress impacts inflammation

Health Psychology November

2002 Vol 21 No 6 531ndash541

ldquoThey had flatter diurnal slopes of cortisol secretionhellip There was

also evidence that chronic stress impaired the immune systemrsquos

response to anti-inflammatory signals The capacity of a

synthetic glucocorticoid hormone to suppress in vitro

production of the pro-inflammatory cytokine interleukin-6 was

diminishedhellipFindings suggest a novel pathway by which chronic

stress might alter the course of inflammatory diseaserdquo

ldquoThis study examined whether

chronic stress impairs the immune

systemrsquos capacity to respond to

hormonal signals that terminate

inflammationrdquo

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

Rhodiola Roseabull Powerful herbal adaptogen (increase resistance to stressors)bull Neuro cardio and hepatoprotective effectsbull Downregulates neuro-excitatory over stimulation anti-nociceptive

effects immunotropic antiviral anti-inflammatory anti-oxidant nootropic and antibacterial properties

bull Regulates catecholamines and can activate central and peripheral opioid receptors

bull Relieve stress related symptoms such as fatigue (mental and physical)bull Enhances mental focus stamina and cognitive functionbull Benefits sleep and mood including anxiety and depression through

modulation of biogenic amines

Journal of Food and Drug Analysis Vol 23 No 3 (2015) 359ndash369 Phytomedicine Vol 17 No 7 (2010) 481ndash493 Planta Medica Vol 75 No 2 (2009) 105ndash112 Phytotherapy Research Vol 30 No 4 (2016) 532ndash539 Evidence Based Complementary and Alternative Medicine Vol 2013 (2013) 514049 Phytomedicine Vol 23 No 7 (2016) 770ndash783Phytomedicine Vol 22 No 3 (2015) 394ndash399 Phytotherapy Research Vol 29 No 12 (2015) 1934ndash1939 Phytotherapy Research Vol 26 No 8 (2012) 1220ndash1225 Nord J Psychiatry 200761343-8

Phytother Res 201226(8)1220-5

Hormones and Pain Perception

Endocrine Reviews Volume 28 521-574 2007Journal of the American College of Cardiology Volume 41 1358-1363 2003Pregnenolone Naturersquos Feel Good Hormone by Ray Sahelian MD Avery PublishingGroup Inc Garden City Park NY 1997

Pain 2014 Dec155(12)2448-60 doi 101016jpain201408027 Epub 2014 Aug 27

Arthritis Res Ther 2009 11(5)241Arthritis Rheum 1998 Oct41(10)1867-73Arthritis Rheum 2006 Oct54(10)3194-204Eur J Pharmacol 2013 Jan 15699(1-3)207-12J Clin Endocrinol Metab 2004 Jul89(7)3313-8

Foundational Natural Therapeutics for Chronic Pain

Foundational Natural Therapeutics for Chronic Pain

Chronic Pain Foundational Natural Health Products

bull Alpha Lipoic Acid bull Boswelliabull Rhodiolabull Sulforaphane Glucosinolatebull Magnesiumbull L-Tryptophan (5-HTP)bull Ascorbate (buffered)bull Bioactive B Complexbull Essential Fatty Acidsbull Cholecalciferol bull Skutellaria

Dr Abhimanyu Sud MD 2012

bull Pain is a reflection of the distortion of the physiologicalpsychologicalspiritual structural web

bull Blocking downstream pain mediators with drugs may uncouple the pain process but not respond to the therapeutic need for healing

bull Management of pain at the level of causation requires a functional medicine approach to maximize patient outcome and be truly evidence based

Dr Jeffrey Bland PhD 2008

Thank you for your time and attention

wwwadvancedmedicineca

bull Pain is a reflection of the distortion of the physiologicalpsychologicalspiritual structural web

bull Blocking downstream pain mediators with drugs may uncouple the pain process but not respond to the therapeutic need for healing

bull Management of pain at the level of causation requires a functional medicine approach to maximize patient outcome and be truly evidence based

Dr Jeffrey Bland PhD 2008

Thank you for your time and attention

wwwadvancedmedicineca

Thank you for your time and attention

wwwadvancedmedicineca

Natural Standards

bull NHPs for Neuropathic Painndash 0075 Capsaicin (active in Capsicum)

bull topically 4xd for 8 weeks led to significant pain reduction

ndash Acetyl-L-Carnitinebull 3 g for 6 to 12 months

ndash ALAbull 600 to 1800 oral and IV (often combined with GLA SOD and

B12) over 4 weeks

ndash CoQ10bull 400 mg for 12 weeks

ndash Post-ca (neuropathic)bull IV Mg up to 1 g

Natural Standards

bull NHPs for Fibromyalgiandash Malate (alpha hydroxy acids)ndash CoQ10 300 mg for 40 days (combined with Ginkgo in 1

trial)ndash Mg 300 mg for 8 weeks

bull NHPs for Headachesndash Butterbur 75 mg bid prevention onlyndash Capsicum intranasal 0025 capsaicinndash Feverfewndash Mgndash Peppermint 10 topicallyndash B2 400 mg as effective as beta-blockers

Natural Standards

bull NHP for LBP

ndash Capsicum

ndash Comfrey 35 4 g tid for 5 days

ndash Devilrsquos Claw 30-100 mg equal to NSAIDs

ndash Willow bark 240 mg (salicin) relief in 1 week equivalent to Vioxx

ndash CRPS

bull DMSO 50 (+NAC) cream

bull Ascorbate 1500 mg

Natural Standards

bull NHPs for Fibromyalgiandash Malate (alpha hydroxy acids)ndash CoQ10 300 mg for 40 days (combined with Ginkgo in 1

trial)ndash Mg 300 mg for 8 weeks

bull NHPs for Headachesndash Butterbur 75 mg bid prevention onlyndash Capsicum intranasal 0025 capsaicinndash Feverfewndash Mgndash Peppermint 10 topicallyndash B2 400 mg as effective as beta-blockers

Natural Standards

bull NHP for LBP

ndash Capsicum

ndash Comfrey 35 4 g tid for 5 days

ndash Devilrsquos Claw 30-100 mg equal to NSAIDs

ndash Willow bark 240 mg (salicin) relief in 1 week equivalent to Vioxx

ndash CRPS

bull DMSO 50 (+NAC) cream

bull Ascorbate 1500 mg

Natural Standards

bull NHP for LBP

ndash Capsicum

ndash Comfrey 35 4 g tid for 5 days

ndash Devilrsquos Claw 30-100 mg equal to NSAIDs

ndash Willow bark 240 mg (salicin) relief in 1 week equivalent to Vioxx

ndash CRPS

bull DMSO 50 (+NAC) cream

bull Ascorbate 1500 mg