Nutritional Supplementation in Pain Management: Clinical

Strategies

Nancy Cotter MDMedical Director

Atlantic Integrative MedicineMorristown Memorial and Overlook Hospitals

Morristown and Summit NJ

Nutraceuticals and pain management

Highlight the use of nutritional supplementation in the context of a holistic approach to pain managementDiscuss evidence based use of nutraceuticals for pain management, site of action, practical aspects of useAnalyze the anti-inflammatory and anti-pain benefits of omega-3 and omega-6 fatty acids, glucosamine sulfate, and other nutrients.Consider nutritional supplementation for patients with pain.

Functional approach to pain management

Assess substrate: state of tissue, circulation, nervous systemExamine structure: musculoskeletal and organ restrictions Evaluate Function:

Physiologic: adequate nutrients and intact biological pathways for proper physiologic functioningMental/ emotional: mind/ spirit axis

Functional approach to pain management

Physical pain may be the final common pathway of single or multiple levels of dysfunction: biological emotional

spiritual

Functional approach to pain management:1. Evaluate inflammatory load, oxidative status, food sensitivities,

health of GI function, levels of key nutrients

2. Decrease inflammatory load through diet

3. Detoxify as necessary by removing aggravating conditions and by upregulation of detoxification pathways

4. Add anti- inflammatory nutraceuticals and intervene at as many sites as possible

5. Modify aggravating structural imbalances: tight muscles, tendons and joint capsules, postural defects, muscle weaknesses

6. Restore energy movement and balance

7. Implement mental/ emotional habits to maintain outlook,

maintain good habits, prevent stress- related aggravation of condition

This is a baseline approach to chronic inflammation- based pain: Rheumatoid and Osteoarthritis, Fibromyalgia, chronic muscular pain, neurodegenerative pain, peripheral vascular pain

OsteoarthritisMyofascial Pain

FibromyalgiaNeurodegenerative painPeripheral Vascular Pain

Pain and the anti- inflammatory

approachInflammatory mediators are also pain mediators: IL2, MCF, TNF, therefore……

Decreasing inflammatory load decreases pain

Anti- inflammatory Diet: Eliminate foods that are pro- inflammatory

Improve overall nutritional status: reduce oxidatve stress to increase tissue responsiveness to natural supplements or other interventions

Exercise and weight loss: Increase lean muscle mass: adipose tissue produces adipokines which likely contribute to joint inflammation separately and distinctly from mechanical stress

Supplementation for Pain Management

1.Modify Cell membrane composition via anti- inflammatory diet and omega-3 supplementation

2. Use supplements that dampen the inflammatory cascade

3. Use supplements that modify structure and disease course if possible

4. Support biological matrix with vitamins, minerals, cofactors

oOmega-6: Linoleic acid (LA)--vegetable oils, seeds, nuts

oArachidonic Acid (AA)--meat and dairy products

o Gamma Linolenic Acid (GLA)--borage and primrose oil

o Omega-3: Alpha Linolenic Acid (ALA)--legumes, leafy vegetables, flax, flaxseed and canola oils

oEicosopentaenoic acid (EPA)-fish oil

oDocosahexaenoic acid (DHA)--fish oil, breast milk

Essential Fatty Acids:

Omega 6 Fatty Acid (Linoleic Acid)

Omega 3 Fatty Acids(alpha-linolenic acid)

Gamma-linolenic acid(GLA)

Arachidonic Acid

LeukotrienesProstaglandins (PGE2)

(Inflammatory)

Lipoxygenase

Cyclo-oxygenase

(COX)

Eicosatetraenoic Acid

ProstaglandinsPGE1, PGE3 5-Leukotrienes

Docosahexaenoic acid(DHA)

Cyclooxygenase(COX )

Elongase

Dihomogammalinoleic acid (DGLA)

Stearidonic acid

Elongase

Δ6-Desaturase

Δ5-Desaturase

Δ6-Desaturase

Eicosapentaenoic Acid

Lipoxygenase(LOX)

Elongase, Δ4-Desaturase

Δ5-Desaturase

Omega 3 Fatty AcidsStandard American Diet 40:1 to 10:1 n=6 to n=3 Omega FA4:1 adequate for healthy individuals1:1 preferred in inflammatory conditions for treatment

Covington M Am Fam Phys 2004; 70:133-40

ω3 Fatty Acid sources: marine

Fish oils: Mackerel, herring, salmon, bluefin tuna, sardinesAll fish have ω3 LCFA; some more concentrated than othersFlax seed oil for vegetarians: high volumes necessary for EPA production

(approx 11:1 ratio); DHA now available from algae

Simopoulos AP. Essential fatty acids in health and chronic

diseases Forum of Nutrition. 2003;56:67-70

Sources of Fish OilFish

Contamination with PCB, dioxin, and HgHigher in AA than fish oil

Crude fish oilHigh contamination

Health food gradeMinimal contamination with PCB’s and dioxins

Ultra-Refined EPA/DHA ConcentratesRemoval of PCB’s and other toxinsCan be used in high doses

ω3 Fatty Acid sources: vegetarian

Flax seed oil for vegetarians: high volumes necessary for EPA production (approx 11:1 conversion ratio ALA: EPA)

1 tbsp flax oil contains approx 7g ALA(www.pbi.nrc.ca/en/bulletin/2002issue2/page5.htm)

Other plant sources: purslane, walnuts, canola

Simopoulos AP. Essential fatty acids in health and chronic

diseases Forum of Nutrition. 2003;56:67-70

o Standard American Diet 40:1 to 10:1

o Maintenance 2.5 g/d of EPA/ DHA

o Strive for Omega 6: Omega-3 ratio of 4:1

o Healing phase 1:1

o Pain management/ treatment chronic pain up to 7.5 g/d

Cleland LG. James MJ. Proudman SM. The role of fish oils in the treatment of rheumatoid arthritis. Drugs. 2003;63(9):845-53

Recommended intake Omega-3 fats:

Omega 6 Fatty Acid (Linoleic Acid)

Omega 3 Fatty Acids(alpha-linolenic acid)

Gamma-linolenic acid(GLA)

Arachidonic Acid

LeukotrienesProstaglandins (PGE2)

(Inflammatory)

Lipoxygenase

Cyclo-oxygenase

(COX)

Eicosatetraenoic Acid

ProstaglandinsPGE1, PGE3 5-Leukotrienes

Docosahexaenoic acid(DHA)

Cyclooxygenase(COX )

Elongase

Dihomogammalinoleic acid (DGLA)

Stearidonic acid

Elongase

Δ6-Desaturase

Δ5-Desaturase

Δ6-Desaturase

Eicosapentaenoic Acid

Lipoxygenase(LOX)

Elongase, Δ4-Desaturase

Δ5-Desaturase

Omega 6 Fatty Acid (Linoleic Acid)

Omega 3 Fatty Acids(alpha-linolenic acid)

Gamma-linolenic acid(GLA)

Evening Primrose OilBorage Oil/ Black Current Oil

Arachidonic Acid

LeukotrienesProstaglandins (PGE2)

(Inflammatory)

Eicosapentaenoic Acid(EPA)

ProstaglandinsPGE1, PGE3

5-Leukotrienes(less inflammatory)

Docosahexaenoic acid(DHA)

Cyclooxygenase(COX )

Δ5-Desaturase

Dihomogammalinoleic acid (DGLA)

Eicosatetraenoic acidElongase

Δ6-Desaturase

Elongase

Δ6-Desaturase

Lipoxegenase (LOX)

Cyclo-oxygenase

(COX) Lipoxygenase

Desaturase is suppressed by excessive intake of saturated, trans fat, insulin excess; requires Mg, Zn*

Free radical peroxidation of AA = isoprostanes (stronger inflamm effect)

*Wallace JM. Nutritional and botanical modulation of the inflammatory cascade Integrative Cancer Therapies, 2002. 1(1):7-37

Arachidonic Acid

Phospholipase A-2

Cyclo-oxygenase

PathwayLipoxygenase

Pathway

Prostaglandins&

ThromboxanesLeukotrienes

SteroidsAspirin

NSAIDs

COX II Inhibitors:

Celebrex, Vioxx, Mobic

Colchicine

Sulfasalazine

Leukotriene Inhibitors:

Accolate, Singulair, Zyflo

Supplementation:

Inflammatory profile modificationStructural modificationMatrix Support

BoswelliaSignificant improvement over placebo for osteoarthritis of the knee

Kimmatkar N. Thawani V. Hingorani L. Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine. 10(1):3-7, 2003

Ammon HP. Boswellic acids in chronic inflammatory diseases. [Review] [69 refs] [Journal Article. Review] Planta Medica. 72(12):1100-16, 2006

BoswelliaPotentiates effects of glucosamine in experimental conditionsSingh et al Bioorganic and Medicinal Chemistry Letters 17 (2007) 3706-3711

Blocks arachidonic acid - to - leukotriene conversionPoeckel D. Werz O. Boswellic acids: biological actions and molecular targets. Current Medicinal Chemistry. 13(28):3359-69, 2006

Standardized to 65% boswellic acids; 300 mg tid

BromelainSulfur containing enzyme from pineapple plantInhibits PGE2 synthesisEnhances PGE1 synthesisDecreases vascular permeabilitySeparate analgesic propertiesEffective Dosage in studies ranges between 100-900+ mg/dayNo significant adverse effects

Brien,S, Lewith, Walker A et al 2004 Evidence based Complementary and Alternat Med(3) :251-257

GingerGinger extract reduced inflammation in synovial cell culturesFrondoza CG. et al In Vitro Cellular & Developmental Biology. 40(3-4):95-101, 2004

Ginger Inhibits COX and LOX pathwaysGrzanna et al J Med Food 2005

8(2)125-132Ginger ass’d w/ weakened delayed -type hypersensitivity in mice

Zhou et al J Ethnopharm 2006 105:101-105

Curcumin

Singh S. Khar A.Current Medicinal Chemistry - Anti-Cancer Agents. 6(3):259-70, 2006

Bright JJ. Curcumin and autoimmune disease. Advances in Experimental Medicine & Biology. 595:425-51, 2007. Shishodia S. Sethi G. Aggarwal BB. Curcumin: getting back to the roots. Annals of the New York Academy of Sciences. 1056:206-17, 2005 Nov.

Harpagophytum procumbens: Devil’s Claw

Harpagophytum and low back painN= 130 treated with H procumbens ; significant improvement with no serious side effectsLaudahn D Walper A 2001 Phytother Res (15)621-624

Likely acts synergistically with NSAIDsBrendler T et al J Herb Pharmacotherapy 6(1): 89-126

COX2 inhibitorHuang et al J Ethnopharmacology 2006; 104:149-155

Omega 6 Fatty Acid (Linoleic Acid)

Omega 3 Fatty Acids(alpha-linolenic acid)

Gamma-linolenic acid(GLA)

Evening Primrose OilBorage Oil/ Black Current Oil

Arachidonic Acid

LeukotrienesProstaglandins (PGE2)

(Inflammatory)

Lipoxygenase

Cyclo-oxygenase

(COX)

Eicosapentaenoic Acid(EPA)

ProstaglandinsPGE1, PGE3

5-Leukotrienes(less inflammatory)

Lipoxygenase(LOX)

Docosahexaenoic acid(DHA)

Cyclooxygenase(COX )

Δ5-Desaturase

Dihomogammalinoleic acid (DGLA)

Eicosatetraenoic acidElongase

Δ6-Desaturase

Elongase

Δ6-Desaturase

Arachidonic Acid

Phospholipase A-2

Cyclo-oxygenase

Pathway

Lipoxygenase

Pathway

Prostaglandins&

ThromboxanesLeukotrienes

SteroidsAspirin

NSAIDsCOX II Inhibitors:

Celebrex, Vioxx, Mobic

ColchicineSulfasalazineLeukotriene Inhibitors:

Accolate, Singulair, Zyflo

Curcumin, Bromelain

Ginger, Devils ClawBoswellia

Turmeric

Horse Chestnut

Treatment of patients with venous insufficiency with fresh plant horse chestnut seed extract: a review of 5 clinical studies.

Suter A. Bommer S. Rechner J. Advances in Therapy. 23(1):179-90, 2006 Horse chestnut seed extract for chronic venous insufficiency

Pittler MH. Ernst E. Cochrane Database of Systematic Reviews. (1):CD003230, 2006

White Willow Bark

Tanacetum parthenium and Salix alba (Mig-RL) combination in migraine prophylaxis: a prospective, open-label study.

Shrivastava R. Pechadre JC. John GW. Clinical Drug

Investigation. 26(5):287-96, 2006 Herbal medicine for low back pain.Gagnier JJ. van Tulder M. Berman B. Bombardier C. Cochrane

Database of Systematic Reviews. (2):CD004504, 2006

α-Lipoic Acid (A-LA)

ALADIN Trial :alpha-lipoic 600 mg/day IV over 3 weeks At 19 days, improvement in total symptom score of at least

30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = 0.002)

Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical reviewTreatments in Endocrinology. 3(3):173-89, 2004 Veresiu IA. Treatment of diabetic polyneuropathy with alpha-lipoic acid is evidence based. Romanian Journal of Internal Medicine. 42(2):293-9, 2004

acetyl l carnitine

Acetyl-L-carnitine in neuropathic pain: experimental data.

Chiechio S. et al CNS Drugs 2007 21 Suppl 1:31-8

Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients.

Rossini M. et al Clinical & Experimental Rheumatology. 25(2):182-8, 2007

St John’s WortAnalgesic and topical anti-inflammatory activity of Hypericum canariense L. and Hypericum glandulosum Ait.

Rabanal RM. Et al Journal of Ethnopharmacology. 96(3):591-

6, 2005 Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L.

Kumar V. Singh PN. Bhattacharya SK. Indian Journal of

Experimental Biology. 39(4):339-43, 2001

Symptom Modification: Glucosamine & Chondroitin

GAIT study Clegg DO et al. NEJM 2006;354:795-808.

GUIDE study Herrero- Beaumont et al Arth Rheum 2007; 555-67

Meta- analysesTowheed TE et al Cochrane Database 2005(2):CD002946

Biggee BA et al Med Health R 2004; 87:176-179 Richy F et al Arch Intern Med 2003; 163:1514-22

Structural Modification: Glucosamine & Chondroitin

Glucosamine sulfate 1500mg qd x 3yearsJoint space narrowing over 3 years -3.1 mm with placebo vs 0.06mm with glucosamine Five year followup RR of lower limb surgery 0.52 compared to control

Reginster Lancet 2001 357:251-56Glucosamine sulfate 1500mg qd x 3yearsJoint space narrowing over 3 years -0.19 mm with placebo vs 0.04 mm with glucosamine Five year followup 75% reduction of knee replacement surgery as compared to control

Pavelka et al. Arch Int Med 2002 162(18):2113-23

Structural modificationS-adenosyl-L-methionine:SAMe

As effective as ibuprofenFetrow CW Avila JR Ann Pharmacotherapy 35(11)1414-25Significant improvement over placeboBradley JD et al J Rheumatol 1994; 21: 905-911

Soeken KL et al J Fam Prac 2002 51:425-430Acts as a restorative after damage induced by TNF alphaGutierrez et al 200737: 27-31

Structural modification:Avocado/ soybean unsaponifiables

Byproduct of soapmakingNot widely available in US currentlySignificant improvement over placebo in multiple trialsErnst E: Clin Rheum 2003; 22(4-5):285-288

Matrix Support: Vitamin D

Vitamin D Evolution and function of vitamin D. Holick MF. Recent Results in Cancer Research. 164:3-28,

2003 Heath K, Elovic E Am J Phys Med Rehab 2006 (85)916-923

Vitamin D deficiency: what a pain it is. Holick MF. Mayo Clinic Proceedings. 78(12):1457-9, 2003

Magnesium, Calcium & Zinc

Other things to consider in context

Muscle weakness, tightness, imbalanceFascial tension and disorganizationMind- body interventions

Route of deliveryOral

Pills and capsules Liquid extractTinctures/teasPatient preference and comfort

Topical preparationsLocal deliveryAvoid systemic effectsKeeps pills at minimum

Combination Products

Allows intervention in multiple pathwaysSynergistic and antagonistic effects under investigationWith potentiation and synergistic activities, may need less of each single agent

Putting it all together

Assess biochemical and tissue health before supplementationLaboratory studies:

Inflammatory load: CRP, ESROxidative stressVitamin levels if deficiency suspected: Vitamin D, B12Critical minerals: Mg, Zn

Assess diet healthAnti- inflammatory dietFat Resistance Diet by Leo Galland

Gives patients recipes and diet plan if structure is desired; guidelines for “design it yourself” approachIf weight loss is desired, begin at Stage IIf weight loss is desired, begin at Maintenance phase

Putting it all togetherSupplementation

Consider waiting until dietary changes have been implemented

Intervene at multiple sites: reduce AA intake/modify FA supply/ COX-LOX / joint modification/ antioxidantsFish oil daily for 3- 6 months, then 5x/week Focus on combination anti- inflammatory productsMay need to try several products for a few weeks each to find best benefit/ side effect ratioMost commonly: GI discomfort; reduce by 1/3 and ramp up 1/3 dose per week; treat GI imbalance It might be useful to have a slide listing all the supplements and the dosages for convenience

In Conclusion:1. Pain is the manifestation of multi- level imbalance2. Inflammation is the final common pathway in many

types of pain3. Multiple natural anti- inflammatory compounds

exist in nature; they are still being defined4. Using an anti- inflammatory diet improves overall

health and tissue responsiveness to interventions6. Optimal supplementation may require some trials in

materials and dosing7. Use supplements to intervene at multiple sites in

the inflammatory cascade8. Supplementation is one modality in holistic pain

management; consider it in the context of structural and mind body interventions

THANK YOU