1. Nutritional Supplementation in Pain Management: Clinical Strategies
Nancy Cotter MD
Medical Director
Atlantic Integrative Medicine
Morristown Memorial and Overlook Hospitals
Morristown and Summit NJ

2. Nutraceuticals and pain management
Highlight the use of nutritional supplementation in the context of a holistic approach to pain management
Discuss evidence based use of nutraceuticals for pain management, site of action, practical aspects of use
Analyze 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.

3. Functional approach to pain management
Assess substrate: state of tissue, circulation, nervous system
Examine structure: musculoskeletal and organ restrictions
Evaluate Function:
Physiologic: adequate nutrients and intact biological pathways for proper physiologic functioning
Mental/ emotional: mind/ spirit axis

4. Functional approach to pain management
Physical pain may be the final common pathway of single or multiple levels of dysfunction:
biological
emotional
spiritual

5. 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

6. Neurodegenerative pain Peripheral Vascular Pain
Osteoarthritis
Myofascial Pain
Fibromyalgia
Neurodegenerative pain
Peripheral Vascular Pain

7. Pain and the anti- inflammatory approach
Inflammatory 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

8. Supplementation for Pain Management
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

9. Essential Fatty Acids:
Omega-6: Linoleic acid (LA)--vegetable oils, seeds, nuts
Arachidonic Acid (AA)--meat and dairy products
Gamma Linolenic Acid (GLA)--borage and primrose oil
Omega-3: Alpha Linolenic Acid (ALA)--legumes, leafy vegetables, flax, flaxseed and canola oils
Eicosopentaenoic acid (EPA)-fish oil
Docosahexaenoic acid (DHA)--fish oil, breast milk

10. (alpha-linolenic acid) Eicosatetraenoic Acid
Omega 6 Fatty Acid
(Linoleic Acid)
Omega 3 Fatty Acids
(alpha-linolenic acid)
Δ6-Desaturase
Δ6-Desaturase
Stearidonic acid
Gamma-linolenic acid
(GLA)
Elongase
Elongase
Eicosatetraenoic Acid
Dihomogammalinoleic acid (DGLA)
Δ5-Desaturase
Δ5-Desaturase
Eicosapentaenoic Acid
Cyclooxygenase
(COX )
Arachidonic Acid
Lipoxygenase
(LOX)
Cyclo-oxygenase
(COX)
Prostaglandins
PGE1, PGE3
Lipoxygenase
5-Leukotrienes
Elongase, Δ4-Desaturase
Prostaglandins (PGE2)
(Inflammatory)
Leukotrienes
Docosahexaenoic acid
(DHA)

11. Omega 3 Fatty Acids
Standard American Diet 40:1 to 10:1 n=6 to n=3 Omega FA
4:1 adequate for healthy individuals
1:1 preferred in inflammatory conditions for treatment
Covington M Am Fam Phys 2004; 70:133-40

12. ω3 Fatty Acid sources: marine
Fish oils: Mackerel, herring, salmon, bluefin tuna, sardines
All fish have ω3 LCFA; some more concentrated than others
Flax 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

13. Sources of Fish Oil Fish Crude fish oil Health food grade
Contamination with PCB, dioxin, and Hg
Higher in AA than fish oil
Crude fish oil
High contamination
Health food grade
Minimal contamination with PCB’s and dioxins
Ultra-Refined EPA/DHA Concentrates
Removal of PCB’s and other toxins
Can be used in high doses

14. 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 (
Other plant sources: purslane, walnuts, canola
Simopoulos AP. Essential fatty acids in health and chronic diseases Forum of Nutrition. 2003;56:67-70

15. Recommended intake Omega-3 fats:
Standard American Diet 40:1 to 10:1
Maintenance 2.5 g/d of EPA/ DHA
Strive for Omega 6: Omega-3 ratio of 4:1
Healing phase 1:1
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

16. (alpha-linolenic acid) Eicosatetraenoic Acid
Omega 6 Fatty Acid
(Linoleic Acid)
Omega 3 Fatty Acids
(alpha-linolenic acid)
Δ6-Desaturase
Δ6-Desaturase
Stearidonic acid
Gamma-linolenic acid
(GLA)
Elongase
Elongase
Eicosatetraenoic Acid
Dihomogammalinoleic acid (DGLA)
Δ5-Desaturase
Δ5-Desaturase
Eicosapentaenoic Acid
Cyclooxygenase
(COX )
Arachidonic Acid
Lipoxygenase
(LOX)
Cyclo-oxygenase
(COX)
Prostaglandins
PGE1, PGE3
Lipoxygenase
5-Leukotrienes
Elongase, Δ4-Desaturase
Prostaglandins (PGE2)
(Inflammatory)
Leukotrienes
Docosahexaenoic acid
(DHA)

17. Prostaglandins Δ6-Desaturase Eicosatetraenoic acid Δ5-Desaturase
Omega 6 Fatty Acid
(Linoleic Acid)
Omega 3 Fatty Acids
(alpha-linolenic acid)
Desaturase is suppressed by excessive intake of saturated, trans fat, insulin excess; requires Mg, Zn*
Δ6-Desaturase
Δ6-Desaturase
Eicosatetraenoic acid
Gamma-linolenic acid
(GLA)
Evening Primrose Oil
Borage Oil/ Black Current Oil
Elongase
Eicosapentaenoic Acid
(EPA)
Δ5-Desaturase
Cyclooxygenase
(COX )
Lipoxegenase (LOX)
Dihomogammalinoleic acid (DGLA)
Free radical peroxidation of AA = isoprostanes (stronger inflamm effect)
Elongase
Prostaglandins
PGE1, PGE3
5-Leukotrienes
(less inflammatory)
Arachidonic
Acid
Cyclo-oxygenase
(COX)
Lipoxygenase
Docosahexaenoic acid
(DHA)
Prostaglandins (PGE2)
(Inflammatory)
Leukotrienes
*Wallace JM. Nutritional and botanical modulation of the inflammatory cascade Integrative Cancer Therapies, (1):7-37

18. Arachidonic Acid Aspirin Steroids Colchicine NSAIDs Sulfasalazine
Phospholipase A-2
Aspirin
Steroids
Colchicine
NSAIDs
Sulfasalazine
Cyclo-oxygenase
Pathway
Lipoxygenase
Pathway
COX II Inhibitors:
Celebrex, Vioxx, Mobic
Leukotriene Inhibitors:
Accolate, Singulair, Zyflo
Prostaglandins
&
Thromboxanes
Leukotrienes

19. Supplementation:
Inflammatory profile modification
Structural modification
Matrix Support

20. Boswellia
Significant 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): , 2006

21. Boswellia
Potentiates effects of glucosamine in experimental conditions
Singh et al Bioorganic and Medicinal Chemistry Letters 17 (2007)
Blocks arachidonic acid - to - leukotriene conversion
Poeckel D. Werz O. Boswellic acids: biological actions and molecular targets. Current Medicinal Chemistry. 13(28): , 2006
Standardized to 65% boswellic acids; 300 mg tid

22. Bromelain
Sulfur containing enzyme from pineapple plant
Inhibits PGE2 synthesis
Enhances PGE1 synthesis
Decreases vascular permeability
Separate analgesic properties
Effective Dosage in studies ranges between mg/day
No significant adverse effects
Brien,S, Lewith, Walker A et al 2004 Evidence based Complementary and Alternat Med(3) :

23. Ginger Ginger extract reduced inflammation in synovial cell cultures
Frondoza CG. et al In Vitro Cellular & Developmental Biology. 40(3-4):95-101, 2004
Ginger Inhibits COX and LOX pathways
Grzanna et al J Med Food (2)
Ginger ass’d w/ weakened delayed -type hypersensitivity in mice
Zhou et al J Ethnopharm :

24. 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.

25. Harpagophytum procumbens: Devil’s Claw
Harpagophytum and low back pain
N= 130 treated with H procumbens ; significant improvement with no serious side effects
Laudahn D Walper A 2001 Phytother Res (15)
Likely acts synergistically with NSAIDs
Brendler T et al J Herb Pharmacotherapy 6(1):
COX2 inhibitor
Huang et al J Ethnopharmacology 2006; 104:

26. Prostaglandins Δ6-Desaturase Eicosatetraenoic acid Δ5-Desaturase
Omega 6 Fatty Acid
(Linoleic Acid)
Omega 3 Fatty Acids
(alpha-linolenic acid)
Δ6-Desaturase
Δ6-Desaturase
Eicosatetraenoic acid
Gamma-linolenic acid
(GLA)
Evening Primrose Oil
Borage Oil/ Black Current Oil
Elongase
Eicosapentaenoic Acid
(EPA)
Δ5-Desaturase
Cyclooxygenase
(COX )
Lipoxygenase
(LOX)
Dihomogammalinoleic acid (DGLA)
Elongase
Prostaglandins
PGE1, PGE3
5-Leukotrienes
(less inflammatory)
Arachidonic Acid
Cyclo-oxygenase
(COX)
Lipoxygenase
Docosahexaenoic acid
(DHA)
Prostaglandins (PGE2)
(Inflammatory)
Leukotrienes

27. Arachidonic Acid Aspirin Colchicine Steroids Sulfasalazine NSAIDs
Phospholipase A-2
Aspirin
Colchicine
Steroids
Sulfasalazine
NSAIDs
Cyclo-oxygenase
Pathway
Lipoxygenase
Pathway
Leukotriene Inhibitors:
Accolate, Singulair, Zyflo
COX II Inhibitors:
Celebrex, Vioxx, Mobic
Boswellia
Turmeric
Curcumin, Bromelain
Ginger, Devils Claw
Prostaglandins
&
Thromboxanes
Leukotrienes

28. 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

29. 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

30. 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

31. acetyl l carnitine
Acetyl-L-carnitine in neuropathic pain: experimental data.
Chiechio S. et al CNS Drugs 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

32. St John’s Wort
Analgesic 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

33. Symptom Modification: Glucosamine & Chondroitin
GAIT study
Clegg DO et al. NEJM 2006;354:
GUIDE study
Herrero- Beaumont et al Arth Rheum 2007;
Meta- analyses
Towheed TE et al Cochrane Database 2005(2):CD002946
Biggee BA et al Med Health R 2004; 87:
Richy F et al Arch Intern Med 2003; 163:

34. Structural Modification: Glucosamine & Chondroitin
Glucosamine sulfate 1500mg qd x 3years
Joint 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 :251-56
Joint space narrowing over 3 years 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 (18):

35. Structural modification S-adenosyl-L-methionine:SAMe
As effective as ibuprofen
Fetrow CW Avila JR Ann Pharmacotherapy 35(11)
Significant improvement over placebo
Bradley JD et al J Rheumatol 1994; 21:
Soeken KL et al J Fam Prac :
Acts as a restorative after damage induced by TNF alpha
Gutierrez et al : 27-31

36. Structural modification: Avocado/ soybean unsaponifiables
Byproduct of soapmaking
Not widely available in US currently
Significant improvement over placebo in multiple trials
Ernst E: Clin Rheum 2003; 22(4-5):

37. Matrix Support: 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)
Vitamin D deficiency: what a pain it is. Holick MF. Mayo Clinic Proceedings. 78(12):1457-9, 2003
Magnesium, Calcium & Zinc

38. Other things to consider in context
Muscle weakness, tightness, imbalance
Fascial tension and disorganization
Mind- body interventions

39. Route of delivery Oral Topical preparations Pills and capsules
Liquid extract
Tinctures/teas
Patient preference and comfort
Topical preparations
Local delivery
Avoid systemic effects
Keeps pills at minimum

40. Combination Products Allows intervention in multiple pathways
Synergistic and antagonistic effects under investigation
With potentiation and synergistic activities, may need less of each single agent

41. Putting it all together
Assess biochemical and tissue health before supplementation
Laboratory studies:
Inflammatory load: CRP, ESR
Oxidative stress
Vitamin levels if deficiency suspected: Vitamin D, B12
Critical minerals: Mg, Zn
Assess diet health
Anti- inflammatory diet
Fat Resistance Diet by Leo Galland
Gives patients recipes and diet plan if structure is desired; guidelines for “design it yourself” approach
If weight loss is desired, begin at Stage I
If weight loss is desired, begin at Maintenance phase

42. Putting it all together
Supplementation
Consider waiting until dietary changes have been implemented
Intervene at multiple sites: reduce AA intake/modify FA supply/ COX-LOX / joint modification/ antioxidants
Fish oil daily for 3- 6 months, then 5x/week
Focus on combination anti- inflammatory products
May need to try several products for a few weeks each to find best benefit/ side effect ratio
Most 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

43. In Conclusion: 1. Pain is the manifestation of multi- level imbalance
2. Inflammation is the final common pathway in many types of pain
3. Multiple natural anti- inflammatory compounds exist in nature; they are still being defined
4. Using an anti- inflammatory diet improves overall health and tissue responsiveness to interventions
6. Optimal supplementation may require some trials in materials and dosing
7. Use supplements to intervene at multiple sites in the inflammatory cascade
8. Supplementation is one modality in holistic pain management; consider it in the context of structural and mind body interventions

44. THANK
YOU