An Integrative Approach to Chronic Pain Management

Alternative Response to A Pharmaceutical Disaster
Karen Sadowsky Kaufman, MS, CCN

It has been estimated that some 20 million people relied on COX-2 inhibitors, such as Vioxx®, taking them on a daily basis to relieve the crippling pain associated with arthritis. In the wake of recent studies linking long-term use of COX-2 inhibitors with increased incidence of fatal heart attack and stroke, many arthritis sufferers are seeking safer methods for dealing with this painful condition.

While chronic pain often necessitates medical therapy, particularly in extreme cases, an integrative approach that combines simple dietary modifications, regular exercise, and nutritional supplements can dramatically improve quality of life and reduce the requirement for non-steroidal anti-inflammatory drugs (NSAIDs) to control pain.

Unfortunately, physicians rarely recommend alternative therapies to patients, either because they are unaware of their potential benefits, or for fear of criticism from their colleagues and peers.

Diet and Arthritis
The "inflammatory cascade" begins with a fatty acid called arachidonic acid (AA). AA is cycled through the COX enzymes to form a family of eicosanoids. Eicosanoids include prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), which are small fatty acid metabolites that have hormone-like activities critical to maintaining normal physiologic functions.

In addition, these fatty acid metabolites are mobilized when the body is confronted with an acute injury. When AA is the substrate for the COX enzyme, the PGs, TXs, and LTs that are produced are quite pro-inflammatory (Fig. 1).


If the long-chain fatty acid at the top of the inflammatory cascade is a different fatty acid such as the omega-3 fatty acids found in fish—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—then the subsequent eicosanoids that are produced are not harmful and actually reduce inflammation. The epidemiological data from the Greenland Eskimos sparked interest in the potential benefits of the omega-3 fatty acids 25 years ago and at this point, numerous scientific studies have affirmed their benefit.(1-3)

Research has shown that certain foods, such as fatty cuts of meat, organ meats and egg yolks provide arachidonic acid to the body. Therefore, it would be beneficial to reduce the consumption of these foods.

If one then increases the intake of foods rich in the omega-3 fatty acids (fish, some seeds and nuts), the omega-3 fatty acids displace AA as the primary substrate for the COX enzymes. This leads to the production of a species of eicosanoids that are far less pro-inflammatory than AA.

In addition to cutting back on foods that are high in AA, I also recommend avoiding foods containing partially hydrogenated oils. Partially hydrogenated vegetable oils, which contain trans fatty acids, actually promote inflammation to an even greater degree than AA. Additionally, trans fatty acids have been shown to be more prone to initiating atherosclerosis than the saturated fats found in meats.(4-6)

In addition to increasing the consumption of fish, nuts and seeds (all high in omega-3 fatty acids), it's a good idea to reduce intake of sugars, starches, and other carbohydrates that break down into simple sugars, and trigger excess production of insulin, a powerful promoter of inflammation.(7)

Many people find that these simple dietary modifications often reduce the severity of pain enough to make exercise possible again—and exercise has been shown to aid in reducing chronic pain suffered by people with inflammatory arthritis.(8)


Nutritional Supplements

Glucosamine, Chondroitin and MSM
Glucosamine and chondroitin belong to a group of substances called glycosaminoglycans (GAGs). People first learned about these nutrients by observing that veterinarians routinely prescribed them for dogs with osteoarthritis. Following the 1997 publication of The Arthritis Cure, by Jason Theodosakis, MD, glucosamine and chondroitin rocketed to the top of the list of best-selling nutritional supplements.

Initially, glucosamine and chondroitin were viewed with skepticism by the medical community, yet the number of positive reports from their patients eventually forced rheumatologists and orthopedists to take notice. Glucosamine and chondroitin soon became the subject of intense research. The weight of evidence from the published research is overwhelmingly favorable.

Glucosamine and chondroitin seem to not only provide the patient with analgesia (pain relief), but also delay the structural progression of osteoarthritis.(9-10) Although most of the studies have focused on osteoarthritis of the knee, a recent case report established the benefits of glucosamine and chondroitin in symptomatic disc degeneration.(11)

In one double-blind trial published last summer, four groups of volunteers were treated three times daily with either 500 mg glucosamine, 500 mg methylsulfonylmethane (MSM), a combination of both agents, or placebo. Over the course of the 12-week trial, pain levels in all treated groups fell. The group experiencing the greatest improvements, however, was the group receiving the combination of both glucosamine and MSM.(12) This recent trial not only established the efficacy of glucosamine and MSM when used individually, but also indicates even greater pain relief when the two agents are used in combination.

S-Adenosyl-Methionine (SAMe)
Another fascinating study compared S-adenosyl-methionine (SAMe) to the COX-2 inhibitor, Celebrex®. People reported significant pain relief from Celebrex® at the end of the first month. However, it was not until the end of the second month that users of SAMe reported significant pain relief.(13) Nevertheless, it may be worth waiting the extra time to experience pain relief from SAMe, since SAMe has few reported side effects and many additional health benefits.(14)

Digestive Enzymes: Not Just For Digestion
In Europe, people commonly take proteolytic enzymes (normally used to aid in the digestion of food) to promote healing from inflammatory conditions and sports injuries.

Anecdotally, we know that when these enzymes are taken on an empty stomach they have the ability to relieve pain, inflammation and swelling. Recently, a double-blind prospective study compared the use of an oral enzyme combination (consisting of rutosid, bromelain, and trypsin) to a conventional prescription NSAID, diclofenac, available in various prescription brand names.

The results of the study revealed that the oral enzyme combination was at least as good, if not better, than diclofenac at providing pain relief, and without the side effects of an NSAID.(15)

Phytonutrients Reduce Inflammation
A number of plant-derived nutrients have been shown to aid in controlling inflammation. Since these phytochemicals are able to modulate COX-2 enzymes naturally, without shutting down the entire metabolic pathway (as pharmaceutical COX-2 inhibitors do), the good and protective eicosanoids can continue to function to some extent.

Most of the literature on plant phytochemicals has focused on two agents: turmeric (a spice with the active ingredient curcumin); and resveratrol (best known as the beneficial ingredient in red wines). Resveratrol is also extracted from other sources.

Turmeric is an Indian spice that makes curry yellow. Reports of the anti-inflammatory benefits of turmeric go back to 1985, well before our current understanding of COX enzymes. Turmeric has been associated with reducing inflammation, decreasing platelet aggregation, and limiting the expression of COX-stimulated colon cancer cells.(16-18)

Resveratrol is found in the skin of dark red grapes and plums. It is one of the phytochemicals in wine that is most associated with health benefits. Recent studies hint at an intriguing role for resveratrol in cancer, heart disease, and pain. Initial investigations have suggested that resveratrol exerts its beneficial effects through an interaction with the COX-2 enzyme.(19-21)

Dehydroepiandrosterone (DHEA) is a hormone produced by the adrenal glands. One well-studied application of DHEA is its role in reducing pain and inflammation in people with Systemic Lupus Erythematosis (SLE).(22)

DHEA seems to be helpful in a number of other chronic inflammatory diseases as well, including Crohn's disease,(23) rheumatoid arthritis and inflammatory arthritis.(24) This adrenal steroid seems to improve the patient's subjective measure of disease activity such as pain and fatigue. How it does this is still not clear, but it appears that DHEA is involved in directly reducing inflammatory cytokines, independent of the COX pathway. There is even a recent report in the literature where DHEA administration has prevented the development of osteoarthritis in animals.(25)

DHEA is typical of many dietary supplements, in that it provides a broad range of beneficial effects with few, if any, adverse effects—in contrast to pharmaceuticals with narrow ranges of benefits and long lists of side effects.

In addition to its profound anti-inflammatory properties, clinical trials with DHEA indicate that it may also be an effective treatment for osteoporosis in both men and women.(26,27) Dosages in the clinical trials have varied from a low of 25 mg to a high of 100 mg. Women should be aware that if they take too much DHEA they may grow a few facial hairs, or experience an episode of acne. However, these side effects are easily and rapidly reversed once the dosage is lowered.


Essential Fatty Acids

More than 25 years ago, epidemiological data on Greenland Eskimos triggered a spate of research into the role of essential fatty acids contained in fish oils. Today, the benefits of eating fish rich in omega-3 fatty acids are well established.

Additionally, a large body of research suggests that consuming fish oil capsules can aid in reducing the symptoms of systemic lupus(28) and rheumatoid arthritis.(29) Supplementing with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also works in much the same way as the dietary modifications discussed at the outset of this article.

The EPA and DHA contained in fish oils compete favorably with AA, and are processed by COX enzymes. The family of eicosanoids produced from omega-3 fatty acids are far less inflammatory than those produced by AA, which is an omega-6 fatty acid. Supplementing with fish oil capsules should be considered in addition to the dietary changes suggested above.

Generally I recommend that clients opt for monounsaturated fatty acids (such as olive, canola, walnut, grapeseed and macadamia nut oils) as their primary edible oils. Additionally, I recommend avoiding most of the polyunsaturated fatty acids found in the American diet, such as corn, sunflower and soybean oils, which are rich in omega-6 fatty acids. The one exception is supplementation with the botanical lipid, GLA.

GLA (gamma-linolenic acid) is an omega-6 fatty that possesses significant therapeutic properties. GLA has been shown to reduce the pain and inflammation of systemic inflammatory diseases—most notably, rheumatoid arthritis.(30) GLA works in much the same way as the omega-3 fatty acids, replacing the arachidonic acid utilized by the COX enzymes. In doing so, GLA supports the production of anti-inflammatory eicosanoids and cytokines.

Supplementing with a combination of omega-3 fatty acids (from fish oil) and omega-6 fatty acids (from GLA) prevents the accumulation of arachidonic acid in the blood, and helps to reduce the pain associated with inflammation.(31) One group from Surrey, England, suggests that combing antioxidants and fatty acids will ameliorate the symptoms of inflammatory systemic illnesses, based upon the growing body of scientific literature.(32)

Nattokinase and Serrapeptase
Patients concerned about being at increased risk of heart attack or stroke from their use of Vioxx will be relieved to learn that this risk dissipates quickly after discontinuing the medication.(33) And while there is no clear evidence of a need for conventional anticoagulant therapy, the addition of clot-busting supplements, such as nattokinase and serrapeptase, might be considered. Nattokinase, an enzyme developed from fermented soy cheese, has strong fibrinolytic (clot-busting) activity.(34)

Serrapeptase, an enzyme derived from silkworms, has been shown to reduce inflammation and pain. Noted German physician Hans Nieper, MD, believed that in addition to its other health properties, serrapeptase can stimulate plaque regression.(35)

The suggestions presented here are by no means a complete list of every strategy that may be helpful in dealing with chronic pain and inflammation. Many of these items are relatively inexpensive, however, and generally have few, if any, side effects. In many cases the nutrients discussed here have additional, global health benefits.

Alpha-lipoic Highly recommended source of nutrients and supplements. vitamins antioxidants supplements

How did we qualify them ?

1. Adam O, Beringer C et al. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int 2003, 23(1):27-36.

2. Skoldstam L, Hagfors L, Johansson G. Mediterranean diet intervention in rheumatoid arthritis. Ann Rheum Dis 2003, 62(3):193-5.

3. Shigemasa C, Tanaka T, Mashiba H. Effect of vegetarian diet on systemic lupus erythematosus. Lancet 1992, 339:1177.

4. Mozaffarian D, Pischon T, Willett WC et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr 2004, 79(4):606-12.

5. Baer DJ, Judd JT, Clevidence BA, Tracy RP. Dietary fatty acids affect plasma markers of inflammation in healthy me fed controlled diets: a randomized crossover study. Am J Clin Nutr 2004, 79(6):969-73

6. Wu D. Modulation of immune and inflammatory responses by dietary lipids. Curr Opin Lipidol 2004, 15(1):43-7.

7. Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol 2003, 18;92(4A):18J-26J.

8. Kettunen JA, Kujala UM. Exercise therapy for people with rheumatoid arthritis and osteoarthritis. Scand J Med Sci Sports 2004, 14(3):138-42.

9. Reginster JY, Bruyere O, Lecart MP, Henrotin Y. Naturocetic (glucosamine and chondroitin sulfate) compounds as structure-modifying drugs in the treatment of osteoarthritis. Curr Opin Rheumatol 2003, 15(5):651-5.

10. Hungerford MW, Valaik D. Chondroprotective agents: glucosamine and chondroitin. Foot Ankle Clin 2003, 8(2):201-19.

11. van Blitterswijk WJ, van de Nes JC, Wuisman PI. Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: biochemical rationale and case report. BMC Complement Altern Med 2003, 3(1):2.

12. Usha PR, Naidu MUR. The effect of glucosamine alone, MSM alone, or in combination on osteoarthritis. Clin Drug Invest 2004, 24:353-363.

13. Najm WI et al. S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculo Dis 2004, 5:1:6.

14. Hardy M et al. Report issued by the Agency for Healthcare Research and Quality, (an agency of the U.S. Department of Health and Human Services) 2002;64:1-3.

15. Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clin Rheumatol 2004, 23(5):410-5.

16. Chauhan DP. Chemotherapeutic potential of curcumin for colorectal cancer. Curr Pharm Des 2002, 8(19):1695-706.

17. Goel A, Boland CR, Chauhan DP. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett 2001, 172(2):111-8.

18. Shah BH, Nawaz Z, Pertani SA, Roomi A, Mahmood H, Saeed SA, Gilani AH. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor-and arachidonic acid-www.ed platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999, 58(7):1167-72.

19. Granados-Soto V. Pleiotropic effects of Resveratrol. Drug News Perspect 2003, 16(5):299-307.

20. Murias M, Handler N, Erker T, Pleban K, Ecker G, Saiko P, Szekeres T, Jager W. Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem 2004, 12(21):5571-8.

21. Guastalla JP, Bachelot T, Ray-Coquard. [Cyclooxygenase 2 and breast cancer. From biological concepts to therapeutic trials] [article in French]. Bull Cancer 2004, 91 Spec No:S99-108.

22. Merrill JT. Dehydroepiandrosterone, a sex steroid metabolite in development for systemic lupus erythematosus. Expert Opin Investig Drugs 2003, 12(6):1017-25.

23. Andus T, Klebl F, Rogler G, Bregenzer N, Scholmerich J, Straub RH. Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study. Aliment Pharmacol Ther 2003, 17(3):409-14.

24. Dessein PH, Joffe BI, Stanwix AE, Moomal Z. Hyposecretion of the adrenal androgen dehydroepiandrosterone sulfate and its relation to clinical variables in inflammatory arthritis. Arthritis Res 2001, 3(3):183-8.

25. Jo H, Ahn HJ, Kim EM, Kim HJ, Seong SC, Lee I, Lee MC. Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis. Arthritis Rheum 2004, 50(8):2531-8.

26. Gordon CM, Grace E, Emans SJ, et al. Effects of oral dehydroepiandrosterone on bone mineral density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metab 2002, 87(11):4935-41.

27. Sun Y, Mao M, Sun L, Feng Y, Yang J, Shen P. Treatment of osteoporosis in men using dehydroepiandrosterone sulfate. Chin Med J 2002, 115(3):402-4.

28. Duffy EM, Meenagh GK, McMillan SA, Strain JJ, Hannigan BM, Bell A. The clinical effect of dietary supplementation with omega-3 fish and/or copper in systemic lupus erythematosus. J Rheumatol 2004, 31(8):1551-6.

29. Kremer JM, Lawrence DA, Petrillo GF, et al. Effects of high dose fish oil on rheumatoid arthritis after stopping non-steroidal anti-inflammatory drugs-clinical and immune correlates. Arthritis Rheum 1995, 38:1107-1114.

30. Zurier RB, Rossettti RG, DeMarco DM, Liu NY, et al. Gamma-linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum 1996, 39(11):1808-17.

31. Barham JB, Edens MB, Fonteh AN et al. Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr 2000, 130(8):1925-31.

32. Darlington LG, Stone TW. Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. Br J Nutr 2001, 85(3):251-6.

33. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004, 351(17):1709-11.

34. Sumi H, et al. Enhancement of the fibrinolytic activity in plasma by oral administration of Nattokinase. Act Haematol 1990, 84:139-43.

35. South J. Nattokinase and serrapeptase: nature's clot busters. Vitamin Research News June 2004, 12-13.


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