Alternative Therapies For Chronic Pain

   Many of my colleagues have voiced concerns regarding the use of nutriceuticals in their practices. The expressed concerns range from “These things are unproven” and “There is no FDA scrutiny over these products” to “They don’t work all the time” and “There are no scientific, double-blind, placebo-controlled studies on their safety or effectiveness.”    I had many of the same doubts before I incorporated nutriceuticals into my practice over 12 years ago. Since my training in podiatry school was allopathic in nature, it was difficult for me to assimilate a new medical model and an integrative approach to the treatment of disease.    However, during my training at the National College of Naturopathic Medicine, I discovered the scientific basis for the use of many nutriceuticals. Indeed, there were numerous double-blind, placebo-controlled studies involving many nutriceuticals.    I also learned that all nutriceutical manufacturers are not alike. There are now several nutriceutical companies in the United States that have voluntarily submitted to credentialing as a Good Manufacturing Practice (GMP) facility with rigorous standard operating procedures. Many of those ethical companies import nutriceuticals from counties like Germany, Japan, Sweden and Italy, where nutriceuticals are made in licensed pharmaceutical manufacturing plants. Some of these nutriceutical products are prescriptions in those countries.    When it comes to treating chronic joint and neuromuscular pain, there are nutriceutical treatment options. Some of these options are offered in combination products and are available from GMP-certified manufacturers. In regard to high-quality nutriceuticals that have evidence-based studies to back them up, I rely on companies like Integrative Therapeutics, Inc. and Mediplex, a California-based company that sells to healthcare practitioners only. These products are conveniently available by phone order and one may dispense them directly from the office.    In light of the emerging research about the adverse reaction profiles of NSAIDs (see “A Closer Look At The Risks Of NSAIDs And Other Therapies” below), clinicians who have diagnosed an arthritic condition should consider the use of nutriceuticals to help restore joint health and function, and relieve pain. In light of the adverse reaction profiles of NSAIDs, the podiatrist needs to explore the use of integrated therapies that have proven clinical results with minimal to no adverse reactions.    Accordingly, let us take a closer look at the following nutriceutical therapies.

Assessing The Merits Of Botanical-Based Extracts For Joint Pain

   I have used botanical-based extracts in combination to help treat joint pain. These extracts include Turmeric, Boswellia serrata, ginger extract and white willow bark extract.    Researchers have shown that Turmeric (curcumin) has potent antiinflammatory activities with specific lipoxygenase and COX-2-inhibiting properties including cytokines (TNF alpha and IL-1 beta).3 Curcuminoids also suppress super oxide anions and inhibit lipid peroxidation.3,4 The appropriate dosage for curcuminoids ranges from 200 to 500 mg qid.    An in vitro study of Boswellia (also known as frankincense) demonstrated a marked inhibitory effect on both the classical and alternate complement systems.5 These researchers also found that Boswellia, in a dose-dependent manner, blocks the synthesis of pro-inflammatory, 5-lipoxygenase including leukotriene B4 LTB4. A randomized double blind study found Boswellia to be effective in treating osteoarthritis of the knee.6 The appropriate dosage for Boswellia is 300 mg tid.    White willow bark extract (salix alba) is effective for the treatment of pain, especially low back pain. In a study comparing the efficacy of white willow bark extract to rofecoxib, researchers assessed 228 randomized patients with low back pain who were treated for a period of four weeks. In all measures of pain relief, The study found that white willow bark extract was just as effective as rofecoxib.7 Salicin from white willow bark extract is converted in the liver to acetylsalicyclic acid.8 The usual dose is 25 mg qid.

A Closer Look At The Risks Of NSAIDs And Other Therapies

   When treating chronic joint and neuromuscular pain, one may consider a number of treatment options. It may be worthwhile to consider nutriceutical therapies given the potential drawbacks of other therapeutic options.    While oral opioid derivatives are excellent medications for short-term pain management, the risk of habituation is prevalent with long-term use.    Oral and injectable steroids are excellent antiinflammatory agents for treating conditions accompanied by acute inflammation. However, long-term use demonstrates many adverse clinical reactions.    Then there are the non-steroidal antiinflammatory drugs (NSAIDs), which have their own set of problems. These medications have been associated with adverse reactions including bone marrow depression, gastrointestinal irritation and bleeding, peptic ulcers, tinnitus, hepatitis and renal dysfunction. In the past year, studies documenting severe cardiovascular risks with COX-2 inhibitors resulted in the removal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market (see page 11, “FDA Calls For Removal Of Bextra From Market,” June issue). The Food and Drug Administration (FDA) has also requested labeling changes to all non-selective NSAIDs in order to raise awareness about potential cardiovascular and gastrointestinal risks.    A little publicized side effect of chronic NSAID use is the reduction in thickness of the hyaline cartilage of joints. Non-steroidal antiinflammatory drugs are prostaglandin inhibitors. They are also proteoglycan synthesis inhibitors. Proteoglycans are essential building blocks for cartilage growth and repair. When it comes to long-term joint pain management, researchers have urged clinicians to avoid NSAID-induced arthropathy and necrosis.1,2

Can Topical Capsaicin Have An Impact?

   Topical preparations of capsaicin have been available over the counter (OTC) for several years. Capsaicin is derived from cayenne pepper, the fruit of capsicum futescens. Studies have shown that capsaicin is effective in the treatment of osteoarthritis, rheumatoid arthritis, peripheral neuropathic pain in patients with diabetes and phantom pain post-amputation.9 I use capsaicin topically to treat certain types of pain syndromes such as diabetic neuropathy, post-herpetic neuralgia and arthritic pain.    When one applies the medication topically, the active ingredient of capsaicin first stimulates and then blocks small diameter pain fibers by depleting them of their neurotransmitter substance “P.” Substance P is thought to be the principal chemomediator of peripheral pain impulses.10    Explain to patients that the topical does cause a burning sensation when they first begin to apply it to the skin. However, the burning sensation subsequently subsides when they apply it three to four times a day. Instruct patients to use caution and avoid applying this to mucus membranes, open wounds or into the eyes.

Key Insights On Ginger And Bromelain

   Studies have shown that topically applied combinations of ginger extract (Zingiber officinalis) inhibit prostaglandin (PGE2) and leukotriene synthesis. Ginger also inhibits platelet aggregation and contains proteases similar to bromelain, an enzyme derived from pineapples.11,12 The dosage of ginger extract is 250 mg tid.    I have recommended NF Formulas Joint Gel, a topical roll-on that contains ginger extract and several other antiinflammatory botanical extracts, as a topical analgesic for joint and muscular pain.    As noted above, bromelain is derived from the stem of the pineapple plant Ananas comosus. It is a mixture of sulfur-containing proteolytic enzymes or proteases. It has been used historically to hasten healing time after athletic injuries and reduce postoperative pain.    When it comes to bromelain, researchers have reported several antiinflammatory mechanisms including the activation of plasmin production from plasinogen, the reduction of kinin via inhibition of the conversion of kinogen to kinin and proteolytic degradation of circulating immune complexes.    In terms of measuring bromelain’s activity, the standard dose of 1,800 mcu to 2,000 mcu (milk clotting units) is equivalent in range to 125 mg to 450 mg. Patients may take this three times a day on an empty stomach. Researchers have shown that bromelain helps reduce the amount of steroids needed for clinical pain relief in patients with rheumatoid disease.13,14

What The Studies Reveal About Glucosamine Sulfate

   Glucosamine sulfate is one of several naturally occurring amino sugars that are essential for rebuilding and maintaining connective tissue via the stimulation of proteoglycan synthesis and inhibiting the degradation of protoglycans. As the body ages, there is increased glycation of hyaline cartilage that reduces the production of proteoglycans involved as joint lubricants. Medical science has recognized this loss of joint lubrication will result in decreased interarticular hydration and joint pain. This glycation of joint cartilage can be reversed in some cases.    Hylan G-F20 (Synvisc, Genzyme) is an injectable glycosaminoglycan hylan polymer produced from chicken combs.15 One may inject this viscous material into knee joints to relieve symptoms associated with osteoarthritis. However, the relief of symptoms is usually temporary.    Glucosamine sulfate is an essential component of proteoglycans and is required to re-establish proteoglycan levels and promote incorporation of essential sulfur into cartilage.    A meta-analysis of 13 double-blind, placebo-controlled clinical trials revealed that stabilized oral glucosamine sulfate was statistically superior to placebo in all 13 studies, as measured by global pain scores in the treatment of osteoarthritis.16    In other clinical trails in which researchers compared stabilized glucosamine sulfate to NSAIDs, they found greater long-term reductions in pain among patients receiving glucosamine sulfate for the treatment of osteoarthritis.17    No LD50 has been established for glucosamine sulfate. The most common side effects reported include epigastric discomfort, heartburn, diarrhea, nausea, dyspepsia, vomiting and constipation.    Complaints are generally mild in character and can be reduced or eliminated by taking glucosamine sulfate with food. All gastrointestinal complaints are reversed when treatment is discontinued.    When it comes to patients with type 2 diabetes, one should monitor the administration of glucosamine sulfate. Evidence from one study shows that glucosamine sulfate may cause an activation of the hexosamine pathway and may induce insulin resistance in multiple insulin sensitive tissues.18

Should You Consider Chondroitin Sulfate?

   Chondroitin sulfate is a glycosaminoglycan that is a major component of cartilage, which is rich in sulfur and related to glucosamine sulfate. The sources of chondroitin sulfate are shark cartilage, bovine cartilage extracts and sea cucumber.    Chondroitin sulfate contains a mixture of intact or partially hydrolyzed glycosaminoglycans with molecular weights ranging from 14,000 to over 30,000. Although chondroitin sulfate is popular with the public, it is less effective than glucosamine sulfate. One sees better clinical results with glucosamine sulfate primarily due to better intestinal absorption. Absorption rates for stabilized glucosamine sulfate range between 90 to 98 percent while absorption rates for chondroitin sulfate are estimated anywhere from zero to 13 percent. Chondroitin sulfate molecules are 50 to 300 times larger than those for glucosamine sulfate.18    If prescribing chondroitin sulfate, use a marine-soured, low molecular weight (less than 16,000 Daltons) for better absorption and mix it with stabilized glucosamine in a dosage of chondroitin sulfate 1,200 mg/day and glucosamine sulfate at 1,500 mg/day.19 I use the PhytoPharmica brand of this compound and have achieved good clinical results.

What The Literature Reveals About The Use Of S- Adenosylmethionine (SAMe)

   S-Adenosylmethionine (SAMe) is formed in the body from the essential amino acid methionine with adenosyl-triphosphate (ATP). The most researched form of supplemental SAMe comes from Italy. Cantoni discovered the molecule in 1952. During the mid-1970s, it became possible to stabilize a salt of this physiologic molecule, which facilitated clinical investigation.20 During clinical trials aimed at evaluating the mood modulating activity of SAMe, researchers discovered that some depressed patients with osteoarthritis reported a marked improvement of their degenerative joint disease after taking SAMe.21    Further studies aimed at the treatment of osteoarthritis confirmed that SAMe was as affective as ibuprofen and ketoprofen in controlling the symptoms of osteoarthritis without the untoward effects of NSAIDs.22,23    Harmand, et. al, showed that SAMe appears to enhance native proteoglycan synthesis and secretion in human chondrocyte cultures that arise in the cartilage of patients with osteoarthritis.24    S-Adenosylmethionine does not appear to share with NSAIDs a common effect on the eicosanoid system so the pharmacologic mechanisms are still unclear. However, we do know that SAMe increases hexuronic acid (a marker of the sugar chains of proteoglycans).    S-Adenosylmethionine is well tolerated by the gastrointestinal tract as well as by other organs. A study by Stranementinoll did not find any interference of SAMe with the eicosanoid system.25 The usual dosage for this medication is 400 mg tid. A deficiency of SAMe is that in joint tissue, it leads to a loss of the gel-like nature of shock-absorbing qualities of hyaline cartilage.    In clinical double-blind trials, researchers treated over 21,000 patients with painful osteoarthritis, utilizing 400 mg of oral SAMe tid. Trial results demonstrated reductions in global pain scores and clinical symptoms similar to NSAIDs such as ibuprofen, indomethacin, naproxen and piroxicam.26    S-Adenosylmethionine is one of the most effective natural antidepressants. When patients received it in an oral dose of 400 mg four times a day, it was as effective as IV dosing.27 Researchers have found that SAMe is better tolerated and has a quicker onset of action than tricyclic antidepressants.27,28

What You Should Know About Methylsulfonylmethane

   Methylsulfonylmethane is a naturally occurring compound and nutritional component of many foods. It is found in the normal diets of humans and almost all other vertebrates.    In a pure manufactured form, methylsulfonylmethane is an oxidized metabolite of dimethylsulfoxide (DMSO). The proper chemical name for methylsulfonylmethane is dimethylsulfone or DMSO 2. Methylsulfonylmethane is a rich source of organic sulfur, which is essential for the health of skin, hair, cartilage and connective tissue. It supports bodily functions dependent upon sulfur and methyl groups. Methylsulfonylmethane, which patients take orally and DMSO, which one applies topically, share several pharmacologic properties such as antiinflammatory actions. They also both soften collagen.    While methylsulfonylmethane is non-toxic, keep in mind there are toxic related chemicals such as dimethyl sulfate, dimethyl sulfite and dimethyl sulfide that should be avoided.29

A Revealing Look At Cetyl Myristoleate (CM)

   Cetyl myristoleate is a naturally occurring ester of a myristolic acid that is commercially obtained from palmitic acid. A study that examined why mice do not get arthritis lead to the discovery of cetyl myristoleate as a natural anti-arthritic substance.30    Diehl, et.al, found that cetyl myristoleate has several mechanisms of action. Cetyl myristoleate serves as a lubricant for joints, functions as an immune modulator and mediates the inflammatory response, promoting a balanced T Helper I to Helper II cellular response.30,31

How Oral Type II Collagen Can Reduce Arthritic Joint Inflammation

   Researchers have shown that orally administered, cartilage-derived type II collagen ameliorates arthritis in patients with joint inflammation. In the multi-site randomized, placebo-controlled study, the researchers utilized doses of 2,500 ug/day.32    There is a growing body of evidence that indicates type II collagen is a major structural protein responsible for tensile strength and toughness in the cartilage. It may also be a potential antigen in people who have rheumatoid arthritis. If it can reduce the activity of T cells that release joint destroying factors, oral type II collagen could improve outcomes for patients suffering from rheumatoid arthritis. A method of achieving down regulation of T-cell activity is termed oral tolerance, a concept that is proving useful in the treatment of autoimmune diseases. Oral tolerance describes a state of immune hypo-responsiveness following oral ingestion of a protein.    I have had clinical success in using an oral collagen product from Mediplex. The dosage of oral type II collagen is 10 mg or less taken on an empty stomach. In several studies, oral type II collagen appears to suppress T-cell mediated inflammation, which is characterized by cytokines, interleukin-4 and interleukin-10. Researchers have seen this in the synoviums of both osteoarthritis and rheumatoid arthritis patients.33

Are Acetyl-L-Carnitine And Alpha Lipoic Acid Effective In Reducing Neuropathic Pain?

   Acetyl-L-carnitine, in the acetylated form of L-carnitine and two compounds, shares similar properties that promote increased energy and increased metabolism. Acetyl-L-carnitine occurs naturally in the body and supports the availability of acetyl-CoA, an important energy generating metabolite. It also supports proper mitochondrial function and cell membrane stability. The acetyl group from acetyl-L-carnitine is an important factor in the production of the neurotransmitter acetylcholine.    Researchers have shown that acetyl-L-carnitine, when it is taken in doses of 1,000 mg tid, is efficacious in alleviating pain in patients who have chronic diabetic neuropathy. The clinical data has shown significant improvement in nerve regeneration and vibratory perceptions.34    Alpha lipoic acid, which is also known as thioctic acid, is a natural antioxidant that is both water- and fat-soluble. This powerful antioxidant neutralizes harmful free radicals and enhances the activity of vitamins C and E. Alpha lipoic acid produces energy in muscles and directs calories into energy production.    Three studies have shown that alpha lipoic acid is an effective and safe treatment for diabetic polyneuropathy. Dosing ranges from 400 to 600 mg qid.35-38    Over a 10-year period, I have used a combination of acetyl-L-carnitine and alpha lipoic acid to treat diabetic neuropathy and found repeated success in compliant patients who also keep their HbA1c between five and six.

What About Celadrin And Iso-Oxygene?

   Celadrin® is a proprietary blend of esterified fatty acid carbons (EFAC) and when it is combined with Iso-Oxygene™ in an oral form, it demonstrates significant relief in joint pain. Iso-Oxygene is an extract from the flowers of Humulus lupulus that impacts the enzymes involved in joint pain.    In a double-blind, placebo- controlled study of patients with knee pain conducted at the University of Connecticut, researchers found that 100 percent of patients using Celadrin topically were able to move faster with less joint pain when climbing stairs or rising from a chair.38 This data along with previous research data on the oral and topical use of Celadrin has shown promise in the treatment of degenerative joint disease.39    Extensive clinical research has shown that the all natural compound of Celadrin has no reported side effects. Toxicity testing has shown that Celadrin is safe and non-toxic at high dose levels.    The therapeutic dose of both components should be 350 mg of Celadrin tid and Iso-Oxyene 300 mg tid when they are given together. This product is available in a combination from Mediplex.38,39

Assessing The Potential Of Flavocoxid For Mild To Moderate Arthritis Pain

   Limbrel (flavocoxid) is a prescription only medical food for the treatment of mild to moderate arthritic pain. This combination of two extracts of Scutellaria and Acacia form the active ingredients. Flavocoxid exhibits antiinflammatory and analgesic activity in animal and human models. The mechanism of action is believed to be due to inhibition of cyclo-oxygenase and 5- lipoxygenase pathways.    Placebo-controlled animal studies of healthy subjects with similar ages and sexes did not demonstrate any changes in renal, hepatic, gastric or duodenal histology. Researchers found that blood electrolytes were unchanged and liver enzyme levels were within normal limits.40    Limbrel has demonstrated significant improvements in the clinical dietary management of osteoarthritis during a 90-day, randomized, double-blind, placebo-controlled trial of 60 patients with osteoarthritis.40    Limbrel is not recommended for patients under 18 years of age. The recommended use of Limbrel is 250 mg, every 12 hours away from food.40

In Conclusion

   There are several natural alternatives to NSAIDs for the treatment of chronic joint pain. These alternative medications have undergone well parametered studies that demonstrate their safety and efficacy. Clinicians should confidently prescribe nutriceutical therapies that are evidenced based in order to help treat patients who suffer from chronic pain. Dr. Hahn is in private practice at Trinity Clinic in Bend, Ore. He is board-certified by the American Board of Podiatric Surgery and is a member of the American Association of Naturopathic Physicians.
 

References:

1. Sheild MJ. Anti-Inflammatory Drugs and Their effects on Cartilage Synthesis and Renal Function. Eur.J. Rheumatology Infl. 13(1993) (7-16)
2. Buchanan W. NSAID and Osteoarthritis - Help or Hinderence, J.Rheumatology, 9(1982):3-5.
3. Gupta CD. Anti-Inflammatory and anti-arthritic activity of the volatile oil of Curcuma longa. Indian J.Med. Res. 1972: 60: 138-42.
4. Satoskor RR, Shah SJ, and Shenoy SG. Evaluation of Anti-Inflammatory Property of Curcumin ( Diferuloyl Methane ) in Patients with Postoperative Inflammation. Int. J. Clin. Parmacol Ther Toxicol 24 (1986):651-4
5. Kimmatkar N, Thawani V, Hingoranil, Kniyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee - a randomized double blind placebo controlled study. Phyomedicine 2003 ; 10: 3-7.
6. 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. Phytomedicie 2003 Jan; 10(1):3-7.
7. Chrubasik S, Künzel O, Model A, Conradt C and Black A. Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain. Rheumatology 2001; 40: 1388-1393.
8. Blumethal M, et.al White Will bark. The Complete German Commission E Monographs. Therapeutic Guide to Herbal Medicine Austin, Tex American Botanical Council; 1998: 230
9. Ellison N, Loprinzi C L, Kugler J. et. al. Phase III placebo - controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J. Clin Oncol 15 (8): 2974 - 80, l997.
10. Deal CZ et.al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 13 (3): 383-95, 1991.
11. Kiuchi F, Iwakami S, Shibuya M, et.al. Inhibition of prostaglandin and leukotriene bio synthesis by gingerols and diarlheptanoids. Chem Pharm Bull. (Tokyo) 40 (2) : 387-91, 1992.
12. Altman RD, Marcussen KC. Effects of ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001 Nov; 44(11):2531-8
13. Cohen A, Goldman J. Bromelain Therapy in Rheumatoid arthritis, Penn Med J. 67 (1964) 27-30
14. Mynott RL, Iadhanas A, Scarmato P, Engwerda CR. Bromelain from pineapple stems, proteoytially blocks activation of extra cellular regulated Kinaso - 2 in Tolls J. Immunol. 1999; 163: 2568 - 2575.
15. Physicians Desk Reference 2005.
16. Drovanti A, et.al. Therapeutic activity of oral glucosamines: A placebo - controlled double - blind investigation. Clin Ther 3, 260-272, 1980.
17. Rovati LC, et.al. A large Randomized, Placebo controlled, double blind study of Glucosamine Sulfate vs Piroxicam and symptomatic Effect in Knee Osteoarthritis. Osteoarthritis Cartilage 2 (Suppl. L)1994:56.
18. Virkanaki A, Daniels MC, Hamalaines,et. al. Activation of Hexosamine pathway by Glucosamine in Vivo induces insulin Resistance in multiple insulin sensitive tissue. Endocrinology 1997; 138-2501-2507.
19. Baici, et. al. Analysis of Glycosaminoglycans in Human Sera after Oral Administration of Chondroitin Sulfate. Rheumatol Int. 12 (1992): 81-88.
20. Cantoni GL. The nature of the active methyl donor formed enzymatically from L-Methionine and adenosinetriphospate. JAM Chem Soc 1952:74:2942-2943
21. Fiecchi A . United States Patent no.3,954,726, May 4th 1976.
22. Ceccato S, Cucinotta D, Carapezzi C, Passeri M. Indagine clinca aperta e comparative sull impiego della SAMe e del Ketoprofen nell osteoarthrosi. Progr Med. 1979 :35: 177-191.
23. Cucinotta D, Mancini M, Cecato S. Studio Clinico controlled sull attivita della SAMe somministrata per via parenterale nella patologia degenerative osteo-articolare. G Clin. Med 1980. 61:553-566.
24. Harman MF, Vilamitjana J, Maloche E, Duphil R, Ducassou D. Effects of S-adenosylmethionine on human articular chondrocyte differention: an in vitro study. Am J Med 1987; 83 (Suppl 5A) : 48-54.
25. Murray M, Pizzorono J. Encyclopedia of Natural Medicine Revised 2nd Edition 998 - pp 695-705.
26. Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine: pharmacokinetics and pharmacodynamics. Am J. Med. 1987: 83 (Suppl. 5 A): 35-42.
27. Janicak PG, et.al. Parenteral S-Adenosylmenthionine in Depression: A Literature Review and Preliminary Report. Psychopharmacology Bulletin 25 (1989):238-41.
28. Bothlieri T, Laundry M, Martin R, et. al. S-Adenosylmethionine Influences Monoamine Metabolism. Lancet: (1984): 224.
29. Appleton J, Stanley J. MSM The Definitive Guide. A Comprehensive Review if the Science ad Therapeutics of Methylsulfonylmethane, Topanga, Ca. Freedom Press 2003.
30. Diehl H, et.al. Cetyl myristoleate isolated from Swiss albino rats, an apparent protective agent against adjuvant arthritis in Rats. Journal of Pharmaceutical Sciences, Vol.83, No 3,March 994.
31. Siemandi H, et.al. The Effect of cis-9-Cetyl Myristolate (MO) and Adjunctive Therapy on the course of Arthritic Episodes in Patients with Various Auto-Immune Diseases characterized by the common terminology, “Arthritis and Psoriasis” HSM Corp. Offices, 738 Design Ct. #301, C.V. Ca, 91911, 1997
32. Barnett M, Kremer J, et.al. Treatment of Rheumatoid Arthritis with Oral Type II Collagen Arthritis and Rheumatism Vol.4, No 2, Feb1998, pp-290-297
33. Trentham D, Halpner A, et.al. Use of Un-denatured Type II Collagen in the Treatment of Rheumatoid Arthritis. Clinical Practice of Alternative Medicine. Vol. 2 No 4, 2001 Original Paper.
34. Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration and vibratory perception in patients with chronic diabetic neuropathy. An analysis of two randomized placebo-controlled trials. Diabetes Care Jan. 2005; 28(1):89-94.
35. Haak E, et. al. Effects of alpha lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. EXP Clin Endocrinol Diabetes 2000; 108:168-174.
36. Veresiu IA. Treatment of polyneuropathy with alpha lipoic acid, a seven-month multicenter randomized controlled trial (ALADIN III) study. Alpa lipoic acid in diabetic neuropathy. Diabetes Care Aug. 1999; 22(8):1296-1301.
37. Negisanu G, Rosu M, Bolte B, Lefter D, et. al. Effects of three-month treatment with the antioxidant alpha lipoic acid in diabetic peripheral neuropathy ROM. J Intern Med. July-Sept. 1999; 37(3):297-306.
38. Hesslink R, Armstrong D, et.al. Journal of Rheumatology 2000; 29: 1708-1712.
39. Hesslink R Armstrong D et. al. Journal of Rheumatology 2004: 31 (4): 767-774.
40. PharmaFab physician literature and www.limbrel.com.