Surgical Neurological International December 2010 Joseph C. Maroon, Jeffrey W. Bost, and Adara Maroon Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh,PA, and Vanderbilt University, Nashville, TN FROM ABSTRACT: The use of both over-the-counter and prescription nonsteroidal medications isfrequently recommended in a typical neurosurgical practice. But persistent long-term use safety concerns must be considered when prescribing these medicationsfor chronic and degenerative pain conditions.Although nonsteroidal medications can be effective, herbs and dietary supplementsmay offer a safer, and often an effective, alternative treatment for pain relief,especially for long-term use. THESE AUTHORS ALSO NOTE: In most cases, the genesis of pain is inflammatory, regardless of theetiology. This inflammation has 2 primary causes: 1) Inflammatory hormones (PGE2, LTB4, etc.)[derived from the omega-6 fatty acid arachidonic acid] 2) Inflammatory cytokines (interleukin ((IL))-1a, IL-1b, IL-6 and tumor necrosisfactor ((TNF-a)).[proteins that are derived form the immune system cells] The use of non-steroidal anti-inflammatory drug (NSAID) medication is stillthe mainstay of most classically taught clinicians for joint and spine relatedinflammatory pain, despite their commonly known side effects.The pro-inflammatory cytokines stimulate the production of the pro-inflammatory hormone prostaglandin E2 (PGE2).NSAIDs ability to interfere with the production of prostaglandin E2 (PGE2) isthe major mechanism for the anti-inflammatory success of these drugs. INFLAMMATORY PATHWAYS Prostaglandins act as short-lived localized hormones that can be released byany cell of the body during tissue, chemical, or traumatic injury, and can inducefever, inflammation, and pain, once they are present in the intercellular space.Thromboxane hormones increase the inflammatory response. A major component of the inflammatory pathway is called the arachidonicacid pathway because arachidonic acid is immediately released from traumatizedcellular membranes.Cell membrane trauma releases arachidonic acid. Arachidonic acid is thentransformed into the pro-inflammatory hormones prostaglandins and thromboxanesthrough the enzymatic action of cyclooxygenase. Nonselective NSAIDs major side effects include significant gastrointestinalupset, gastritis, ulceration, hemorrhage, and even death. By blocking COX-1, whichalso normally acts to protect the gastrointestinal mucosa, nonselective NSAIDs andaspirin can cause significant gastric tissue damage. NSAIDs can delay muscle regeneration and may reduce ligament, tendon,and cartilage healing.NSAIDs also have adverse effects on kidney function. The National KidneyFoundation asserts that approximately 10% of kidney failures per year are directlycorrelated to substantial overuse of NSAIDs. Selective COX-2 inhibiting NSAIDs were thought to reduce inflammatory painwithout enhancing GI bleeding. Celebrex was FDA approved in 1998, followed bythe approval of Vioxx and Bextra in 1999. These drugs quickly became themainstay for the treatment of chronic pain conditions related to inflammation. On September 30, 2004, Vioxx was withdrawn because it doubled the risk ofserious thromboembolic events, including myocardial infarction.Natural compounds for inflammation Because of the significant side effect profiles of steroidal and NSAIDmedications, there is a greater interest in natural compounds, such as dietarysupplement and herbal remedies, which have been used for centuries to reducepain and inflammation.Nuclear Factor kappa-B (Nf-kB) controls the transcription of DNA for theperpetuation of the inflammatory immune response. It acts as a switch to turninflammation on and off in the body. Plant- and animal-derived nutraceutical preparations have been used forhundreds and even thousands of years to obtain effective pain relief. Herbalmedications are becoming increasingly popular because of their relatively few sideeffects. The US governmental agencies, through the FDA and others, routinelyinspect the manufacture of vitamins or supplements made in this country, as theydo for any other food product. Products such as omega-3 essential fatty acids (EFAs) (O3) do have strongscientific support to be considered as an alternative and/or complementary agent toNSAIDs. Published studies have shown the effectiveness of O3 to successfully treatspine-related pain. Omega-3 EFAs (fish oil)The use of fish oil for the treatment of muscular, skeletal, and discogenicdiseases, can be traced back to the late 18th century. Research has shown that the omega-3 polyunsaturated fatty acids are someof the most effective natural anti-inflammatory agents available. [7 references] With the discovery that vascular inflammation is the underlying cause ofcoronary artery disease, fish and fish oil supplements are now recommended by theAmerican Heart Association for the prevention of this disease. Countries that have the highest fish consumption also have a lower incidenceof neurodegenerative disease and depression. The biological basis for the effectiveness of fish oil in treating arthritis hasbeen well documented with many positive clinical studies, when compared totraditional pharmaceutical anti-inflammatory agents. The active ingredients in fish oil, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), enhance the conversion of COX to prostaglandin E3. Anatural anti-inflammatory agent, prostaglandin E3 competitively inhibits the effectsof the arachidonic acid conversion to prostaglandin E2, a highly inflammatorysubstance. Prostaglandin E3 also inhibits the synthesis of TNF-a and IL1b, both of whichare inflammatory cytokines. The EPA and DHA can inhibit the 5-LOX pathway, which convertsarachidonic acid to inflammatory leukotrienes. When EPA and DHA are incorporated into articular cartridge chondrocyte cellmembranes, there is a dose-dependent decrease in the expression and activity ofthe enzymes that degrade cartilage.Omega-3 EFA, found in fish oil, can directly reduce the degenerative enzymesand reduce the inflammation in synovial cartilage.Belching may occur if fish oil supplements are not taken with meals. Persons on a regimen of anticoagulant medications should not take omega-3EFAs because of the possibility of increasing the bleeding potential. White willow barkBark from the white willow tree has analgesic and antipyretic properties.Salicin from white willow bark is converted to salicylic acid by the liver and isconsidered to have fewer side effects than aspirin. White willow bark should not be used in children (to avoid the risk of Reyessyndrome), or in patients with peptic ulcer disease, poorly controlled diabetes,hepatic or renal disorders, or other conditions in which aspirin would becontraindicated. The usual dose of white willow bark is 240 mg/day.Curcumin (turmeric) Curcumin is a naturally occurring yellow pigment derived from turmeric, aflowering plant of the ginger family. It has traditionally been used as a coloring andflavoring spice in food products. Curcumin is an anti-inflammatory agent, and hasantioxidant, anti-inflammatory, and antineoplastic effects. Curcumin is known to inhibit inflammation by suppressing NF-kB and COXenzymes, and it may be considered a viable natural alternative to nonsteroidalagents for the treatment of inflammation. The usual dosage of standardized turmeric powder is 400 – 600 mg takenthree times per day. Green tea Green tea has cardiovascular and cancer preventative characteristics due toits antioxidant properties; its use in the treatment of arthritic disease as an anti-inflammatory agent is more recent. The constituents of green tea include polyphenolic compounds calledcatechins; epigallocatechin-3 galate is the most abundant catechin in green tea.Epigallocatechin-3 galate inhibits NF-kB and the production of pro-inflammatory cytokines.Green tea inhibits the aggrecanases that degrade cartilage.Green tea has both anti-inflammatory and chondroprotective effects.Increased green tea consumption in Asia may lead to significantcardiovascular, neuroprotective and cancer prevention properties. The recommendation for green tea consumption is 3 – 4 cups a day, or greentea extract dosage of 300 – 400 mg a day. Pycnogenol (maritime pine bark) Pycnogenol is derived from the bark of the maritime pine tree and has beenused for more than 2000 years.Pycnogenol is helpful for wound healing, treating scurvy, healing of ulcers,and reducing vascular inflammation.Pycnogenol contains a potent blend of active polyphenols, which includescatechin, taxifolin, procyanidins, and phenolic acids. It is one of the most potentantioxidant compounds currently known.Pycnogenol inhibits NF-kB production of pro-inflammatory cytokines. Studies have shown that pycnogenol is 50 – 100 times more potent thanvitamin E in neutralizing free radicals and that it helps to recycle and prolong theactivity of vitamins C and E. Studies have shown pycnogenol to be effective in reducing blood pressureand reducing the risk of venous thrombosis by its effect on vascular endothelium.The usual dosage is 100 – 200 mg daily.Because pycnogenol enhances immune system function, it should not betaken by patients who are being treated with immunosuppressants or by thosereceiving corticosteroid drugs, both of which have the opposite effect on theimmune system.Boswellia serrata resin (Frankincense) Boswellia possesses anti-inflammatory, anti-arthritic, and analgesicproperties.Boswellia can inhibit the leukotriene biosynthesis, thus affecting variousinflammatory diseases that are perpetuated by leukotrienes.Clinically, Boswellia is used in the treatment of degenerative andinflammatory joint disorders. A combination of Boswellia and curcumin showed superior efficacy andtolerability compared with nonsteroidal diclofenac for treating active osteoarthritis. Boswellia typically is given as an extract standardized to contain 30-40%boswellic acids (300-500 mg two or three times/day). Resveratrol Resveratrol is a plant-based polyphenol molecule that is found in manydifferent plant sources, but the skins of red wine grapes are believed to have thehighest concentration.In plants, resveratrol protects the plant from infection, excessive UV radiationand aids in general plant defense. Resveratrol has also been found to have significant anti-mutation, anti-inflammatory, antioxidant and DNA protective actions, when consumed by animalsand humans. Most of the active research with resveratrol has been done in neuro andcardioprotection, but several studies are being reported on resveratrols use forarthritic joint pain.Resveratrol inhibits NFkB and the production of pro-inflammatory cytokines.The typical dose for Resveratrol is 50 to 500 mg daily. Uncaria tomentosa (cats claw) The bark of cats claw is used to treat arthritis, bursitis, and intestinaldisorders. The active ingredients appear to be polyphenols (flavonoids,proanthocyanidins, and tannins), alkaloids, and sterols.Cats claw inhibits NFkB and the production of pro-inflammatory cytokines. Cats claw can be consumed as a tea (1000 mg root bark to 8 oz water), oras a dry, standardized extract in a capsule (20-60 mg daily).Capsaicin (chili pepper)Capsicum accentuates chilis stinging pungency.Capsaicin produces highly selective regional anesthesia by causingdegeneration of capsaicin-sensitive nociceptive nerve endings which can producesignificant and long-lasting increases in nociceptive thresholds.Capsaicin inhibits NF-kB, thus producing an anti-inflammatory effect. CONCLUSIONS Anti-inflammatory agents such as NSAIDs can have undesirable side effectssuch as gastric ulceration and, infrequently, myocardial infarction and stroke. For centuries, natural anti-inflammatory compounds have been used tomediate the inflammatory process and often with fewer side effects [than NSAIDs]. PLA2 = Phospholipase A2 (the enzyme that cleaves AA from the cell membrane following trauma / injury) AA = Arachidonic Acid (an omega-6 fatty acid commonly found in cellmembranes) LOX = Lipoxygenase (the enzymes that converts AA into pro-inflammatory LThormones) COX = Cycloxygenase (the pro-inflammatory enzymes that convert AA into thepro-inflammatory PG and TXA hormones) LT = Leukotrienes TXA = Thromboxanes PG = Prostaglandins Interleukin-1a = IL1a (a pro-inflammatory cytokine protein) Interleukin-1b = IL1b (a pro-inflammatory cytokine protein) Interleukin-6 = IL6 (a pro-inflammatory cytokine protein) Tumor Necrosis Factor alpha = TNFa (a pro-inflammatory cytokine protein) NF-kB= Nuclear Factor kappaB (pro-inflammatory protein that lives in the cellcytoplasm) IkB = Inhibitory kappaB ( a protein that when attached to NFkB inhibits itspro-inflammatory influence; consequently its an anti-inflammatoryprotein) IkBK = Inhibitory kappaB Kinase (an enzyme that cleaves NFkB away from itsinhibitory Ikb protein, allowing NFkB to cross into the nucleus andactivate the genes that produce pro-inflammatory cytokines) CK = Cytokines (pro-inflammatory proteins made by immune system cells) EPA = Eicosapentaenoic Acid (anti-inflammatory omega-3 fatty acid)8 These authors indicate that the inflammatory mediators above can be triggered asa consequence of: Stress Infection Radiation Trauma/Injury Arachidonic Acid Inflammatory Diet Allergic Immune Response This inflammation is a factor in: Pain Cancer Thrombosis Atherosclerosis Insulin Resistance Neurodegeneration