Natural compounds for inflammation
Because of the significant side effect profiles of steroidal and NSAID medications, there is a greater interest in natural compounds, such as dietary supplement and herbal remedies, which have been used for centuries to reduce pain and inflammation. Many of these natural compounds also work by inhibiting the inflammatory pathways in a similar manner as NSAIDs.
Examples of natural anti-inflammatory
Plant- and animal-derived nutraceutical preparations have been used for hundreds and even thousands of years to obtain effective pain relief. Herbal medications are becoming increasingly popular because of their relatively few side effects. Nevertheless, there are problems associated with these dietary supplements, and their use requires knowledge of their biological action, clinical studies (both affirmative and negative), and potential interactions with other nutraceutical products and prescription medications.
The evaluation of nutraceutical preparations with appropriately designed controlled studies has exploded in recent years. There is now a greater degree of confidence based on controlled study design and improved quality of the investigators that has strengthened positive findings found using natural compounds to treat diseases. It is important for healthcare practitioners to learn about these scientific studies to counsel patients who are taking various dietary supplements, herbs minerals and vitamins for both disease treatment and prevention.
Omega-3 EFAs (fish oil)
The use of fish oil (in the form of cod liver oil), an omega-3 EFA, for the treatment of muscular, skeletal, and discogenic diseases, can be traced back to the late 18th century as detailed by Curtis et al., Unfortunately, because of the rapid onset of rancidity of this polyunsaturated oil when exposed to air, and hence it’s disconcerting odor, cod liver oil fell out of favor. With improved extraction techniques, such as using a protective nitrogen blanket and enhanced oxygen-free encapsulation methods, there is less chance of oxidation during the manufacturing process. The therapeutic benefits of fish oil can now be realized without the regurgitation and odor of previous products caused by peroxides and rancid tasting fish oil.
Research has shown that the omega-3 polyunsaturated fatty acids are some of the most effective natural anti-inflammatory agents available. With the discovery that vascular inflammation is the underlying cause of coronary artery disease, fish and fish oil supplements are now recommended by the American Heart Association for the prevention of this disease. Countries that have the highest fish consumption also have a lower incidence of neurodegenerative disease and depression. The biological basis for the effectiveness of fish oil in treating arthritis has been well documented with many positive clinical studies, when compared to traditional pharmaceutical anti-inflammatory agents.
Rare side effects include steatorrhea and occasional belching if the supplements are not taken with meals. Typically, persons on a regimen of anticoagulant medications should not take omega-3 EFAs because of the possibility of increasing the bleeding potential.
White Willow Bark
Bark from the white willow tree is one of the oldest herbal remedies for pain and inflammation, dating back to ancient Egyptian, Roman, Greek, and Indian civilizations, as an analgesic and antipyretic agent. Because of the gastric side effects of aspirin, there has been a resurgence in the use of white willow bark for the treatment of inflammatory syndromes. The mechanism of action of white willow bark is similar to that of aspirin which is a nonselective inhibitor of COX-1 and COX-2, used to block inflammatory prostaglandins.
Various randomized, placebo-controlled studies comparing white willow bark with nonsteroidal agents have shown an efficacy comparable to these agents and aspirin. Salicin from white willow bark is converted to salicylic acid by the liver and is considered to have fewer side effects than aspirin. However, it is costlier than aspirin, and should not be used in children (to avoid the risk of Reye’s syndrome), or in patients with peptic ulcer disease, poorly controlled diabetes, hepatic or renal disorders, or other conditions in which aspirin would be contraindicated. The usual dose of white willow bark is 240 mg/day.
Curcumin is a naturally occurring yellow pigment derived from turmeric (Curcuma longa), a flowering plant of the ginger family. It has traditionally been used as a coloring and flavoring spice in food products. Curcumin has long been used in both Ayurvedic and Chinese medicines as an anti-inflammatory agent, a treatment for digestive disorders, and to enhance wound healing. Several clinical trials have demonstrated curcumin’s antioxidant, anti-inflammatory, and antineoplastic effects. Results of a study by Zandi and Karin suggested that curcumin might be efficacious in the treatment of cystic fibrosis because of its anti-inflammatory effect. Curcumin is known to inhibit inflammation by suppressing NF-kB, restricting various activators of NF-kB as well as stemming its expression.
Curcumin has also been suggested as a treatment for colitis, chronic neurodegenerative diseases, arthritis, and cancer. In addition, it regulates the activity of several enzymes and cytokines by inhibiting both COX-1 and COX-2. Most studies to date have been performed in animals, but given the centuries of use of curcumin, as well as its now demonstrated activity in the NF-kB, COX-1, and COX-2 inflammatory pathways, it may be considered a viable natural alternative to nonsteroidal agents for the treatment of inflammation.
The usual dosage of standardized turmeric powder is 400–600 mg taken three times per day. Side effects are few, but with extended use, this agent can cause stomach upset, and in extreme cases gastric ulcers may occur at very high doses. Caution should be used if the patient is taking anticoagulant medications or high doses of nonsteroidal drugs. Studies have shown that curcumin may be used in combination with lower doses of nonsteroidal medications.
Green tea has long been recognized to have cardiovascular and cancer preventative characteristics due to its antioxidant properties. Its use in the treatment of arthritic disease as an anti-inflammatory agent has been recognized more recently. The constituents of green tea are polyphenolic compounds called catechins, and epigallocatechin-3 galate is the most abundant catechin in green tea.
Epigallocatechin-3 galate inhibits IL-1–induced proteoglycan release and type 2 collagen degradation in cartilage explants. In human in vitro models, it also suppresses IL-1b and attenuates activation of the transcription factor NF-kB. Green tea also inhibits the aggrecanases which degrade cartilage.
Green tea research now demonstrates both anti-inflammatory and chondroprotective effects. Additionally, green tea research includes the “Asian paradox”, which theorizes that increased green tea consumption in Asia may lead to significant cardiovascular, neuroprotective and cancer prevention properties. The usual recommendation is 3–4 cups of tea a day. Green tea extract has a typical dosage of 300–400 mg. Green tea can cause stomach irritation in some, and because of its caffeine content, a decaffeinated variety is also available; but the polyphenol content is currently unknown.
Pycnogenol (Maritime Pine Bark)
Pycnogenol, like white willow bark, is a nutraceutical material that has been used since ancient times. Pycnogenol is derived from the bark of the maritime pine tree (Pinus maritima) and has been used for more than 2000 years. It has been considered helpful for wound healing, treating scurvy, healing of ulcers, and reducing vascular inflammation. It contains a potent blend of active polyphenols, which includes catechin, taxifolin, procyanidins, and phenolic acids. It is one of the most potent antioxidant compounds currently known.
Pycnogenol inhibits TNF-α–induced NF-kB activation as well as adhesion molecule expression in the endothelium. Grimm et al, recently reported that oral intake of pycnogenol inhibited NF-kB activation in lipopolysaccharide-stimulated monocytes as well, thus decreasing the inflammatory response. It also statistically significantly inhibited matrix metalloproteinase-9.This matrix-degrading enzyme is highly expressed at sites of inflammation, and contributes to the pathogenesis of various chronic inflammatory diseases.
Studies have shown that pycnogenol is 50–100 times more potent than vitamin E in neutralizing free radicals and that it helps to recycle and prolong the activity of vitamins C and E. Studies have shown pycnogenol to be effective in reducing blood pressure and reducing the risk of venous thrombosis by its effect on vascular endothelium. The usual dosage is 100–200 mg daily. Few side effects from the use of pine bark extracts have been reported, the most frequent being mild gastrointestinal effects such as diarrhea and upset stomach. Pycnogenol should not be taken by patients who are being treated with immunosuppressants or by those receiving corticosteroid drugs because it can enhance immune system function and interact with drugs that suppress the immune system.
Boswellia Serrata Resin (Frankincense)
The Boswellia species are trees located in India, Ethiopia, Somalia, and the Arabian Peninsula, and they produce a gum resin called olibanum, better known in the western world as frankincense. This resin possesses anti-inflammatory, anti-arthritic, and analgesic properties. Boswellia can inhibit the leukotriene biosynthesis in neutrophilic granulocytes by inhibiting 5-LOX, thus affecting various inflammatory diseases that are perpetuated by leukotrienes. Clinically, the substance is used in the treatment of degenerative and inflammatory joint disorders. It reduces the total white blood cell count in joint fluid, and it also inhibits leukocyte elastase, which is released in rheumatoid arthritis. In one recent study, a statistically significant improvement in arthritis of the knee was shown after 8 weeks of treatment with 333 mg B. serrata extract taken three times a day. The treatment improved function, but radiographically there was no change in the affected joints.
A combination of Boswellia and curcumin showed superior efficacy and tolerability 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). Boswellia has been well tolerated in most studies, although some people may experience stomach discomfort, including nausea, acid reflux, or diarrhea.
Resveratrol is a plant-based polyphenol molecule that is found in various concentrations of many different plant sources. The plant is called Japanese Knot weed or Polygonum cuspidatum, and the skins of red wine grapes are believed to have the most concentrated amounts of resveratrol. In plants, resveratrol is generally found in the plant skin and acts as a phytoalexin to protect the plant from infection, excessive UV radiation and aide in general plant defense. Resveratrol has also been found to have significant anti-mutation, anti-inflammatory, antioxidant and DNA protective actions, when consumed by animals and humans.
Most of the active research with resveratrol has been done in neuro and cardioprotection, but several studies are being reported on resveratrol’s use for arthritic joint pain. Elmali et al, reported in 2007 using animals that intra-articular injection of resveratrol protects cartilage and reduces the inflammatory reaction in simulated knee osteoarthritis. The anti-inflammatory properties of resveratrol have also been observed in experimental animal models with paw edema, which is attributed to suppression of inflammatory prostaglandin synthesis. Resveratrol is also a potent and specific inhibitor of TNF-α- and IL-1b-induced NF-kB activation. Resveratrol shows the anti-inflammatory properties as it suppresses COX-2 by blocking NF-kB activation.
Resveratrol is available commercially as a dietary supplement capsule, generally from the P. cuspidatumsource. The trans-resveratrol is the active form, and although there is not an established dosing range, the typical dose is from 50 to 500 mg daily. Any significant side effect or safety issues with resveratrol have not been established, but due to an experimentally shown anti-platelet effect, caution should be exercised when taking other prescription or herbal anti-platelet or coagulation altering products.
Uncaria Tomentosa (Cat’s Claw)
Uncaria tomentosa and Uncaria guianensis are Peruvian herbs derived from woody vines with small claw-like thorns (hence the vernacular name, cat’s claw) at the base of the leaf, which allow the plant to climb to heights of up to 100 ft. Traditionally, the bark of cat’s claw is used to treat arthritis, bursitis, and intestinal disorders. The active ingredients appear to be polyphenols (flavonoids, proanthocyanidins, and tannins), alkaloids, and sterols. Various studies indicate that this Peruvian herb induces a generalized reduction in proinflammatory mediators.
This herb has been shown to prevent the activation of the transcriptional factor NF-kB and it directly inhibits TNF-α production by up to 65-85%. It inhibits the expression of inducible genes associated with inflammation, specifically negating the expression of inducible nitric oxide synthase, and hence attenuates nitrous oxide production. Side effects may include nausea, although it has shown an impressive protective effect on indomethacin-induced enteritis in laboratory studies.
In general, toxicity and side effects are considered minimal. Two case reports of acute renal failure in a patient with lupus erythematosus have been recorded. Cat’s claw can be consumed as a tea (1000 mg root bark to 8 oz water), or as a dry, standardized extract in a capsule (20-60 mg daily).
Capsaicin (Chili Pepper)
Capsicum annum is a small spreading shrub which was originally cultivated in the tropical regions of the Americas but is now grown throughout the world, including the US. The small red fruit commonly used to accentuate chili owes its stinging pungency to the chemical, capsaicin. This was isolated by chemists more than a century ago and constitutes approximately 12% of the chili pepper. This fruit has been used for various medicinal purposes by the native peoples of the American tropics for hundreds of years.
Capsaicin produces highly selective regional anesthesia by causing degeneration of capsaicin-sensitive nociceptive nerve endings which can produce significant and long-lasting increases in nociceptive thresholds. Capsaicin potently activates transient receptor potential vanilloid 1, which is a main receptor underlying nociception. It also inhibits NF-kB, thus producing an anti-inflammatory effect. Capsaicin can cause a burning sensation when it comes in contact with human flesh, and also in the digestive tract. This herb is rarely used alone but is generally mixed into other natural anti-arthritic preparations. There are topical capsaicin formulations now available to treat post-herpetic neuralgia. Other uses have been studied for peripheral neuropathies and chronic musculoskeletal pain.
The human body’s natural response to injury results in inflammation-induced pain, swelling, and erythema. In order to reduce pain, anti-inflammatory agents such as NSAIDs act on the multiple inflammatory pathways, which, although often very effective, can have undesirable side effects such as gastric ulceration and, infrequently, myocardial infarction and stroke.
For centuries, natural anti-inflammatory compounds have been used to mediate the inflammatory process and often with fewer side effects. We have briefly reviewed several of the most commonly used plant- and animal-derived natural compounds that may possess similar effectiveness in treating the inflammatory reaction seen in both chronic and sub-acute pain syndromes encountered in a typical neurosurgical practice. Ongoing experiments and clinical trials should be continued to guide and provide their scientifically based effectiveness to reduce inflammation and promote wellness.