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Preventing the Most Common Cause of Chronic Pain with Nutrition

The end of February is almost here, which means that our next Functional Medicine CE symposium is 1 week away! Dr. Frank Bodnar is rounding out his contribution to the blog with a great discussion on chronic pain and how we can use nutrition to improve inflammation. If you want to learn more and hear from Dr. Bodnar and our other speakers. Please make sure you sign up!

Dr. Hartzler

You’ve seen many patients walk into your clinic with a limp, antalgic posture or heard the grunts and groans of pain as they get in and out of their chairs. Thousands of people visit their local pharmacy for a remedy to ease their chronic ache and recurring nagging pain. There’s no doubt that inflammation is an underlying cause in the majority of your patient’s pain. We can help our patients break the cycle of grabbing a Tylenol off the shelf, only to return a few weeks later looking worse. At the end of the day, are your patients getting better?

You’re probably wondering where to start. You can get started by focusing on the most common cause of chronic pain, arthritis. And if we drill down into the term arthritis and look at a specific diagnosis, we see that osteoarthritis (OA) is the most common cause of chronic pain from a single disease standpoint. Not only is it the most common cause of chronic pain but also the leading cause of disability worldwide, affecting mobility, physical function and quality of life.1OA, or joint degeneration is the culprit behind the majority of your patients’ aches and pains.

Unfortunately, the problem isn’t going away any time soon. Epidemiological data shows that the US population continues to age, and by 2040, 1 in 5 people in the United States will be 65 or older—about equal in size to the cohort of those who are 18 years of age or younger. One in two adults aged 65 and older already have some form of arthritis, but nearly two-thirds of those with arthritis are under 65. By 2030, it is projected some form of arthritis will affect 67 million adults. Both osteoarthritis and inflammatory forms of arthritis are more common in women.

The problem of OA and joint degeneration isn’t new to any clinician but may be one of the most neglected in the functional medicine and pharmacy arenas because we assume patients may not seek us out as an option for such an uncomplicated condition. Most patients rely on self-care via anti-inflammatory and analgesic medication as a remedy. While this approach may get them through their day, we know this is symptom management and doesn’t really do anything to reduce inflammation over the long-term or prevent further joint degeneration. 

If we want to make a dent in the pain problem and prevent more invasive therapies in our aging population, we need to offer safe and effective treatments for the musculoskeletal system, which is the largest contributor to chronic pain.2 We’re going to cover the a few specific options that can make an immediate impact in breaking the vicious pain cycle your patients are stuck in. The aging process affects all aspects of a joint beyond just cartilage breakdown. The surrounding muscle begins to lose strength due to a decrease in muscle fibers and fiber size, and a reduction in muscle protein synthesis. Surrounding tendons also lose the ability to maintain water, lose tensile strength and elasticity and fibroblasts decrease glycosaminoglycan (GAG) production. Bones that surround primary weight bearing loads begin to decrease in strength due to less mineral content leading to more fragility, and the process of bone remodeling slows as well. Cartilage also loses its ability to decompress and hold water, along with a decreased ability to maintain joint lubrication through less hyaluronic acid production.3

When most clinicians think of OA, the first thing that comes to mind is a disease of “wear and tear.” We consider what we were taught during our training, which is to focus on the loss of joint space and a degradation of cartilage. While this isn’t completely inaccurate what we now know is that OA is much more involved than what we learned in pharmacy school even 10 years ago. A more accurate description of OA would be “whole joint failure,” just as loss of full function on the heart is diagnosed as heart failure and loss of full function of the kidney is diagnosed as renal failure. Whole joint failure involves not only the cartilage, but helps us take into consideration the underlying bone, synovial membrane, synovial fluid, tendons, muscles, nerves, nociceptor sensitivity and underlying metabolic factors (TIMP/MMP activity).4

Traditional drugs such as aspirin, ibuprofen, naproxen, celecoxib and steroids target primarily 5-LOX, COX-1, COX-2, PLA2 inflammatory pathways via oral medication or intraarticular injection to provide pain relief. Analgesics such as acetaminophen, narcotics and oxycodone may also provide symptomatic relief. However, this relief comes at a cost of more also blocking the body’s repair process and more cartilage loss than previously thought and higher risks than many are aware. Given the constraints of NSAIDs, especially in those with high cardiovascular risk, gastrointestinal and renal comorbidities, and constraints of acetaminophen in those with high risk of liver injury or at risk for multiple medication adverse reactions safer alternatives should be a primary consideration. In fact, a recent study at Boston University School of Medicine found accelerated arthritis and joint destruction can be the unintended result of intra-articular corticosteroid injections.5 Given the chronicity of OA we need alternatives that are safe and effective and can be taken long-term without the major side effects. 

Dietary Changes Can Reduce Inflammation and OA Progression

Diet has been shown to greatly influence the rate of joint degeneration, especially when obesity and insulin resistance are involved. Obesity is now a recognized generator of inflammation and adds to the mechanical pressure on a joint. The inflammatory and metabolic mechanisms as contributing factors to OA can no longer be ignored. A recent laboratory study testing synovial tissue from mice and individuals with type 2 diabetes suggested that the insulin resistance of type 2 diabetes may promote OA.6

Research also has shown that diet plays a key role in the regulation of inflammation, elevating C-reactive protein (CRP)7, and because there is a relationship between inflammation and the development and progression of OA, consuming diets shown to have anti-inflammatory effects may be an important step in preventing and halting the progression of the disease. In fact, even a single meal high in calories, fat, and highly palatable carbohydrates can induce an acute inflammatory response,8possibly contributing to flare-up and pain in OA.


The Standard American Diet is characterized by a high intake of processed meat, refined sugars, saturated fat, little fiber, and high arachidonic acid. This dietary pattern triggers the release of proinflammatory cytokines and reduce the production of anti-inflammatory cytokines.9Consuming trans fats from cakes, cookies, pie crusts, biscuits, margarine, and commercially fried foods have been shown to increase biomarkers of inflammation, specifically CRP and IL-6, especially in people who are overweight.10,11Focusing on whole unprocessed foods appears to be the most prudent strategy. One study using an inflammatory food index found that an anti-inflammatory diet consisting of foods rich in fish, fruits and vegetables, and olive oil was associated with lower levels of CRP.12

Specific Nutraceuticals to Mitigate Joint Degeneration and OA Progression

The other part of the equation is offering patients options that have been clinically proven to be effective for OA. Glucosamine sulfate and chondroitin sulfate are two nutraceuticals that are structural building blocks of the GAG polymers found in cartilage that play key roles in absorbing water, contributing to greater joint space, cartilage volume and give cartilage its ability to compress and decompress from forces and friction encountered throughout the day.13 Glucosamine sulfate and chondroitin sulfate at low-molecular weights (<17,000 kD) have also shown potent anti-inflammatory action by modulating the COX-1 and COX-2 pathways, and the ability to decrease cartilage degradation markers in human OA studies.

In a 2008 study published in the Journal of Orthopedics Traumatology, 104 patients diagnosed with OA of the hands, knee or hip were evaluated on pain scores (VAS), radiographic imaging and had biomarkers of cartilage degradation measured via urinary C-terminal crosslinking telopeptides of type II collagen (uCTX-II), and bone degradation measured via urinary C-terminal cross-linking telopeptides of type I collagen (uCTX-I). Scientists used these tests to evaluate the structural progression of OA and potential therapeutic efficacy of glucosamine sulfate and chondroitin sulfate. All measures were taken at baseline, 6 months and 1 year to gauge progression. After 6 months and 1-year they found the uCTX-I and uCTX-II markers were significantly lower in the glucosamine sulfate and chondroitin sulfategroups, along with VAS scores, compared to baseline measures. Radiographic evaluation showed a reduced progression in the hand OA group after 1 year. The authors concluded that glucosamine sulfate and chondroitin sulfatein combination can provide a protective effect in OA patients and shows evidence that they slow the progression of OA.14

Other notable clinical trials include a randomized, double-blind, placebo-controlled study called the GAIT Trial, which is the largest NIH funded study on joint health supplements to date. In the trial GS and CS where evaluated individually and in combination and compared to celecoxib for therapeutic efficacy.  In the study 1,583 OA patients were evaluated and it was found that those who received the most benefit in the moderate to severe pain group were given 1500 mg/day of glucosamine sulfate and 1200 mg/day of chondroitin sulfate. The study ran for 2-years with patients receiving a daily dose of glucosamine sulfate and chondroitin sulfate. Initial conclusions found no benefit for mild OA, however upon secondary analysis in the moderate to severe OA pain group glucosamine sulfate and chondroitin sulfatewas found to not only be effective for pain reduction but outperform celecoxib at the doses mentioned.15

In another randomized, double-blind, placebo-controlled study,called the MOSAIC Trial, 194 OA patients at five medical centers in Quebec were enrolled to gauge the efficacy of low-molecular weight chondroitin sulfatein comparison to celecoxib. Half of the patients received 1200 mg/day chondroitin sulfateand half received 200 mg/day of celecoxib over a 2-year period. Three MRIs, a clinical assessment, and WOMAC score were used to assess structural changes. These evaluation methods were done at the beginning, one year in and the end of the study. Loss of cartilage was a primary assessment. It was found that the chondroitin sulfatepatients had much slower progression of OA in comparison to celecoxib group. Both treatments were equal in pain reduction, maintaining function, joint stiffness, joint swelling and both improved symptoms by 50%. The authors noted the positive outcomes with chondroitin sulfate, as well as the fact that chondroitin sulfate doesn’t carry the risk of side effects as anti-inflammatory medications.16

Another randomized, double-blind, placebo-controlled study, called the CONCEPT Trial, compared celecoxib therapy to low-molecular weight chondroitin sulfate. Over 600 OA patients received either 800 mg/day of chondroitin sulfateor celecoxib. The study found 800 mg/day of low-molecular weight chondroitin sulfateto be superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee OA patients. The authors concluded that this formulation of chondroitin sulfateshould be considered a first-line treatment in the medical management of knee OA.17

Finally, a study recently just published in Diabetes Carein January 2020. Found an association between glucosamine users and a lower incidents of Type 2 Diabetes (T2D). Since glucosamine is a glycosaminoglycan (GAG), the authors were looking to see if there was an association between glucosamine supplement use and an increase occurrence of diabetes. Previous scientific commentaries on glucosamine have hinted at glucosamine being avoided in the general population, and by diabetics, due to “possible” negative blood sugar consequences that would worsen insulin sensitivity and contribute to the onset or worsening of diabetes.

This study shows however that glucosamine may actually be protective against or hinder the onset of diabetes. The study analyzed over 400,000 individuals that had data input into the UK Biobank who were free of diabetes, cancer and cardiovascular disease at baseline (8 years prior). The authors then evaluated the association between glucosamine supplementation and risk of incident of Type 2 Diabetes (T2D). After adjusting for age, sex, BMI, race, lifestyle factors, history of disease, genetics and other supplement use they found that glucosamine was associated with significantly lower risk of T2D. The really exciting part was that that they found the strongest association in those that had the highest inflammatory levels of C-reactive protein (hs-CRP).18

How could a sugary protein possibly influence a metabolic disease like T2D? While most of us think about glucosamine as simply a “building block” in cartilage, pharmaceutical-grade glucosamine (low molecular weight) actually has a robust anti-inflammatory mechanism that is overlooked.19 This anti-inflammatory mechanism is most likely why glucosamine displayed such a strong association of less incidents of T2D in those with higher hs-CRP levels. Inflammation can affect everything from our cell’s ability to metabolize sugar efficiently to our pancreas’s ability to produce insulin, leading to hyperinsulinemia.

Glucosamine’s anti-inflammatory action also makes it ideal as a chondroprotective, helping cartilage cells, that grow and reproduce very slowly, stay alive longer and thrive by decreasing the inflammatory signaling that damages the cells directly and inhibits the activation of a class of cartilage degrading enzymes called matrix metallopeptidases (MMPs).19

Quality is the key when it comes to recommending a glucosamine sulfateor chondroitin sulfate product. Martel-Pelletier (2015) showed discrepancies of chondroitin quality and ranging levels of efficacy due to quality. It was found that low-molecular weight chondroitin sulfateis the only reliable form on the market, and larger chondroitin sulfate molecules could actually be pro-inflammatory in nature.20 Previous studies have also shown that large chondroitin sulfate molecules will not pass through the intestinal epithelium barrier, further contributing to the poor results of past trials with lower quality chondroitin sulfate. 

Glucosamine should be dosed at 1500 mg/day and chondroitin sulfate in combination at 800-1200 mg/day. Glucosamine does carry a precaution as a shellfish warning, and if pregnant or nursing it is recommended to consult a physician prior to use. Taking chondroitin in combination with glucosamine might increase the anticoagulant effects of warfarin (Coumadin) and increase the risk of bruising and bleeding as well. Generally both glucosamine sulfate and chondroitin sulfate are broken up to 2 or 3 daily doses and taken on an empty stomach.

References

  1. Neogi, T. (2013). The epidemiology and impact of pain in osteoarthritis. Osteoarthritis and Cartilage21(9), 1145-1153. 
  2. Castillo, S. (2016). The Burden of Musculoskeletal Diseases in the United States: Prevalence, Societal and Economic Cost (3rd Edition), United States Bone and Joint Initiative, NFP (USBJI) 
  3. Effects of Aging – OrthoInfo – AAOS. (2009), from https://orthoinfo.aaos.org/en/staying-healthy/effects-of-aging/
  4. O’Neill, T. and Felson, D. (2018). Mechanisms of Osteoarthritis (OA) Pain. Current Osteoporosis Reports,16(5), pp.611-616. 
  5. Andrew J. Kompel, Frank W. Roemer, Akira M. Murakami, Luis E. Diaz, Michel D. Crema, Ali Guermazi. Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Radiology,2019; 190341 
  6. Hamada D, Maynard R, Schott E, et al. Suppressive effects of insulin on tumor necrosis factor-dependent early osteoarthritic changes associated with obesity and type 2 diabetes mellitus. Arthritis Rheumatol. 2016;68(6):1392-1402
  7. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48(4):677-685.
  8. Emerson, S., Kurti, S., Harms, C., Haub, M., Melgarejo, T., Logan, C., & Rosenkranz, S. (2017). Magnitude and Timing of the Postprandial Inflammatory Response to a High-Fat Meal in Healthy Adults: A Systematic Review. Advances In Nutrition: An International Review Journal8(2), 213-225. 
  9. Clinton CM, O’Brien S, Law J, Renier CM, Wendt MR. Whole-foods, plant-based diet alleviates the symptoms of osteoarthritis. Arthritis. 2015;2015:708152.
  10. Mozaffarian D, Pischon T, Hankinson SE, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004;79(4):606-612.
  11. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005;135(3):562-566.
  12. Cavicchia PP, Steck SE, Hurley TG, et al. A new dietary inflammatory index predicts interval changes in serum high-sensitivity C-reactive protein. J Nutr. 2009;139(12):2365-2372.
  13. Tang, Y., Cui, Y., De Agostini, A., & Zhang, L. (2019). Biological mechanisms of glycan- and glycosaminoglycan-based nutraceuticals. Progress In Molecular Biology and Translational Science, 445-469. 
  14. Scarpellini, M., Lurati, A., Vignati, G. et al.Biomarkers, type II collagen, glucosamine and chondroitin sulfate in osteoarthritis follow-up: the “Magenta osteoarthritis study”. J Orthopaed Traumatol9, 81–87 (2008).
  15. Clegg, D., Reda, D., Harris, C., Klein, M., O’Dell, J., & Hooper, M. et al. (2006). Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. New England Journal Of Medicine354(8), 795-808. 
  16. Pelletier, J., Raynauld, J., Beaulieu, A., Bessette, L., Morin, F., & de Brum-Fernandes, A. et al. (2016). Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis Research & Therapy18(1). 
  17. Reginster J, Dudler J, Blicharski T, et al. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT)Annals of the Rheumatic Diseases2017;76:1537-1543.
  18. Ma, H., Li, X., Zhou, T., Sun, D., Liang, Z., & Li, Y. et al. (2020). Glucosamine Use, Inflammation, and Genetic Susceptibility, and Incidence of Type 2 Diabetes: A Prospective Study in UK Biobank. Diabetes Care, dc191836. 
  19. Jerosch, J. (2011). Effects of Glucosamine and Chondroitin Sulfate on Cartilage Metabolism in OA: Outlook on Other Nutrient Partners Especially Omega-3 Fatty Acids. International Journal Of Rheumatology2011, 1-17.
  20. Martel-Pelletier J, Farran A, Montell E, Vergés J, Pelletier JP. Discrepancies in composition and biological effects of different formulations of chondroitin sulfate. Molecules. 2015;20(3):4277–4289. Published 2015 Mar 6.

3 Ways Nutrition Can Help with Acute Pain and Inflammation

I know it’s been awhile since I’ve posted here. One reason is I’ve been busy with the launch of FunctionalMedicineCE.com a few months ago. We are hosting our second virtual symposium in a few weeks on February 29th. Dr. Frank Bodnar, DC is one of our speakers and he wrote this great post about ways we can use nutrition in inflammation and addressing pain. I hope this is beneficial to both pharmacists and patients out there as we journey on to healing together.

Dr. Hartzler

Pharmacists play a crucial role in treating acute pain and inflammation. If patients don’t head to the emergency room or urgent care center, their local pharmacy is certainly the next destination. The advantage as a pharmacist is that managing acute conditions doesn’t have to require a lengthy consultation or a complex workup. While providing clarity on the best over-the-counter analgesic to help manage acute symptoms is crucial, the value pharmacists can provide extends well beyond the normal transaction. You observe not only the grimaces, body language and postures of different pain issues but can offer an effective nutraceutical solution that targets the same biochemical pathway as traditional pharmaceuticals that a patient would otherwise never hear about.   

It’s fair to say that most pharmacists want the best for their patients’ health and are a highly trusted player on the patient’s health care team. Offering nutritional recommendations to a patient’s self-care acute pain strategy doesn’t have to be complicated. The most common traditional treatments of acute pain and inflammation reinforce blocking inflammation as the primary strategy. Nutraceuticals also have literature that show NFkB, PLA2, 5-LOX, COX-2 and COX-1 pathway modulation and clinical efficacy with a variety of inflammatory conditions.1-5

No clinician would disagree that controlling inflammation, reducing pain and improving a patient’s function as quickly as possible are good, ethical strategies. A patient-centered pharmacist understands not only the side effects and nutrient depletions but the best long-term healing mechanisms that should be considered as well. The value is more complete healing, less future pain and a satisfied patient that will let others know about their experience and your expertise.

Acute pain and inflammation can last anywhere from 1-3 days, with cardinal signs of heat, redness, swelling, pain and loss of function lingering a bit longer. Acute inflammation is driven by the body’s immune system responding to tissue injury and plays a key role in stimulating the pain signaling from the peripheral tissue. Local chemokines and pain hormones signal the initiation of vasodilation, white blood cell infiltration and clotting factors and immunoglobulins, soon followed by tissue regenerating cells such as fibroblasts. Biochemically we see acute-phase proteins such as C-reactive protein (CRP), cytokines, growth factors, eicosanoids, adhesion molecules and matrix metalloproteinases elevated.6If inflammation and free radical damage continues tissue injury and fibrosis can occur.7

The body does a great job of stopping the damage, cleaning the injured area and quickly beginning the repair process, and we want to support these processes as much as possible rather than just focusing on their inhibition. Emerging studies are showing that blocking the inflammatory response may result in delayed healing in bone in the short-term and possibly other connective tissues over the long run, possibly resulting in tissue that is at risk for future irritation and injury.8,9 Diet and supplementation have been shown to support healing and inflammatory mechanisms10 and offer a key strategy beyond resting, icing, compressing and elevating (RICE) an injury. 

During acute pain and inflammation there are three primary nutritional recommendations that can be incorporated to enhance your patient’s outcomes.

  1. 14-Day Anti-Inflammatory Diet: even with trauma, infection and surgery implementing a diet that focuses on fresh fruits, vegetables, nuts, seeds, anti-inflammatory fats and high-quality sources of protein can enhance the acute healing process and help reduce the potential for pain and inflammation to be further perpetuated. Omega-3 fatty acids, monounsaturated fatty acids, phytonutrients that are packed with antioxidants and natural anti-inflammatory compounds and lean proteins all play pivotal roles in reducing the inflammatory response and aiding in the healing process. The Anti-Inflammatory diet template and should include high amounts of nutrient dense foods:
    1. Protein: Fish, lean meat (beef, chicken), omega-3 eggs, high-quality rice and pea protein powders
    1. Green leafy and cruciferous vegetables: kale, collard greens, spinach, red cabbage, beets, watercress, romaine lettuce, cauliflower, broccoli, artichokes and brussels sprouts
    1. Healthy fats: avocado, olive oil, coconut oil and see list of nuts and seeds
    1. Fruits (high in antioxidants and fiber): strawberries, blueberries, blackberries, raspberries, cranberries, red or purple grapes, kiwi, pineapple, grapefruit, apples, pomegranate, mango, oranges, apples, papaya and cherries
    1. Tubers and others: sweet potatoes, carrots, acorn squash and butternut squash, zucchini, beans, olives, tomatoes, peppers, onions and garlic
    1. Nuts and seeds: almonds, pistachios, walnuts, cashews, pecans, macadamia, brazil nuts, and hazelnuts 
  • Whole Turmeric Matrix Supplementation: 500 – 1,000 mg/day for 14 days

The phytochemical analysis of turmeric has revealed that there are 200-plus bioactive molecules present in the natural matrix of turmeric that contribute to its health benefits. The main constituents are the curcuminoids, which include curcumin, demethoxy curcumin and bis-demethoxy curcumin. In addition to this, the non-curcuminoid components like turmerin, turmerones, elemene, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone11-14all showing the ability to reduce pain and inflammation separate from curcumin.15,16,19-23The broad-spectrum of bioactives mechanistically go above and beyond the primary targets traditional therapies (COX-2, 5-LOX and TNF-α). Whole turmeric root modulates NFkB and pretty much every downstream cytokine and growth factor resulting in less COX-2 activation, MAPK p38 pathway modulation and iNOS expression,12,13which for a patient means less pain, less inflammation and less swelling. Recently, scientists have discovered that the microbiome metabolizes these bioactives and they enhance the anti-inflammatory signaling capacity of turmeric’s bioactives. Studies show turmeric’s bioactives increase microbiome diversity, inhibit and protect the body from LPS-induced inflammation,17fortifying enterocyte tight junctions and increasing afferent vagus nerve signaling.18These broad mechanisms provide a range of benefits that truly match the mechanistic needs of arthritic joints beyond a wear and tear, and local inflammatory approach. 

Multiple double-blind, placebo-controlled clinical trials of osteoarthritis and rheumatoid arthritis patients have shown not only a decrease in pain, increase in joint function, and improved inflammatory and autoimmune biomarkers, but have also outperformed NSAIDs in head-to-head trials.15,19-23

  • Flavonoid and Bromelain Supplementation Recommendation: Bromelain 240 mg (576 GDU)/day, Quercetin Dihydrate 240 mg/day, and Rutin 50 mg/day for 14 days. 

Bromelain is a mixture of enzymes found in the stem of the pineapple (Ananas comosus) that exhibit proteolytic characteristics. Bromelain also supports the chondrocyte’s normal cell cycle via the p53, NFkB and Bcl-2 pathways, and balances IL-1B, IL-6, INF-y, TNF-α cytokines via PGE-2 and COX-2 activity during normal local immune responses. Locally bromelain modulates plasma kinins and fibrin/fibrinogen proteins via MMP, VEGF, bFGF, and EGF activity which all contribute to normal vascular and blood supply to connective tissue and prevent excess fibrosis.24

  • A randomized, double-blinded, placebo-controlled study done on performed on 176 boxers found that bromelain supported exercise recovery with notable improvements in bruising on the face and orbits, lips, ears, chest and arms in as little as four days compared to placebo.22
  • A 2017 randomized clinical study published in Rheumatology and Orthopedic Medicine, compared standard medical therapies to proteolytic enzyme therapy in 74 patients with acute joint pain. Patients were evaluated with joint outcome measures, VAS score, hs-CRP, ESR, and liver (ALT, AST) and kidney (creatinine) markers. The results showed that bromelain lowered hs-CRP, ESR improved joint function scores and while keeping normal liver and kidney function and showing no damage the gastric mucosa.23

Quercetin is a powerful antioxidant flavonoid in plants including oak trees, onions and tea. Cell studies show quercetin inhibits COXs and LOX enzymes which produce prostaglandins and leukotrienes; reduces inflammatory pain by inhibiting oxidative stress and cytokine production; LPS-induced TNF-a, IL-8, IL-1a release; prevents mast cell release of histamine and inhibits adhesion molecules such as VCAM-1.25Similar to turmeric quercetin has also been shown to support barrier function in the intestines,26,27modulate NFkB, MAP kinases and inhibit hyaluronidases and MMPs, which are degradatory connective tissue enzymes.25

  • A 2019 meta-analysis combined the data of six randomized controlled trials consistent improvements in the acute-phase biomarker, hs-CRP, and while other cytokines such as IL-6 and TNF-a were found to be decreased in individual studies a statistical significance wasn’t reached in the combined data. Overall the authors concluded that quercetin supplementation for pain and inflammation is a promising therapeutic.28

Rutin is a flavonol found abundantly in plants such as apples, tea, buckwheat and passionflower. Rutin supports connective tissue health by inhibiting the enzymes hyaluronidase, collagenase, LOX and COXs, which all contribute to the degradation of connective tissue, and exhibits neuroprotective, analgesic, antiarthritic, broad-spectrum anti-inflammatory support and speeds wound healing in vitro.29

  • A meta-analysis of six randomized controlled trials published in the Journal of Pain Research, compared 270 knee patients who received a combination of rutin and bromelain (OEC) to 266 standard patients who received standard medical therapy. The authors found OEC to be comparable for efficacy while tolerable and safe.30

References:

  1. Al-Okbi, S. (2012). Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis. Toxicology and Industrial Health30(8), 738-749. 
  2. Sevda Inan (2019). The Potential Role of Nutraceuticals in Inflammation and Oxidative Stress, Nutraceuticals – Past, Present and Future, María Chávarri Hueda, IntechOpen, DOI: 10.5772/intechopen.83797.
  3. Gupta, S., Prasad, S., & Aggarwal, B. (2016). Anti-inflammatory Nutraceuticals and Chronic Diseases(1st ed., pp. 1-25). Cham: Springer International Publishing.
  4. Al-Okbi, S. (2012). Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis. Toxicology and Industrial Health30(8), 738-749.
  5. Ravalli S, Szychlinska MA, Leonardi RM, Musumeci G. Recently highlighted nutraceuticals for preventive management of osteoarthritis. World J Orthop 2018; 9(11): 255-261
  6. Jain, S., Gautam, V., & Naseem, S. (2011). Acute-phase proteins: As diagnostic tool. Journal of pharmacy & bioallied sciences3(1), 118–127. doi:10.4103/0975-7406.76489
  7. Edwards, S. (2020). Pathophysiology of Inflammation – Pharmacology – Manual. Retrieved 10 Jan. 2020, from https://www.merckvetmanual.com/pharmacology/anti-inflammatory-agents/pathophysiology-of-inflammation
  8. Su, B., & O’Connor, J. (2013). NSAID therapy effects on healing of bone, tendon, and the enthesis. Journal of Applied Physiology115(6), 892-899. doi: 10.1152/japplphysiol.00053.2013 
  9. Serra, M., et al. (2017). From Inflammation to Current and Alternative Therapies Involved in Wound Healing. International Journal of Inflammation2017, 1-17. doi: 10.1155/2017/3406215
  10. Seaman, D. (2017). An Anti-inflammatory Diet for Pain Patients. Retrieved 10 February 2020, from https://www.practicalpainmanagement.com/treatments/complementary/anti-inflammatory-diet-pain-patients
  11. Suzuki, M and T Nakamura. “Elucidation of Anti-Allergic Activities of Curcumin-Related Compounds with a Special Reference to their .” Biol. Pharm(2005): 1438-1443 
  12. Panahi, Y., Darvishi, B., Ghanei, M., Jowzi, N., Beiraghdar, F., & Varnamkhasti, B. (2016). Molecular mechanisms of curcumins suppressing effects on tumorigenesis, angiogenesis and metastasis, focusing on NF-κB pathway. Cytokine & Growth Factor Reviews, 28, 21-29. 
  13. Camacho-Barquero, L., Villegas, I., Sánchez-Calvo, J., Talero, E., Sánchez-Fidalgo, S., Motilva, V., & Alarcón de la Lastra, C. (2007). Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. International Immunopharmacology, 7(3), 333-342. 
  14. Kumar S, Ahuja V, Sankar MJ, Kumar A, Moss AC. Curcumin for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev(2012 Oct 17;10:CD008424.
  15. Daily, J and Mini, Park, S Yang. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trial. Journal of Medicine Food(2016): 717-729
  16. Amalraj, A, K Varma and Joby Jacob. “A Randomized, Double Blind, Placebo-Controlled, Two Dose, Three Arm, and Parallel-Group Study.” Journal of Medicinal Food(2017): 1022-1030
  17. Peterson, C., Vaughn, A., Sharma, V., Chopra, D., Mills, P., Peterson, S., & Sivamani, R. (2018). Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Journal of Evidence-Based Integrative Medicine, 23, 2515690X1879072. doi: 10.1177/2515690×18790725
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