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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.

Sub-Acute Pain and Healing Support with Nutraceutical and Lifestyle Recommendations

Pain is the number #1 reason why people enter the system. Pharmacists get questions about pain management strategies on a daily basis regardless of their setting. This is one of the reasons we choose pain and inflammation to be our next symposium topic for FxMedCE.com. We want more providers to understand the types of pain and how to help our patients. I hope you enjoy another great blog post from Dr. Frank Bodnar, DC. He is will be one of the speakers, make sure you sign up to hear from him as well as others who have spoken across the globe. Continuing Education Credit is available for Pharmacists and Certified Nutrition Specialists (CNS). Others are welcome to join!

Dr. Hartzler

One of the most overlooked phases of pain and healing is the sub-acute phase. There’s some uncertainty about how to best approach sub-acute pain from a pharmacist’s perspective since it’s not really acute, and it’s not chronic. Often this puts patients in a “no-man’s-land” of self-management with no clear direction of where we want them to go and why, so patients do what they’ve always done. They go back to the medicine cabinet for another pain reliever. 

Helping patients navigate the middle ground of pain and healing presents a fantastic opportunity where pharmacists can help prevent the cycle of pill dependency for pain. This shift allows the body to do the healing. After all the injury didn’t occur by a deficiency in ibuprofen or acetaminophen and won’t fully support the body’s middle phase of structural healing if the cycle continues. The cycle of dependency may lead the patient down a road of more potent like a cortisone injection or even a prescription opioid. Pharmacists can alter this trajectory.

The majority of the time the sub-acute phase of care is treated with the exact same approach as an acute phase, despite there being clear physiologic differences. It’s understandable that there is some overlap between the acute and sub-acute phases and major guidelines may overlook the need for a different approach.  

Traditionally the American College of Physiciansrecommends a number of both pharmaceutical and non-pharmaceutical options for sub-acute low back pain,1and within the realm of therapies available there are a number of other options available as well:

  • Cryotherapy
  • Heat
  • Electrotherapy
  • Ultrasound
  • Low level laser
  • TENS Machine
  • Electrical Stimulation
  • Spinal manipulation
  • Massage
  • Acupuncture
  • Dry needling
  • Kinesio taping
  • Instrument assisted soft tissue mobilization
  • Exercise rehabilitation
  • Anti-inflammatory drugs
  • Topical analgesic 
  • Skeletal muscle relaxants

While all of the therapies listed above are traditionally appropriate in the management of sub-acute pain and healing, they are primarily focused on symptom management and leave out nutrition completely. Healing is a complex process that requires proper key nutrients for inflammatory control, new tissue formation, and tissue remodeling to occur within a specific time frame to get back to optimal function. Simply reaching for the bottle in the medicine cabinet isn’t sufficient.

In some cases, all three phases of the healing process may take 12-18 months to be fully completed depending on the tissue type and injury severity.2Managing patient expectations is an essential part of pain management. If patients understand the phases of healing and goal of therapies at each phase, you can begin to provide the roadmap to a pain-free future.

During sub-acute pain the focus of the body with many injuries is connective tissue repair and rebuilding structural integrity. Connective tissue regeneration and repair begins with fibroblasts producing type I and type III collagen fibers, which are randomly orientated, immature, and weak in comparison to the well-organized, dense fibers of type I collagen. Depending on the structure, type II collagen and extracellular matrix material like hyaluronic acid and other polysaccharides help to aggregate, organize and allow proper structure movement to occur.3

The remodeling phase requires gradual collagen and connective tissue cross-linking, which is dependent on the vital cofactor vitamin C. Vitamin C activates hydroxylases, allowing proper collagen fiber assembly and helical structure formation to occur.4If connective tissue alignment and aggregation is limited, collagen fiber orientation remains disorganized and overall function remains limited. This area will likely be a site of reinjury, and vitamin C plays a key role in preventing this.5

Clinical studies on nutraceuticals as bioactive collagen peptides, type I collagen, hyaluronic acid and essential cofactors for collagen formation have shown they not only reduce rehabilitation time, but also endogenously stimulate chondrocytes, fibroblasts and synovial cells to produce their native raw materials. In addition, these studies also show reduced cytokines such as IL-1β, which stimulate a class of connective tissue-degrading enzymes called matrix metalloproteinases (MMPs) .6-8Structural support and inflammatory support at the cellular level are essential to reducing the risk of re-injury in all connective tissues.

The best nutraceuticals to offer patients during a sub-acute pain episode is a combination of high-quality type I and type II collagen peptides, hyaluronic acid, mucopolysaccharides, vitamin C and magnesium. These nutrients cover over 90% of the connective tissue in the body and undoubtedly would enhance he sub-acute phase of healing and repair. Not only do they support the connective tissue cells, the process of protein synthesis and collagen cross-linking but they also have clinical studies with positive clinical outcomes. Of course, sometimes simply offering an alternative to a muscle-relaxer may be appropriate as well. 

Tendinopathies are largely an overuse injury and represent a good example of what will also support connective tissue regeneration and repair during a sub-acute phase of pain and healing. A 2014 study out of Barcelona and Madrid, Spain treated tendinopathy patients at multiple hospitals and sports rehabilitation clinics around the area with high-quality type I collagen peptide that also contained vitamin C, magnesium and naturally occurring mucopolysaccharides. A total of 98 patients with Achilles tendinitis, patellar tendinitis and lateral epicondylitis received a dose of 435 mg mucopolysaccharides, 75 mg type I collagen peptides and 60 mg of vitamin C for 90 days. Clinical symptoms improved by 38% (during activity and rest) on average and a decrease in tendon thickness was observed upon ultrasound evaluation – indicating less inflammation and tendon hypertrophy.9

There are valid options available that get results and support the body during the healing process and your patients should be aware. Below are some key evidence-based sub-acute pain and healing nutraceuticals:

NutrientDoseMechanism
GABA10250mg/day for 30 days Primary inhibitory neurotransmitter of the brain promotes relaxation and inhibits over-firing that results in muscle spasm and pain. Also shown clinically to improve sleep, promote alpha brain waves and improve REM sleep cycle. 
Glycine11225mg/day for 30 days Primary inhibitory neurotransmitter of the spinal cord promotes relaxation and inhibits over-firing that results in muscle spasm and pain, as well as promoting sleep quality. 
Cramp Bark12200mg/day for 30 days Anti-inflammatory and promotes smooth muscle relaxing effects. Not only effective for muscle spasms of the neck and low back but has shown effectiveness with menstrual cramping as well. 
Dong Quai Root Extract12150mg/day for 30 days Anti-inflammatory and promotes smooth muscle relaxing effects. Not only effective for muscle spasms of the neck and low back but has shown effectiveness with menstrual cramping as well.
Type I collagen peptides with mucopolysaccharides13-16500 mg/day for 90-180 days Type I collagen building block and stimulates tenocytes and fibroblasts to produce type I collagen in tendons, ligaments and skin. Clinical studies have shown improvement in medial and lateral epicondylitis, Achilles tendinitis and patellar tendinitis. 
Type II collagen peptides17-195 g/day for 90-180 days Type II collagen building block and stimulates chondrocytes and to produce type II collagen in cartilage and stimulates chondrocytes to endogenously produce more type II collagen.
Hyaluronic acid20-2240-80 mg/day for 90-180 days Increases hyaluronic acid concentration in synovial fluid and stimulates synoviocytes to increase HA production for joint and connective tissue hydration and lubrication. Clinical studies have shown improvements in pain scores, mobility and decreased synovitis in OA patients. 
Vitamin C23100 mg/day for 90-180 days Maximizes hydroxylases for optimal collagen and hyaluronic acid production and provides antioxidant support to optimize connective tissue healing, decreases histamine production, modulates immune response and new studies show potential reduction of pain.
Magnesium24135 mg/day for 90-180 days Co-factor for over 350 enzymes in the body, decreases chronic pain signaling via NMDA receptors, and shown to decrease pain in low back and headache patients. 

Supporting the body’s natural healing process is paramount and in some patients, this means digging a little deeper into lifestyle factors that can limit this process. The final missing variables in the sub-acute pain and healing equation is addressing the patient’s lifestyle by doing a quick evaluation of their stress levels and sleep quality. We know that the stress response can delay healing, and sleep is the primary time when the body is in repair mode. In a clinical trial published in Psychoneuroendocrinology, scientists looked at participants’ cortisol levels, perceived stress and health behaviors and how all of the factors affected wound healing. What they found was that cortisol had a considerable influence on wound healing independent of participants’ health behaviors. 25 

Multiple studies have also looked at sleep quality on healing, showing that poor sleep elevates cortisol, increases fatigue and errors made at work and results in worse patient health outcomes.26,27In one study the health of patients recovering in hospitals revealed that sleep was crucial for healing and survival of critically ill patients and greatly influenced the outcomes of patients suffering from a myriad of diseases. In fact, less sleep disruptions in critically ill patients showed much better outcomes in the literature compared to those with constant disruptions from health care practitioners during their recovery time.27       

Changing the patient’s perspective on pain and implementing easy nutrient and lifestyle recommendations doesn’t have to be a complicated process. There are cortisol tests and sleep study methods available, but many patients want an immediate solution that will allow them to improve immediately. Simply having a conversation about how to best serve a patient will reveal the best nutrient offering and implementing a 5-minute stress questionnaire can reveal how stress and sleep may be limiting the sub-acute healing process. Start by simply engaging patients and offering the best recommendation for their specific situation and you’ll put them on the path to letting he body do what it does best.

References:

  1. Qaseem, A., Wilt, T., McLean, R., & Forciea, M. (2017). Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine166(7), 514. 
  2. Reichert, W., Stroncek, J., & Reichert, W. (2008). Indwelling Neural Implants: Strategies for Contending With the in Vivo Environment (Frontiers in neuroengineering)(Chapter 1: Overview of Wound Healing in Different Tissue Types). Boca Raton, FL: CRC Press.
  3. Broughton, G., 2nd, J. E. Janis, et al. (2006). “The basic science of wound healing.” Plast Reconstr Surg 117(7 Suppl): 12S-34S
  4. DePhillipo, N. N., Aman, Z. S., Kennedy, M. I., Begley, J. P., Moatshe, G., & LaPrade, R. F. (2018). Efficacy of Vitamin C Supplementation on Collagen Synthesis and Oxidative Stress After Musculoskeletal Injuries: A Systematic Review. Orthopaedic journal of sports medicine6(10), 2325967118804544. 
  5. Ömeroğlu, S., Peker, T., Türközkan, N., & Ömeroğlu, H. (2008). High-dose vitamin C supplementation accelerates the Achilles tendon healing in healthy rats. Archives of Orthopaedic And Trauma Surgery129(2), 281-286. 
  6. Iwai K, Hasegawa T, Taguchi Y, Morimatsu F, Sato K, Nakamura Y, Higashi A, Kido Y, Nakabo Y, Ohtsuki K, 2005. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem, 53, 6531-6536.
  7. Oesser S, Adam M, Babel W, Seifert J, 1999. Oral administration of (14) C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). JNutr, 129, 1891-1895.
  8. P. Lundquist, P. Artursson . Oral Absorption of peptides and nanoparticles across the human intestine. Advanced Drug Delivery Reviews106 (2016) 256–276
  9. Arquer, A., et al. (2014). The efficacy and safety of oral mucopolysaccharide, type I collagen and vitamin C treatment in tendinopathy patients.
  10. Yoto, A., et al. (2011). Oral intake of γ-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks. Amino Acids, 43(3), pp.1331-1337. 
  11. Kawai, N., et al. (2014). The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus. Neuropsychopharmacology, 40(6), pp.1405-1416. 
  12. Nicholson, J. A., Darby, T. D., and Jarboe, C. H. Viopudial, a hypotensive and smooth muscle antispasmodic from Viburnum opulus. Proc.Soc. Exp Biol.Med. 1972;140(2):457-461) 
  13. Schunk M and Oesser S. Specific collagen peptides benefit the biosynthesis of matrix molecules of tendons and ligaments. J Int Soc Sports Nutr. 2013; 108. 
  14. Shakibaei M, Buhrmann C, Mobasheri A. Anti-inflammatory and anti-catabolic effects of TENDOACTIVE® on human tenocytes in vitro. Histol Histopathol. 2011 Sep;26(9):1173-85.
  15. Balius et al. A Randomized, Placebo-Controlled Study to Evaluate Efficacy and Safety of A Dietary Supplement Containing Mucopolysaccharides, Collagen Type I and Vitamin C for Management of Different Tendinopathies. Ann Theum Dis. 2014;73, Suppl. 2:299- 30018. 
  16. Proksch E, Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. Skin Pharmacol Physiol. 2014;27(3):113-9. doi: 10.1159/000355523. 
  17. McAlindon TE, Nuite M, Krishnan N, Ruthazer R, et al. Changes in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis and Cartilage19 (2011) 399e405 7.
  18. Zuckley L, Angelopoulou K, Carpenter MR: Collagen hydrolysate improves joint function in adults with mild symptoms of osteoarthritis of the knee. Medicine and Science in Sports and Exercise 2004, 36 (Supplement), 153 – 155. 
  19. Clark KL, Sebastianelli W, Flechsenhar KR, Aukermann DF, Meza F, Millard RL, Deitch JR, Sherbondy PS, Albert A: Long-term use of collagen hydrolysate as a nutritional supplement in athletes with activity-related joint pain. Curr Med Res Opin. 2008 May;24(5):1485-96.6.
  20. Torrent A, Ruhí R, Theodosakis J, et al. Comparative efficacy of IB0004, extracted hyaluronic acid (HA) and fermented HA on the synthesis of endogenous HA by human synoviocytes. Osteoarthritis Cartilage. 2009;17(Suppl 1):S278-79. – 10x HA secretion9. 
  21. Torrent A, Ruhí R, Martínez C, et al. Anti-inflammatoryactivity and absorption of a natural rooster comb extract. Osteoarthritis and Cartilage. 2010 Oct;18(Suppl 2):S246-47. 
  22. Möller I, Martinez-Puig D, Chetrit C. Oral administration of a natural extract rich in hyaluronic acid for the treatment of knee OA with synovitis: a retrospective cohort study. Clinical Nutrition Supplements2009;4(2):171-17211
  23. Carr, A., & McCall, C. (2017). The role of vitamin C in the treatment of pain: new insights. Journal of Translational Medicine, 15(1). doi: 10.1186/s12967-017-1179-7
  24. Na HS, Ryu JH, Do SH. The role of magnesium in pain. In: Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
  25. Ebrecht, M., Hextall, J., Kirtley, L., Taylor, A., Dyson, M., & Weinman, J. (2004). Perceived stress and cortisol levels predict speed of wound healing in healthy male adults. Psychoneuroendocrinology,29(6), 798-809. 
  26. Niu, S., Chung, M., Chen, C., Hegney, D., O’Brien, A., & Chou, K. (2011). The Effect of Shift Rotation on Employee Cortisol Profile, Sleep Quality, Fatigue, and Attention Level. Journal of Nursing Research19(1), 68-81. 
  27. Tembo, A., & Parker, V. (2009). Factors that impact on sleep in intensive care patients. Intensive and Critical Care Nursing25(6), 314-322. 

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
  18. Wang, J., Ghosh, S., & Ghosh, S. (2017). Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions. American Journal of Physiology-Cell Physiology, 312(4), C438-C445. 
  19. ZHAO, F., GONG, Y., HU, Y., LU, M., WANG, J., & DONG, J. et al. (2014). Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide: Translocation of nuclear factor-κB as potential target. Molecular Medicine Reports, 11(4), 3087-3093. doi: 10.3892/mmr.2014.3079
  20. Rathnavelu, V., Alitheen, N., Sohila, S., Kanagesan, S., & Ramesh, R. (2016). Potential role of bromelain in clinical and therapeutic applications. Biomedical Reports, 5(3), 283-288. 
  21. Pavan, R., Jain, S., Shraddha, & Kumar, A. (2012). Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International, 2012, 1-6. 
  22. Blonstein JL, Practitioner, Control of swelling in boxing injuries. 01 Aug 1969, 203(214):206].
  23. LS, M., M, et al. (2017). Efficacy of a combination of fixed doses of serratiopeptidases, bromelain and methylsulfonylmethane in inflammatory joint diseases. Rheumatology And Orthopedic Medicine, 2(3).
  24. Pavan, R., Jain, S., Shraddha, & Kumar, A. (2012). Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International, 2012, 1-6.
  25. Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M., & Wang, S. et al. (2016). Quercetin, Inflammation and Immunity. Nutrients,8(3), 167.
  26. Lee, B., Moon, K., & Kim, C. (2018). Tight Junction in the Intestinal Epithelium: Its Association with Diseases and Regulation by Phytochemicals. Journal of Immunology Research, 2018, 1-11.
  27. Amasheh M, et al. Quercetin enhances epithelial barrier function and increases claudin-4 expression in Caco-2 cells. J Nutr2008 Jun;138(6):1067-73.
  28. Ou, Q., Zheng, Z., Zhao, Y., & Lin, W. (2019). Impact of quercetin on systemic levels of inflammation: a meta-analysis of randomised controlled human trials. International Journal Of Food Sciences And Nutrition, 1-12.
  29. Ganeshpurkar, A., & Saluja, A. (2017). The Pharmacological Potential of Rutin. Saudi Pharmaceutical Journal, 25(2), 149-164.
  30. Ueberall, M., Mueller-Schwefe, G., Wigand, R., & Essner, U. (2016). Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials. Journal Of Pain Research, (9), 941-961.