Research Review By Dr. Colin O’Brien©


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Date Posted:

December 2015

Study Title:

Dietary influence on pain via the immune system


Totsch SK, Waite ME & Sorge RE

Author's Affiliations:

Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA

Publication Information:

Progress in Molecular Biology and Translational Science 2015; 131: 435-469.

Background Information:

Chronic pain is an extremely prevalent symptom in the Western world, with an estimated 30% of the North American population being affected. The total annual costs of chronic pain in the USA are projected as high as $625 billion per year (!) when considering lost productivity at work, legal costs, treatment costs and other factors (1). This often-debilitating concern has implications not only for public health, but also for personal quality of life. Chronic pain can cause significant strain on relationships, finances, mental-emotional health, productivity and, ultimately, fulfillment of life.

Despite the vast negative outcomes associated with chronic pain, its treatment and ongoing resolution is largely unsatisfactory. Even with advances in analgesic medications, physical therapies, injections and procedures, it is still rare to achieve the complete elimination of pain.

While many factors are known to contribute to the development of chronic pain (including trauma, psychosocial considerations, peripheral and central sensitization), one commonality in chronic pain sufferers is the presence of pro-inflammatory cytokines in blood samples. Understanding the factors that result in a shift of immune activity toward pro-inflammatory pathways and away from neutral or anti-inflammatory pathways is crucial for the long-term management of chronic pain.

Th1 cells tend to be mainly pro-inflammatory in nature (leading to IL-2, IFN-gamma and Tumor Necrosis Factor-alpha [TNF-α]) while Th2 cells are generally anti-inflammatory (leading to mainly IL-4 and IL-10 release). When testing for widespread inflammation, C-reactive protein (CRP) has been recognized as a predictable marker, while TNF-alpha has been found to be elevated in those with widespread pain and neuropathic pain (2, 3). It has also been established that anti-inflammatory cytokines are decreased in these same populations. Therefore, it may be a dual action involving the imbalance of “good” and “bad” cytokines that aggravates chronic pain sufferers (2, 3).

With this in mind, a shift in the understanding and focus of chronic pain treatment is necessary. Environmental factors such as diet must also be considered in its progression or resolution. The aim of this review paper was to examine the effects of various foods on immune cells and, ultimately, the implications of these immune activators on chronic pain.


Few foods have been directly studied for their effects on chronic pain in humans, via immune cell activation. However, the following foods have been studied within these circumstances:

Omega 3 Fatty Acids: In humans with rheumatoid arthritis, 24 weeks of supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduced IL-1 secretion by as much as 54% and also reduced number of tender joints and swollen joints as early as 12 weeks. Other studies have found omega-3 supplements to decrease IL-6 and TNF-alpha after 16 weeks (54). Also serum levels of Omega-3 are inversely related to IL-6, CRP and TNF-alpha.

Soy Products: One human study found that 3 months of soy protein consumption in osteoarthritis sufferers led to reduced pain and increased range of motion.

Carotenoids: Lycopene, the well-known active ingredient found in tomatoes, is the most established carotenoid for impacting immune inflammatory markers. Tomato drink has effectively reduced TNF-alpha in human blood samples, as well as decreased COX-2 expression. However, only one human trial has evaluated lycopene and pain. It was found to reduce bone pain in patients with prostate cancer and reduced the need for analgesic use in these same patients.

Ginger: In healthy controls, ginger has been found to reduce muscle soreness and muscle pain after exercise. In addition, ginger is effective for reducing pain associated with moderate and severe dysmenorrhea and osteoarthritis. From the perspective of immune modulation, it has been shown to suppress TNF-alpha, IL-6 and CRP levels in type 2 diabetes mellitus.

Curcumin: Curcumin has been shown to suppress NFkB, IL-1β, TNF-alpha and IL-8, while also reducing pain in osteoarthritis patients. Curcumin is the active anti-inflammatory ingredient found in turmeric spice. However, only a very small proportion of turmeric root is curcumin and it is notorious for its poor bioavailability.

Ginseng: One small human trial found that ginseng was as effective as other common analgesics in fibromyalgia sufferers.

Gluten and Whole Grains: In patients with celiac disease and comorbid fibromyalgia syndrome, a full year of a gluten-free diet decreased pain and fatigue symptoms. However, while gluten may aggravate pain in those with celiac disease, there is correlational evidence showing that humans with high levels of whole grain or bran in their diet tend to have lower levels of TNF-alpha and CRP in their blood.

Fasting, Vegetarian and Vegan Diets: A fasting period followed by a 1-year vegetarian diet reduced pain, swollen joints, tender points and CRP levels in patients with RA. These improvements were noted after only 4 weeks of diet implementation. A separate study on fibromyalgia syndrome patients showed reduction of pain after only 3 months of a vegan diet.

Caloric Restriction: In those with OA, reductions in pain and IL-6 levels were noted after caloric restriction and exercise. It is worth noting that caloric restriction was responsible for a greater effect on pain than exercise, irrespective of weight loss.

Many specific foods and diet types have been directly associated with immune cell responses or changes in pain measures, but not necessarily both within the same study. Collectively, various studies have found strong implications for either the up or down regulation of inflammation and pain via dietary interventions. These foods and diets include the following:

General Comment on Obesity: Adiposity is known to release leptin, a hormone that activates the immune system and causes release of proinflammatory cytokines. Therefore, it should not be surprising that high adiposity was found to directly correlate with elevated CRP levels. Obesity has been linked to pain in weight bearing and non-weight-bearing joints, suggesting that increased pressure and sustained loads on the joints is not the only mechanism involved (21, 22). Weight loss has also been shown to reduce CRP and TNF-alpha levels (39-41).

“Western” vs. “Mediterranean” Diet: Three months of a “Mediterranean diet” (unrefined carbohydrates, nuts, fish, and olive oil) reduced IL-6 and CRP levels. A separate study found implementation in females with rheumatoid arthritis to reduce pain after 3-6 months.

Saturated Fats: High in dairy and meat, this fat type increases inflammatory cytokine gene expression directly via toll-like receptor 4 (TLR4) expression. Interestingly, animal studies have found that polyunsatured fatty acids (such as omega-3, 6 and 9 fats) were able to “block” the inflammatory activation of the TLR4 and COX-2 pathway.

Proanthocyanidins: These anti-oxidant and anti-inflammatory agents are the active ingredients found in grape seed extracts and bilberry. One study found that in those with symptoms of metabolic syndrome, a diet rich in bilberries reduces CRP, IL-6 and IL-12 levels. No human clinical trials have measured the impact of proanthocyanidins on pain.

Green tea extract: To date, only experimental pain models in animals have shown benefit of green tea and its active component, epigallocatechin gallate (ECGC), on chronic pain measures. However, human research has shown that high amounts of ECGC and green tea are well tolerated.

Broccoli (and broccoli extracts): Broccoli contains the active ingredient isothiocyanate sulforaphane, which has been extensively studied in experimental pain models in animals and found to produce anti-inflammatory activity via multiple mechanisms of the immune system. However, there are no human trials to date on the effect of broccoli extracts in chronic pain.

Clinical Application & Conclusions:

Dietary intake clearly has an impact on the human immune system and inflammatory immune cells. It is appropriate to consider that dietary factors may be impacting the course of chronic pain by either preventing recovery or aggravating current injury.

Given the extremely high safety profile of such dietary interventions, it is reasonable to include basic dietary suggestions in all chronic pain patients. These interventions may be as simple as one or all of the following:
  • Reduce animal fat and consider the benefits of a more plant-centric diet
  • Increase daily omega-3 fatty acid intake through fish, flax seeds and high-quality nutritional supplements
  • Increase daily intake of green tea, broccoli, ginger, soy, grapes, berries and whole grains
  • Eat closer to a “Mediterranean” diet as opposed to a “Western” diet by including more nuts, fish and olive oil, and less refined sugars
  • Work with qualified practitioners to reduce adiposity levels through diet and exercise, thereby reducing the expression of pro-inflammatory signals within the body
  • Consider testing for celiac disease if other signs and symptoms of gluten intolerance present, such as chronic diarrhea, weight loss, anemia or fatigue (4)
While strong clinical and interventional research has yet to elucidate the impact of many of these dietary changes on chronic pain, as a worst-case scenario, their implementation should result in widespread health improvements beyond the immune system. Superior cardiovascular health, improved cognitive health and cancer prevention are just a few examples of better established outcomes from many of the above-mentioned dietary alterations (5).

Study Methods:

This was a traditional narrative literature review. It cannot be considered a systematic review, as it made no attempt to be systematic in the formulation of questions, the search for relevant evidence or the summary of the evidence. For example, no mention was given as to the search criteria, search terms utilized, or types of databases used. It is clear that the authors’ goal was to simply review all obtainable research within the realm of this topic and no exclusion criteria were considered.

Study Strengths / Weaknesses:

This literature review did an excellent job of summarizing much of the relevant data in the connection between diet, immune system activation and pain. However, limited available research in many areas does limit the applicability of much of the information. For example, some foods only have in vitro and animal research that exhibit an anti-inflammatory action via the immune system and, as a result, conclusions that these foods have a positive effect on pain measures in humans are only speculative and do not take into account the many complexities of the human body.

Many other limitations exist with this review, including the following:
  • inconsistent mention of participant numbers in studies
  • lack of proper methodological descriptions
  • high variability and inconsistency of study design, including very few double-blinded, randomized controlled trials
  • high probability of convenience sampling
  • no mention of demographic characteristics for almost all studies
  • no mention of these many limitations within the discussion or conclusion portion of the research summary
On the whole, this study serves as an introductory look at the connection between diet, the immune system and pain without meeting the rigorous research standards needed to truly validate the many dietary associations. Although it offers a unique perspective of pain treatment, it is clear that higher quality research must be done in the future to better establish the connection of diet and pain. Interventional trials with crossover methods, subjective and objective markers of pain, and peer evaluation are necessary to validate these many preliminary findings.

Additional References:

  1. Dansie EJ and Turk DC. Assessment of patients with chronic pain. Br J Anaesthesia 2013; 111(1): 19–25.
  2. Uceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006; 54(8): 2656–2664.
  3. Uceyler N, Rogausch JP, Toyka KV, Sommer C. Differential expression of cytokines in painful and painless neuropathies. Neurology 2007; 69(1): 42–49.
  4. Unknown author (May 2015). About Celiac Disease. Retrieved from
  5. Serra-Majem L, Roman B, Estruch R. Scientific evidence of interventions using the Mediterranean diet: a systematic review. Nutr Rev 2006 Feb; 64(2 Pt 2): S27-47.