beyond reason
우리는 흔히 통증이 있을때 어딘가를 다쳐서 발생한다고 단순하게 생각할 수 있다.
통증은 어딘가 손상을 입을때만 발생하는 것이 아니라 '스트레스, 수면부족, 과도한 운동, 염증을 악화시키는 식사'로 인해 만성미세염증(chronic microinflammation)이 일어난다. 그 외에서 POPs(persistent organic pollutants), 중금속(수은, 비소, 납, 카드뮴) 중독 등이 만성미세염증의 원인임.
아래 논문은 이 문제를 해결하기 위한 통찰을 제공한다.
만성염증과 함께 분비되는 염증매개물질들 : C-reactive protein(CRP), Cytokine(사이토카인 단백질), growth factors(성장인자), eicosanoids, adhesion molecules, matrix metalloptoteinase
Eicosanoids에 대하여
1) COX1, COX2 : 프로스타글란딘, 트롬복산
2) LOX : 류코트리엔
스트레스는 직접적으로 염증에 영향을 줌
스트레스와 eicosanoids의 관계는 잘 밝혀져 있지 않음.
염증을 일으키는 조건 : 손상, 스트레스, 수면부족, 운동과다, 염증야기 음식
염증매개 세포 : neutrophils, lymphocytes, macrophages, platelets, fibroblast, endothelial cell
염증 촉진 - 류코트리엔, 프로스타글란딘, 트롬복산, 히스타민, 인터류킨, tnf, 성장인자
염증 억제 - LTB5, PGE1, 2, Lipoxin, resolvins, maresins, TXA1,3, IL-1O, Opioids
물질 P --> NF-kB --> 신경염증 --> 통증
염증촉진 음식과 염증반응기전
1) 설탕, 사탕, 음료수, 빵, 과자, 밀가루음식, 시리얼 등 혈당을 높이는 음식 - 산화스트레스 증가, 교감신경 흥분, 염증야기
2) 오메가 6지방이 많은 지방, 트랜스지방 - 염증성 사이토카인, eicosanoids증가, LDL콜레스테롤 증가, 염증야기
3) 마그네슘섭취 부족 - ATP감소, 활성산소증가, 흥분성 자극 증가, 염증야기
4) 포타슘 섭취부족 - 저산소, 활성산소증가, 인슐린저항성 증가, 산성화, 염증야기
5) phytonutrient 섭취부족(야채, 녹황색채소 섭취부족) - 활성산소증가, 염증야기
6) 장내유해균 - LPS증가, 염증야기
7) 비타민 d 결핍 - 항염증 IL-10감소, 염증야기
염증제거 음식
1) 생선, 고기, 오메가 3
2) 야채, 과일, 토마토
3) 견과류
4) 녹차, 생강, 울금, 강황, 마늘, 양파 등
5) 올리브오일, 코코넛오일, 버터 - 케톤체 생성 지방
오메가 6지방산이 염증을 일으키는 기전
오메가 3지방산이 염증을 제거하는 기전
- 녹황색야채, 아마씨, chia, hemp seeds
음식으로 염증야기 기전
- 고혈당, 고지혈, 산화스트레스 - LPS, IL-1,6, TNF, Substance P
- 대식세포 - 섬유아세포 - group IV Afferents
염증마커
1) 혈당, 중성지방, HDL콜레스테롤, 혈압, 허리둘레
2) body mass index, waist/hip ratio, hs-CRP, 비타민 d, 공복시 중성지방, 2시간후 혈당
An Anti-inflammatory Diet For Pain Patients
Numerous papers have been published that describe how diet can promote or reduce inflammation, but very few studies have specifically looked at how diet can impact pain syndromes.1-14 In 1991, Kjeldsen-Kragh et al examined how the expression of rheumatoid arthritis would be impacted by a vegetation-based diet.14 The outcome was a striking reduction in pain, joint inflammation, and duration of morning stiffness—these benefits were still present at 1-year follow up.
Recently, it has been shown that patients are more likely to suffer with musculoskeletal pains and tendinopathy if they also have metabolic syndrome—which is, in part, treated by adopting anti-inflammatory dietary changes.15-21 In fact, a Mediterranean-style diet has been used to reduce cardiovascular risk factors,22achieve 100% resolution of metabolic syndrome,23 and reduce or resolve non-alcoholic fatty liver disease.24 The ketogenic Mediterranean diet includes olive oil, green vegetables, salads, fish (as the primary protein), lean meat, fowl, eggs, shellfish, cheese, and moderate amounts of red wine.
Regarding pain, a more traditional high-fat ketogenic diet has also been examined. In one animal study, a high-fat paste was fed to rats and within 3 weeks there was a significant reduction in pain and inflammation markers in the animals.25 Multiple anti-nociceptive and anti-inflammatory mechanisms have been proposed to explain this outcome.26
Taken together, these studies support the hypothesis that an anti-inflammatory diet should be applied in pain patients.13 This article will briefly review the chemistry of pain and inflammation and examine various components of the diet, which reduce the expression of pain/inflammation chemistry.
What Is Chronic Inflammation?
Low-grade chronic inflammation is now known to be a driver of most chronic degenerative diseases.1-14 It is important to understand that low-grade chronic inflammation is not associated with an obvious injury or infection (ie, acute inflammation) and does not predictably resolve.1,2,27 Low-grade chronic inflammation manifests itself both locally and systemically due to the increased cellular release of a variety of inflammatory mediators (Table 1).
These mediators are found to be elevated in seemingly distinct chronic disease such as atherosclerosis28 and osteoarthritis.29This finding suggests that we should begin to look at chronic diseases as having similar chemical conditions (pro-inflammatory state), which manifest with symptoms that affect particular organs and systems.30
Pain as a Manifestation Of Chronic Inflammation
Multiple cells are involved in the release of inflammatory mediators, which lead to the cellular communication that can generate pain in somatic tissues, such as joint, muscle, disc, ligament, tendon, fascia, or epineurium (Figure 1).31 Nerve cells, especially group IV afferents (sensory C-fibers) and postganglionic sympathetic fibers (motor C-fibers) dominate the innervation of somatic tissues and play an important role in the inflammatory process and tissue homeostasis.29,31-34
Pain researchers describe group IV afferents as having the ability to “taste” the local tissue chemistry, which then, from an operational perspective, leads to their subsequent activation (if the “flavor” is inflammatory), or inhibition, modulation, and/or healing (if the tissue chemistry “flavor” is anti-inflammatory).33Group IV afferents release a host of mediators, the most well known being substance P. Substance P serves to communicate with local cells by activating cell-signaling molecules, such as nuclear factor κ-B (NF-κB).35 The outcome of substance P stimulation and NF-κB activation is the release of mediators (ie, prostaglandins and cytokines) by the cells, a process that often is referred to as neurogenic inflammation.36 If the mediators released are pro-inflammatory, then inflammation and group IV activation will continue, leading to additional substance P release and the conduction of nociceptive impulses, which lead to pain. In addition to exciting or modulating group IV afferents, the mediators released by local cells will serve to excite or modulate neighboring cells in a paracrine fashion.36 In this context, inflammation and pain necessarily would become chronic, unless local cells release anti-inflammatory mediators.
An interesting fact, as mentioned above, is that cells have the ability to release both pro-inflammatory and anti-inflammatory mediators and in doing so, determine the “flavor” of the tissue chemistry that is “tasted” by group IV afferents. Germane to the topic of this paper, it appears that nutrition is likely a key determining factor that generates the tissue “flavor” of inflammation and, thus, pain expression.
Diet-induced Pro-inflammatory Mediator Release
Multiple factors contribute to chronic “dietary injury,” a term that may be helpful to appreciate how diet can cause chronic inflammation and pain. Dietary injury should be viewed as a cumulative and chronic event, such that monotherapies with nutritional supplements or medications are unable to counteract the multiple “hits” delivered by a pro-inflammatory diet. Table 2 lists the primary sources of dietary injury and their inflammatory consequences.12,37-73 By making unhealthy lifestyle choices, an individual’s body is transformed into a “state” of chronic inflammation. The patient may not feel this transformation until an obvious clinical sign or symptom is present. We now know that stress, lack of sleep, lack of exercise, and inflammatory dietary choices represent types of “non-traumatic” biochemical injury, which causes our cells to generate a low-grade chronic inflammatory state by releasing increased levels of the previously mentioned inflammatory mediators.74-78 Diet is most important because the chemistry of the diet is reflected as the chemistry of the cells.
The most obvious dietary example involves the excess consumption of omega-6 (n-6) fatty acids that become part of cell membranes. An excess of n-6 arachidonic acid, a polyunsaturated n-6 fatty acid, is consumed directly from grain-fed animals and farm-raised fish, most notably catfish and tilapia.79,80 Foods processed with oils from corn, safflower, sunflower, and cottonseed contain mostly n-6 linoleic acid, which is converted by the human body into arachidonic acid and incorporated into cell membranes throughout the body.
Inflammatory stimuli activate phospholipase A2 (PLA2), which clips the polyunsaturated fatty acid from the middle carbon in the cell membrane phospholipid and delivers it to the cytoplasm. The most commonly liberated fatty acid is n-6 arachidonic acid because we now eat n-6 fatty acids at unprecedented levels.11,37,38 Other liberated fatty acids include n-6 dihomo-γ-linolenic acid, omega-3 (n-3) eicosapentaenoic acid (EPA), or n-3 docosahexaenoic acid (DHA) (Figure 2). When in the cytoplasm, arachidonic acid is acted on by cyclooxygenase (COX-1 or COX-2) and lipoxygenase (LOX). COX enzymes convert arachidonic acid into pro-inflammatory eicosanoids including prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), and thromboxane A2) while LOX converts arachidonic acid into pro-inflammatory leukotriene B4 (LTB4).37-40
The expression of painful osteoarthritis has been linked to the accumulation of dietary arachidonic acid in joint tissues. Interestingly, we are born without n-6 fatty acids in our joints, but as we age, levels steadily increase due to diet.41-43 With this example, it is possible to embrace the fact that we literally eat ourselves into an “injured” and painful state; that is, we eat excessive amounts of arachidonic acid that is converted into painful prostaglandins and leukotrienes.
The reduction in n-3 fatty acid intake adds to the inflammatory/painful state because n-3s convert to mediators that resolve inflammation and reduce pain. These mediators are derived from EPA and DHA and are called resolvins, protectins, and maresins.39,40,44
As noted, the dietary injuries listed in Table 2 are generated by our adherence to a pro-inflammatory diet that is substantially lacking in macronutrient balance and micronutrient density due to the overconsumption of food sources that were not available to preagricultural humans. Almost 60% of our calories now come from flour, sugar, and n-6 refined seed oils.79 An additional 10% of calories come from dairy. A strong argument has been made against the regular consumption of whey and casein because they have pro-inflammatory effects via insulin signaling, insulin resistance, and chronic disease.81-83 Approximately 20% of calories come from meat sources. Many of these meat sources are obese and are fed a pro-inflammatory diet, which contain elevated pro-inflammatory n-6 fatty acids and reduced levels of anti-inflammatory n-3 fatty acids.79 This leaves approximately 10% of calories that come from vegetables, fruits, nuts, whole grains, and legumes—too little to counteract the pro-inflammatory effects of the other 90% of calories.
With the above in mind, an anti-inflammatory diet can be constructed that applies to all patients and can be modified based on a patient’s food category preferences. Such a diet must be calorically appropriate and have a low glycemic index/load, have adequate amounts of protein and lipids, adequate n-3 fatty acids, and be rich in phytonutrients, micronutrients, and fiber. Table 3 lists the primary components of such an anti-inflammatory diet, which reverse the dietary injury factors listed in Table 2.5,11-13,84-88 Supplementation with magnesium, n-3 fatty acids, probiotics, fiber, and vitamin D can be considered to support the anti-inflammatory diet.88,89
The practical application of eating anti-inflammatory foods should not be a complicated activity for patients. Meat, fish, and chicken portions should essentially remain the same. Vegetable and fruit intake should be increased substantially and replace refined sugars and flour products. For perspective, 6 cups of cooked brocolli represents approximately 300 calories and in 1 head of romaine lettuce there is about 100 calories. Two cups of blueberries is approximately 160 calories and an apple and orange contain approximately 75 and 85 calories, respectively. This volume of vegetation represents only 700 calories. Additional calories can come from sweet potatoes, other tubers, and raw or dry roasted nuts. For patients who want specific recipes, the best suggestion is to consider various ethnic cookbooks and simply replace flour products and grains with additional vegetables.
How Diet Perpetuates Inflammation and Pain
Despite the relationships discussed in the previous section, it can be somewhat difficult to envision how diet can specifically drive inflammation. There appears to be 2 mechanisms by which this occurs, one being anatomical in nature and the other metabolic.
An example of an anatomical problem involves the overconsumption of n-6 fatty acids, which leads to a change in cell membrane anatomy as described earlier in the case of osteoarthritis. Arachidonic acid levels steadily increase with age, and chronic joint pain is the diet-derived outcome. This anatomical scenario is not unique to joint tissues.
A metabolic mechanism of diet-driven pain and inflammation is best illustrated by NF-κB signaling. NF-κB is the most comprehensively researched cell-signaling molecule, and it has been directly linked to pain expression.90,91 In fact, efforts have been directed at developing pain medications that inhibit NF-κB.92 As illustrated in Figure 1, NF-κB is stimulated by group IV afferent-derived substance P. Figure 3 illustrates that NF-κB also is stimulated by various nutritional factors, such as the overconsumption of sugar and flour, and the related oxidative stress and free radical production.
NF-κB normally resides in the cytoplasm. When inflammatory stimuli impact immune and resident tissue cells, cytoplasmic NF-κB is transported to the nucleus, where it stimulates protein synthesis. Proteins can be enzymes such as PLA2, COX, and LOX, which function to convert dietary arachidonic acid into PGE2 and LTB4 and are then released by the cell to promote inflammation and pain. NF-κB also directs the production and release of inflammatory proteins such as cytokines (ie, interkeukin-1, interleukin-6, and tumor necrosis factor). The outcome is that cells can perpetuate inflammation in a paracrine fashion that can be continuously promoted by the pro-inflammatory diet.
Studies have demonstrated that postprandial surges of blood sugar and lipids activate NF-κB signaling.93,94 In one study, after an 8- to 9-hour overnight fast, normal-weight subjects consumed a 910 calorie meal containing egg-muffin and sausage-muffin sandwiches and 2 hash browns, which contained 81 g carbohydrates, 51 g fat, and 32 g protein. Blood samples were taken 1, 2, and 3 hours after they ate. Controls drank only water. NF-κB signaling was significantly elevated in the test subjects.95
Postprandial inflammation also can be generated by a postprandial low-grade endotoxemia. Lipopolysaccharide (LPS), also referred to as endotoxin, is a unique glycolipid in the outer membrane of human intestinal gram-negative bacteria. LPS absorption is known to activate NF-κB signaling in peripheral cells.96
Normal subjects with a mean body mass index of 23 were fed a typical American breakfast including a cup of tea, three slices of toast, and butter, which amounted to 900 calories. Compared to controls, LPS levels in the study group increased significantly, indicating that this common breakfast promotes low-grade endotoxemia.97 Subsequent studies suggest that overeating simple carbohydrates and fat is associated with endotoxemia in apparently healthy men.98
To avoid meal-related activation of NF-κB caused by excess calories and endotoxemia, it is clear that patients should curtail substantially the consumption of sugar, flour, refined oils, and meat (from obese animals), which dominate the current American diet. In contrast, the consumption of vegetables, wine, and spices is known to reduce post-prandial inflammation.99-102 Even the addition of orange juice to the abovementioned toast and butter breakfast can reduce endotoxemia.103 And while red meat is often impugned, studies have demonstrated that the consumption of lean red meat does not lead to post-prandial inflammation, and the substitution of lean red meat for carbohydrates had a blood pressure lowering effect in hypertensive men.104,105
While often touted as a healthy anti-inflammatory food, whole grains may contribute to low-grade chronic inflammation. It is known that lectins from all grains and gluten from wheat, rye, and barley can disrupt gut barrier integrity and allow for the absorption of dietary and bacterial antigens, such as lipopolysaccharide.11,106 Gliadin from gluten is known to stimulate enterocyte production of zonulin, which disrupts intestinal tight junctions and can lead to systemic inflammation.107
An additional promoter of systemic endotoxemia is metabolic syndrome, which manifests itself, in part, by low levels of high-density lipoprotein (HDL). This is relevant because HDL binds to endotoxin in the blood and clears it from the circulatory system.108 Low levels of dietary n-3 fatty acids also potentiate endotoxemia. LPS is rendered less toxic by an intestinal alkaline phosphatase, which is stimulated by resolving E1 from eicosapentaenoic acid.109
Systemic endotoxemia is most noted for its ability to potentiate atherogenesis and diabetes103,108; however, endotoxemia also is linked to the expression of widespread pain, malaise, and depression.110-112
Practical Applications And Considerations
As described in this article, foods can acutely stimulate inflammation and lead to the development of a chronic pro-inflammatory state. Patients in pain already are inflamed and need to be educated about the importance of consuming the anti-inflammatory foods listed in Table 2.
Keeping track of laboratory and physical findings also can be useful for patients and doctors. Table 4 includes markers for the pro-inflammatory metabolic syndrome and other markers that suggest the presence of a pro-inflammatory state. The goal should be to normalize the markers as patients go through the process of adhering to the anti-inflammatory diet and related anti-inflammatory lifestyle changes, which should include adequate sleep, exercise, and stress reduction.
Editor's Note: Considerable scientific information and clinical observation have accumulated in recent years showing that chronic pain—particularly the debilitating, severe form requiring opioid treatment—needs a “chronic pain” diet. I have been a proponent of a high-protein diet with avoidance of carbohydrates.1 The fundamental principle of the diet is that patients with chronic pain need to avoid high-glycemic foods (sugars and starches) and eat more protein and vegetables to promote strength, movement, energy, and mental function.
The “anti-inflammatory” diet presented here mirrors many of my personal recommendations, and most experts consider this diet to be healthy. The problem for pain practitioners is that we really don’t know how significant a role inflammation plays in chronic pain states. Consequently, neither this diet nor any others have shown conclusively that pain can be controlled by diet. Despite the lack of “evidence,” Practical Pain Management commends the thoroughness of this article and encourages pain practitioners to advise their patients to eat a healthy diet, exercise, and take supplements, when appropriate.
Reference
1. Tennant F. A diet for patients with chronic pain. Pract Pain Manage.2011;11(6):22-30.