**4. The Underlying Potential Mechanisms That Explain the Interaction between Nutrition and Chronic Pain**

The interaction between nutrition and chronic pain is bidirectional. However, it is not clear how nutritional factors interact with the pain generating mechanisms and the potential mechanisms that contribute to this relationship. Identifying and understanding these mechanisms can potentially increase the effectiveness of nutrition assessments and treatments in chronic pain management. The potential action mechanisms of the nutritional factors in chronic pain management have been identified and illustrated in Figure 2.

#### *4.1. Inflammation and Oxidative Stress*

Oxidative stress is defined as an increase in the reactive oxygen species produced as a byproduct of oxygen metabolism and a decrease in the ability of antioxidative compounds to detoxify cells and tissues. In addition to other factors (e.g., radiation, smoking, air pollution), dietary induced oxidative stress is one factor that can initiate and contribute to the immune cell activation and inflammation [88]. The immune cell activation, followed by a rise in oxygen consumption, also raises the amount of reactive oxygen species which can create an oxidative stress—inflammation cycle [88]. Thus, it is possible to say that the consequence of oxidative stress becomes its cause. The decreased antioxidative and detoxifying ability of the body can play a role in inflammation induced pain mechanisms [89]. Inversely, there is some evidence that an increased dietary antioxidant intake and the increased detoxifying ability of the body can alleviate pain among a chronic musculoskeletal pain population [90]. In the latest pain research, it is known that inflammation can interact with various pain mechanisms including nociceptive (pain arising due to activation of nociceptors), neuropathic (pain arising due to direct damage to the peripheral and central nervous system), and nociplastic (altered nociceptive system despite the absence of a clear nociceptive and neuropathic input) pain mechanisms [91].

**Figure 2.** Potential Mechanisms of the Interaction Between Nutrition and Chronic Pain.

Inflammation is the body's immediate, natural, and protective response against infections and injuries. Physiologically, inflammatory processes, as a part of the immune reactions, are regulated by time. A late or prolonged inflammatory response might lose its protective effectiveness. A persistent proinflammatory state has been identified as an important risk factor for several pathophysiological conditions, including atherosclerosis, cardiovascular diseases, diabetes mellitus, obesity, cancer, and chronic pain [92]. Chronic and uncontrolled inflammation can be harmful and can lead to many acute and chronic diseases, including maintenance, occurrence, and prognosis of chronic pain [92]. This finding is supported by several pain studies on the immune system. To exemplify, immune cells evoke pain via the stimulation of nociceptors, changes in neuronal structures, and sensitization of the peripheral and central nervous systems via the release of inflammatory biomarkers [91,93].

Neuroinflammation is a localized inflammatory response that occurs in the peripheral and central nervous system [91]. In chronic pain conditions, neuroinflammation is characterized with the glial cell activation and an increased production of inflammatory biomarkers which can lead to peripheral and central nervous system sensitization [91]. Abnormal central nervous system glial cell activity has been reported in chronic pain conditions, especially nociplastic-related conditions, such as chronic non-specific low back pain, fibromyalgia, migraine, and spinal radiculopathy [94].

#### *4.2. Microbiota-Gut-Brain Axis*

Gut microbiota plays an important role in the human body and contributes to many structural, protective, and metabolic functions [95]. Thus, gut health constitutes an essential place in the maintenance of general health. The gut and brain have a bidirectional communication pathway and the intestinal microbiota has a modulating effect on this gut-brain axis [96]. The evidence shows that this link occurs through the connection between the vagus nerve and brainstem, via spinal afferents to the spinal cord [96]. Diversity of the gut microbiota is influenced by various factors, including medication use, mental health, infection, and nutrition which can lead to the dysregulation of the gut microbiota [97,98]. Dysregulation of the microbiota-gut-brain axis has been identified among various pathologic conditions, such as inflammatory bowel disease, diabetes, obesity, autism, depression, and chronic pain [97,98]. The accumulating evidence shows that the interrelation between nutrition and the microbiota-gut-brain axis can have a modulating effect in acute and chronic pain pathophysiology [97,98].

Microbes residing in the gut can be modified by nutritional factors. Thus, the microbiotagut-brain axis has been identified as a target for nutritional interventions [99]. The differences in the diversity of the microbiome among the various populations that follow certain dietary patterns, such as vegetarian, vegan, and omnivorous diets, has been well documented [100]. Energy dense, unhealthy, proinflammatory dietary patterns that are nutrient poor and high in unsaturated fats, refined carbohydrates, and low in fruits and vegetables can cause a diet induced inflammation in the gut [94]. Proinflammatory cytokines released in response to unhealthy dietary patterns, activate the vagus nerve receptors located in the gastrointestinal tract. Upon activation, the vagus nerve can trigger the glial cell activation and the neuroinflammation process in the central nervous system [94]. Peripheral and central proinflammatory responses, including the aberrant glial cell activity, contribute to the maintenance, occurrence, and prognosis of chronic pain [94]. Targeting the gut microbiota with nutritional interventions in chronic pain populations is a promising approach for pain management.

#### *4.3. Disturbed Glucose Metabolism*

Diabetes has been reported as an important risk factor for chronic pain. In addition to neuropathic pain, chronic non-neuropathic pain conditions, such as fibromyalgia, chronic wide-spread pain, chronic low back, and neck pain are more common among people with diabetes, compared to people without diabetes, especially amongst those who have poorly controlled diabetes [101,102]. Patients with chronic musculoskeletal pain have been identified as having a disturbed glucose metabolism, including an increased fasting glucose level, an increased insulin resistance, a higher postprandial glycemic response, and a higher prevalence of type-2 diabetes mellitus [103]. A well-known antihyperglycemic medicine, metformin, which is commonly used to treat type-2 diabetes has also shown it can significantly alleviate pain in chronic pain populations and thus could be a potential treatment for people experiencing chronic pain [104].

An excessive carbohydrate intake and a decrease in glucose metabolism efficiency can increase reactive oxygen species and evoke an oxidative stress response [105]. The oxidative stress response is an endogenous factor that can activate toll like receptors and initiate inflammatory reactions in the peripheral and central nervous systems [105]. Thus, the identification of a disrupted glucose metabolism and targeting glucose regulation constitute significant places in chronic pain management [105]. Studies exploring the effect of low-carbohydrate diets, including the ketogenic diet, have revealed promising results including improvements in the glucose metabolism [106]. In another study, people with chronic musculoskeletal pain, who followed a low carbohydrate diet, had a decrease in serum inflammatory biomarkers and pain sensitivity [107]. Studies that explored the action mechanism of a ketogenic diet on chronic pain suggested that the carbohydrate intake played a role in neuroinflammation and central sensitization [108]. However, it is also important to consider the weight reducing effect of low-carbohydrate diets. A decrease in

adipose tissue may also improve pain sensitivity in chronic pain populations and therefore, obesity requires special attention in terms of its role in the interaction between nutrition and pain generating mechanisms [6,109].

### *4.4. Disrupted Lipid Metabolism*

Lipids are essential for several bodily functions, and are one of the body's main energy sources. Nutrition strategies, including the modification of single nutrients, supplements, or overall eating patterns, can affect serum lipid profiles in both positive and negative ways. To exemplify, an excessive intake of saturated fats, dietary fructose, and an overall western style of eating increases low-density lipoprotein (LDL), triglycerides, and decreases highdensity lipoprotein (HDL). A high LDL cholesterol level increases the risk of cardiovascular disease (CVD) and is commonly known as "bad cholesterol", while a high HDL cholesterol level is protective, reduces the risk of CVD, and is often referred to as "good cholesterol". Omega-3 unsaturated fatty acids, antioxidants, intermittent fasting, and adherence to the Mediterranean diet, can have the reverse effects on the same lipid biomarkers [110–114].

A disrupted lipid metabolism also plays a role in various health conditions, such as atherosclerosis, diabetes, cardiovascular diseases, metabolic syndrome, and obesity. [115]. The role of a disrupted lipid metabolism in chronic pain is gaining more attention and targeting this mechanism via dietary factors is a promising approach for chronic pain management. For instance, low back pain has been found to be prevalent among individuals with a decreased lumbar blood supply [116]. The relationship between the decreased lumbar blood supply and spinal pain constitutes a base for the atherosclerosis theory of the persistent non-specific low back pain. Prevalence of low back pain has been found inversely associated with the serum HDL cholesterol and positively associated with serum triglycerides and LDL cholesterol, which overall contribute to the atherosclerosis hypothesis [116,117]. Additionally, compared to healthy controls, fibromyalgia patients have shown a disrupted serum lipid profile and this disruption was found to be positively associated with pain sensitivity [118]. In a systematic review, the biomarkers of the serum lipid metabolism, including the decreased serum HDL cholesterol, the increased serum LDL cholesterol, and triglycerides, was found to be strongly associated with musculoskeletal pain arising from tendinopathy [119].

#### *4.5. Obesity/Overweight*

Obesity is associated with a proinflammatory state and is an important risk factor for various metabolic changes and chronic diseases, including cardiovascular diseases, cancer, diabetes mellitus, and chronic pain [109,120,121]. The existing evidence suggests that there is a concurrence and bidirectional relationship between obesity and chronic pain [109]. Obesity has been associated with several chronic musculoskeletal pain conditions including osteoarthritis, fibromyalgia, pelvic pain, and chronic low back pain [122]. It has been hypothesized that overweight/obesity play an important role in chronic pain by two main mechanisms; first increasing the mechanical load on neuromusculoskeletal structures and second, initiating or contributing to neuroimmune reactions, namely chronic low grade systemic inflammation [123].

Increased adipocytes and adipose tissue are positively associated with increased macrophages and promote inflammatory responses such as an increase in inflammatory cytokines (IL-6, TNF-alpha) and acute phase proteins (CRP) [124]. Excessive adipose tissue also increases the relocation of inflammatory cytokines into the central nervous system and promotes the activation of glial cells which can eventually play a role in nociplastic pain [125].

Exposure to high saturated fat and energy dense dietary patterns increase the circulated inflammatory cytokine levels. An in vivo study using an animal model suggests that exposure to a diet rich in saturated fat for one day causes the glial cell activation for two weeks in rats [126]. Dietary patterns that restrict the caloric intake have been shown to relieve pain in people with chronic musculoskeletal pain [127].

#### *4.6. Epigenetic Factors*

Epigenetics can be explained as a change in the gene expression without any change in the deoxyribonucleic acid (DNA) sequence. Epigenetic mechanisms are divided into three main categories, namely DNA methylation, histone modifications, and non-coding ribonucleic acid (RNA) interference [128]. Almost every cell in the body has the same DNA. However, each cell has different activated or highlighted genes in the DNA. Epigenetics explains the interaction between nature (genes) and nurture (environment), and how the genes we inherit interact with environmental factors including diet [128]. Many epigenetic mechanisms are reversible and modifiable which make them an attractive therapeutic target.

Nutrition is a major modifiable lifestyle factor that has the ability to alter the epigenetic regulation and can cause an epigenetic dysregulation. Additionally, epigenetic markers also have the ability to alter the body's response to certain dietary intake and patterns [129,130]. Dysregulation of the epigenetic markers can alter the gene expression, protein synthesis, cell function, and metabolism and can lead to chronic diseases [131,132].

Recent findings show that epigenetic changes can alter the expression of nociceptive or antinociceptive genes [133]. Moreover, the epigenetic dysregulation can play a role in the transition from acute to chronic pain [134]. Preclinical studies have shown an increase in inflammatory responses after the consumption of a diet rich in saturated fats and a high-carbohydrate diet via DNA methylation [135]. The DNA methylation level of genes that promote inflammatory cytokines, especially TNF-alpha, has been associated with obesity and an omega-6 polyunsaturated fatty acids intake [136]. Saturated fatty acids are known for their inflammatory characteristics and a higher intake of saturated fatty acids has been associated with the DNA methylation level of the genes that play an essential role in the inflammatory biomarker synthesis and insulin resistance [137]. Alternatively, nutrients and foods with anti-inflammatory properties, such as omega-3 polyunsaturated fatty acids, extra virgin olive oil, curcumin, and polyphenols showed anti-inflammatory effects via its effects on the DNA methylation processes in immune cells [138]. Early findings show that there is an interaction between nutrition and the epigenetic factors and this has an important role in chronic pain and the associated mechanisms, such as obesity, a disturbed glucose metabolism, and gut microbiota diversity. Although the use of genetic and epigenetic data in chronic pain management is still in a very early phase, the potential for the development of personalized pain medicine, or precision pain medicine is both promising and innovative [139].

#### **5. Implementation and Scope of Nutrition in Chronic Pain Management**

The relationship between nutrition and chronic pain is important and complex, yet traditionally, nutrition has been underrepresented in the evidence-based biopsychosocial and lifestyle approach to pain management. Pain management is multifaceted and must include an interdisciplinary approach. As such, health professionals need to be aware of, and be able to identify nutrition-related risk factors associated with chronic pain, provide basic nutrition-based treatment strategies, and know when and how to refer to a dietitian for more complex issues and advice. A thorough nutrition assessment and treatment plan should be included in all pain management programs. Dietitians can be a valuable part of a multidisciplinary team and can provide comprehensive assessments and treatments.

#### *5.1. Nutrition Assessment for Chronic Pain*

There is growing evidence to show that there is an association between diet and health outcomes that are important for people experiencing chronic pain. Therefore, a nutrition assessment should be conducted early in treatment. This may be through a brief, opportunistic intervention that a health professional (e.g., general practitioner (GP), nurse or allied health professional) may provide to a patient, a structured nutrition screening process at a pain clinic, or a comprehensive dietary assessment conducted by a dietitian. There are several nutrition-related risk factors associated with chronic pain and these

should be addressed in a dietary assessment. The factors include malnutrition, weight change, the presence of other comorbidities, abnormal biochemistry results, appetite or gastrointestinal complaints, and a poor dietary intake.

#### 5.1.1. Malnutrition Screening

Malnutrition screening is a vital component to consider when conducting a nutrition assessment for people experiencing pain. It is essential for those at an increased risk of malnutrition, such as older adults, those with orofacial pain or functional gastrointestinal conditions [30,38,46–49]. The process should include the use of a validated malnutrition screening tool. There are several validated malnutrition screening tools, such as the Malnutrition Universal Screening Tool, Malnutrition Screening Tool, Mini Nutritional Assessment-Short Form, and the Nutrition Risk Screening Tool [140,141]. These tools use similar parameters and are reliable in identifying people who are malnourished or at risk of malnutrition. Most health services or facilities use a specific screening tool based on their population, the complexity, and sensitivity of the tool. This serves as guide for health professionals when choosing the tool. People who fall into the malnutrition or in the at risk of malnutrition categories, should be referred to a dietitian.
