Article

Effects of a Low-Carbohydrate Ketogenic Diet on Reported Pain, Blood Biomarkers and Quality of Life in Patients with Chronic Pain: A Pilot Randomized Clinical Trial

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Abstract

Background A low-carbohydrate ketogenic diet has been reported to improve chronic pain by reducing inflammation, oxidative stress, and sensitivity within the nervous system. The main aim of this trial is to evaluate the effects of a ketogenic diet on reported pain, blood biomarkers and quality of life in patients with chronic pain. Methods Participants with chronic musculoskeletal pain were recruited for a 12-week diet intervention that commenced with a 3-week run-in diet removing ultra-processed foods, followed by randomisation to either a whole-food/well-formulated ketogenic diet (WFKD) or to continue with the minimally processed whole-food diet (WFD). Outcome measures included: average pain (visual analogue scale VAS), blood biomarkers, anthropometrics, adherence, depression, anxiety, sleep, ketones, quality of life, diet satisfaction and macronutrient intake. Results Average weekly pain improved for both groups. WFKD group VAS reduced by 17.9 ± 5.2 mm (p = 0.004) and the WFD group VAS reduced 11.0 ± 9.0 mm (p = 0.006). Both groups also reported improved quality of life (WFKD = 11.5 ± 2.8%, p = 0.001 and WFD = 11.0 ± 3.5%, p = 0.014). The WFKD group also demonstrated significant improvements in pain interference (p = 0.013), weight (p < 0.005), depression (p = 0.015), anxiety (p = 0.013), and inflammation (hsCRP) (p = 0.009). Significant average pain reduction remained at three-month follow-up for both groups (WFKD p = 0.031, WFD p = 0.011). Conclusion The implementation of a whole-food diet that restricts ultra-processed foods is a valid pain management tool, however a low-carbohydrate ketogenic diets may have potentially greater pain reduction, weight loss and mood improvements.

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... We recently reported pain outcomes for a 12-week randomized controlled trial comparing a whole-food diet (WFD) that eliminated ultraprocessed foods to a whole-food/well-formulated ketogenic diet (WFKD) [23]. That trial demonstrated a significant improvement in average weekly pain for both the dietary groups, but additional significant improvement in depression, anxiety and inflammation measures for the WFKD group. ...
... The study protocol was prospectively registered on the Australian and New Zealand Register of Clinical Trials (ACTRN12620000946910) with ethics approval from The University of Sydney Human Research Ethics Committee (HREC 220/557). The protocol, informed consent procedures and methods have been reported in detail and published previously [23,24]. The methods are briefly outlined below. ...
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Aim: To report the experience of chronic pain participants after a well-formulated ketogenic diet (WFKD) or whole-food diet (WFD). The quantitative outcomes for this trial have been published separately (clinical trial registration number ACTRN12620000946910). Patients & methods: The experience of 24 participants was evaluated after 12 and 24 weeks of dietary intervention using survey responses and open questions. Results & conclusion: Retention rates for the WFKD and WFD groups were 93 and 89%, respectively. Average adherence to the WFKD was 82% and to the WFD was 87%. The WFKD enjoyment was rated at 66 and 81% for the WFD group. The ease of adhering to the diet varied more widely for the WFKD group. Barriers included knowledge integration, time management, navigating social food environments and emotional attachment to eliminated foods. Facilitators included structured support and coaching, and comprehensive learning materials. The WFKD was shown to be a feasible and effective treatment option for chronic pain.
... In women with gestational diabetes, or overweight or obese adults, low-carbohydrate mixed meals had significantly reduced iAUC in blood glucose and/or insulin [27,28]. In addition, the intake of a low-carbohydrate ketogenic diet for 12 weeks had an effect in reducing body weight and BMI [29]. Gene expression involved in nutrient metabolism is also different during day and night and depends on meal composition [30]. ...
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During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms are unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+/NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-kB and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise and ketogenic diets. This article is protected by copyright. All rights reserved.
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Obesity and pain present serious public health concerns in our society. Evidence strongly suggests that comorbid obesity is common in chronic pain conditions, and pain complaints are common in obese individuals. In this paper, we review the association between obesity and pain in the general population as well as chronic pain patients. We also review the relationship between obesity and pain response to noxious stimulation in animals and humans. Based upon the existing research, we present several potential mechanisms that may link the two phenomena, including mechanical/structural factors, chemical mediators, depression, sleep, and lifestyle. We discuss the clinical implications of obesity and pain, focusing on the effect of weight loss, both surgical and noninvasive, on pain. The literature suggests that the two conditions are significant comorbidities, adversely impacting each other. The nature of the relationship however is not likely to be direct, but many interacting factors appear to contribute. Weight loss for obese pain patients appears to be an important aspect of overall pain rehabilitation, although more efforts are needed to determine strategies to maintain long-term benefit.
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Background Other than activity and exercise, lifestyle practices such as not smoking and healthy nutrition, well established for preventing and managing lifestyle-related non-communicable diseases (i.e., heart disease, cancer, hypertension, stroke, obstructive lung disease, diabetes, and obesity), are less emphasized in the physical therapy guidelines for addressing chronic pain, e.g., back pain. This state-of-the-art review examines the relationships between lifestyle behaviours and musculoskeletal health, with special reference to chronic pain, and their clinical and research implications. Discussion A state-of-the-art review was conducted to synthesize evidence related to lifestyle factors (not smoking, healthy diet, healthy weight, optimal sleep and manageable stress, as well as physical activity) and musculoskeletal health, with special reference to chronic pain. The findings support that health behaviour change competencies (examination/assessment and intervention/treatment) may warrant being included in first-line management of chronic pain, either independently or in conjunction with conventional physical therapy interventions. To address knowledge gaps in the literature however three lines of clinical trial research are indicated: 1) to establish the degree to which traditional physical therapy interventions prescribed for chronic pain augment the benefits of lifestyle behaviour change; 2) to establish the degree to which adopting healthier lifestyle practices, avoids or reduces the need for conventional physical therapy; and 3) to establish whether patients/clients with healthier lifestyles and who have chronic pain, respond more favourably to conventional physical therapy interventions than those who have less healthy lifestyles. Summary Lifestyle behaviour change is well accepted in addressing lifestyle-related non-communicable diseases. Compelling evidence exists however supporting the need for elucidation of the role of negative lifestyle behaviours on the incidence of chronic pain, and the role of positive lifestyle behaviours on its incidence and effective management. Addressing lifestyle behaviour change in patients/clients with chronic pain, e.g., back pain, as a first-line intervention might not only constitute a novel approach, but also reduce the socioeconomic burden related to chronic pain as well as non-communicable diseases.
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The inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk, or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines. The benefits of carbohydrate restriction in diabetes are immediate and well documented. Concerns about the efficacy and safety are long term and conjectural rather than data driven. Dietary carbohydrate restriction reliably reduces high blood glucose, does not require weight loss (although is still best for weight loss), and leads to the reduction or elimination of medication. It has never shown side effects comparable with those seen in many drugs. Here we present 12 points of evidence supporting the use of low-carbohydrate diets as the first approach to treating type 2 diabetes and as the most effective adjunct to pharmacology in type 1. They represent the best-documented, least controversial results. The insistence on long-term randomized controlled trials as the only kind of data that will be accepted is without precedent in science. The seriousness of diabetes requires that we evaluate all of the evidence that is available. The 12 points are sufficiently compelling that we feel that the burden of proof rests with those who are opposed. (C) 2015 The Authors. Published by Elsevier Inc.
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We compared the effects of two diets on glycated hemoglobin (HbA1c) and other health-related outcomes in overweight or obese adults with type 2 diabetes or prediabetes (HbA1c>6%). We randomized participants to either a medium carbohydrate, low fat, calorie-restricted, carbohydrate counting diet (MCCR) consistent with guidelines from the American Diabetes Association (n = 18) or a very low carbohydrate, high fat, non calorie-restricted diet whose goal was to induce nutritional ketosis (LCK, n = 16). We excluded participants receiving insulin; 74% were taking oral diabetes medications. Groups met for 13 sessions over 3 months and were taught diet information and psychological skills to promote behavior change and maintenance. At 3 months, mean HbA1c level was unchanged from baseline in the MCCR diet group, while it decreased 0.6% in the LCK group; there was a significant between group difference in HbA1c change favoring the LCK group (−0.6%, 95% CI, −1.1% to −0.03%, p = 0.04). Forty-four percent of the LCK group discontinued one or more diabetes medications, compared to 11% of the MCCR group (p = 0.03); 31% discontinued sulfonylureas in the LCK group, compared to 5% in the MCCR group (p = 0.05). The LCK group lost 5.5 kg vs. 2.6 kg lost in MCCR group (p = 0.09). Our results suggest that a very low carbohydrate diet coupled with skills to promote behavior change may improve glycemic control in type 2 diabetes while allowing decreases in diabetes medications. This clinical trial was registered with ClinicalTrials.gov, number NCT01713764.
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Objectives Ketogenic diets have reported efficacy for neurological dysfunctions however there are limited published human clinical trials elucidating the mechanisms by which nutritional ketosis produces therapeutic effects. The purpose of this present study was to investigate animal models that report variations in nervous system function by changing from a standard animal diet to a ketogenic diet, synthesise these into broad themes, and compare these with mechanisms reported as targets in pain neuroscience to inform human chronic pain trials. Methods An electronic search of seven databases was conducted in July 2020. Two independent reviewers screened studies for eligibility, and descriptive outcomes relating to nervous system function were extracted for a thematic analysis then synthesised into broad themes. Results One hundred and seventy studies from 18 different disease models were identified and grouped into 14 broad themes including: alterations in cellular energetics and metabolism, biochemical, cortical excitability, epigenetic regulation, mitochondrial function, neuroinflammation, neuroplasticity, neuroprotection, neurotransmitter function, nociception, redox balance, signalling pathways, synaptic transmission and vascular supply. Discussion The mechanisms presented centred around the reduction of inflammation and oxidative stress as well as a reduction in nervous system excitability. Given the multiple potential mechanisms presented, it is likely that many of these are involved synergistically and undergo adaptive processes within the human body, and controlled animal models that limit the investigation to a particular pathway in isolation may reach differing conclusions. Attention is required when translating this information to human chronic pain populations due to the limitation outlined from the animal research.
Article
Introduction: A ketogenic diet has been shown to influence the nervous system and can potentially improve maladaptive changes occurring with chronic pain, specifically neuroinflammation and nervous system sensitisation. However, there is limited research on whether altering a standard western diet high in ultra-processed foods to a well-formulated ketogenic diet (WFKD) may reduce chronic pain. The aim of this clinical trial is to evaluate the effects of a WFKD on patients with chronic pain. Methods: This is a 12-week pilot randomised clinical trial of adults with chronic musculoskeletal pain. All participants will commence with a 3-week run in whole-foods diet removing ultra-processed foods. At week 4 they will be randomised to either continue the whole food diet or start a WFKD (carbohydrate intake <50g/day). Finger prick ketone testing will evaluate the level of nutritional ketosis, and carbohydrate levels adjusted accordingly to achieve the target ketone level 0.5-3.0 mmol/L. Reported chronic pain levels, blood ketone levels, metabolic markers, inflammation and quality of life will be measured at baseline, post-intervention, and 3- months follow-up. Conclusion: This trial will evaluate the effects of a whole-food well formulated ketogenic diet on chronic pain perception. It attempts to address the commonalties between reported dietary approaches (diet quality and nutrient density) by using a comparator of equal food quality to allow the clinical evaluation of the ketogenic diet specifically on pain mechanisms. It will further the research on how a ketogenic diet may modulate physiology linked to chronic pain mechanisms such as metabolic dysregulation and inflammation.
Article
In the past decade, ketogenic diet (KD) has gained some popularity as a potential treatment for a wide range of diseases, including neurological and metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat and carbohydrate-restricted regimen causes changes in the metabolism, leading, through the b-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), which are used by many extrahepatic tissues as energy fuels. Once synthetized, KBs are delivered through the systemic circulation to all the tissues of the organism, where they play pleiotropic roles acting directly and indirectly on various targets, and among them ion channels and neurotransmitters. Moreover, they can operate as signaling metabolites and epigenetic modulators. Therefore, it is inappropriate to consider that the KD regimen can improve the patients' clinical condition simply by means of specific and localized effects; rather, it is more correct to think that KBs affect the organism as a whole. In this review, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention on the excitable ones, namely the nervous system, heart, and muscles. b-hydroxybutyrate; diet therapy; excitable tissues; ketogenic diet; low carbohydrate high fat diet
Article
Background The standard Western diet is high in processed hyperpalatable foods that displace nutrient-dense whole foods, leading to inflammation and oxidative stress. There is limited research on how these adverse metabolic drivers may be associated with maladaptive neuroplasticity seen in chronic pain and whether this could be attenuated by a targeted nutritional approach. The aim of this study was to review the evidence for whole-food dietary interventions in chronic pain management. Method A structured search of eight databases was performed up to December 2019. Two independent reviewers screened studies and evaluated risk of bias by using the National Institutes of Health assessment tool for controlled or pre–post studies and the Joanna Briggs checklist for case reports. A meta-analysis was performed in Review Manager. Results Forty-three studies reporting on 48 chronic pain groups receiving a whole-food dietary intervention were identified. These included elimination protocols (n = 11), vegetarian/vegan diets (n = 11), single-food changes (n = 11), calorie/macronutrient restriction (n = 8), an omega-3 focus (n = 5), and Mediterranean diets (n = 2). A visual analog scale was the most commonly reported pain outcome measure, with 17 groups reporting a clinically objective improvement (a two-point or 33% reduction on the visual analog scale). Twenty-seven studies reported significant improvement on secondary metabolic measures. Twenty-five groups were included in a meta-analysis that showed a significant finding for the effect of diet on pain reduction when grouped by diet type or chronic pain type. Conclusion There is an overall positive effect of whole-food diets on pain, with no single diet standing out in effectiveness. This suggests that commonalities among approaches (e.g., diet quality, nutrient density, weight loss) may all be involved in modulating pain physiology. Further research linking how diet can modulate physiology related to pain (such as inflammation, oxidative stress, and nervous system excitability) is required.
Purpose of review: To summarize the underlying biochemical basis for low-carbohydrate and ketogenic diets (LC/KD) and provide mechanisms to account for demonstrated effectiveness. Recent findings: LC/KD continue to have success, to outperform other diets as well as most drugs for weight loss and diabetes treatment. In many cases, LC/KD can effect remission (absence of drugs) or reversal (only metformin or nondiabetes drugs) of type 2 diabetes and a significant adjunct to pharmacology in type 1. Medication is reduced or eliminated in most cases. The results are consistent with the biochemical rationale which stresses the global effects of the glucose-insulin axis. Summary: Evidence for the superior effectiveness of LC/KD for metabolic disease is now overwhelming. At the same time, the approach has received only limited support, and in many cases, persistence of the traditional opposition. Clinical practice or research must confront this crisis in order to bring practice in line with current science and to avoid continued harm to medicine and ultimately, the patient.
Article
Background Studies have consistently shown that patients with epilepsy could benefit from ketogenic diets (KDs). Recent evidence suggests that KD could be used in the treatment of central nervous system (CNS) diseases. The aim of this systematic review was to investigate the use and efficacy of KD, modified Atkins diet (MAD) and medium-chain triglyceride (MCT) diet in infants, children, adolescents, and adults with CNS diseases. Methods This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main databases, i.e. EMBASE, PubMed and PsycINFO, were searched on 4 December 2019. Only randomized clinical trials (RCTs) were included and only if they reported KD, MCT or MAD interventions on patients with CNS diseases. Results Twenty-four publications were eligible for inclusion (n = 1221). Twenty-one publications concerned epilepsy, two concerned Alzheimer’s disease (AD), and one concerned Parkinson’s disease (PD). All studies regarding epilepsy reported of seizure reduction compared to baseline. MCT did not significantly change regional cerebral blood flow (rCBF) in patients with AD, but MAD significantly improved memory at 6 weeks (p = .03). KD significantly improved motor and nonmotor functions in patients with PD at 8 weeks (p < .001). There was a trend towards fewer adverse effects in MAD compared to KD. Conclusion In conclusion, various forms of KDs seem tolerable and effective as part of the treatment for epilepsy, AD and PD, although more investigation concerning the mechanism, efficacy and adverse events is necessary.
Article
Background and Objective Mechanisms underpinning symptoms in non‐traumatic neck pain (NTNP) and whiplash‐associated disorder (WAD) are not comprehensively understood. There is emerging evidence of systemic inflammation in musculoskeletal pain conditions, including neck and back pain. The aim of this systematic review was to determine if raised blood inflammatory markers are associated with neck pain. Databases and Data Treatment MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science databases were searched. Two independent reviewers identified studies for inclusion and extracted data. Meta‐analysis was performed by random‐effects model to calculate standard mean differences (SMDs). Risk of bias of individual studies was assessed using the Newcastle‐Ottawa Scale. Overall quality of evidence from meta‐analysis was assessed by Grades of Recommendation, Assessment, Development, and Evaluation approach. Results In total, ten studies were included comprising 706 participants. Three studies provided data for acute WAD, two for chronic WAD, four for chronic NTNP, and one for chronic mixed WAD and NTNP. Meta‐analysis indicated increased interleukin 1β (SMD: 0.84 [95% CI 0.24, 1.44], p = 0.01, I² = 59%) and tumour necrosis factor α (SMD: 0.59 [0.09, 1.09], p = 0.02, I² = 45%) in chronic neck pain compared to controls, but no increase in monocyte chemoattractant protein‐1. Some inflammatory markers were associated with clinical variables (including pain intensity and disability). Quality of evidence was mostly low due to small samples and high heterogeneity. Conclusions Findings imply that raised blood inflammatory markers are present in chronic neck pain, which may represent an ongoing inflammatory process in this population.
Article
The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.
Article
Ketogenic diet is a low carbohydrate and high fat diet that has been used for over 100 years in the management of childhood refractory epilepsy. More recently, ketogenic diet has been investigated for a number of metabolic, neurodegenerative and neurodevelopmental disorders. In this comprehensive review, we critically examine the potential therapeutic benefits of ketogenic diet and ketogenic agents on neurodegenerative and psychiatric disorders in humans and translationally valid animal models. The preclinical literature provides strong support for the efficacy of ketogenic diet in a variety of diverse animal models of neuropsychiatric disorders. However, the evidence from clinical studies, while encouraging, particularly in Alzheimer’s disease, psychotic and autism spectrum disorders, is limited to case studies and small pilot trials. Firm conclusion on the efficacy of ketogenic diet in psychiatric disorders cannot be drawn due to the lack of randomised, controlled clinical trials. The potential mechanisms of action of ketogenic therapy in these disorders with diverse pathophysiology may include energy metabolism, oxidative stress and immune/inflammatory processes. In conclusion, while ketogenic diet and ketogenic substances hold promise pre-clinically in a variety of neurodegenerative and psychiatric disorders, further studies, particularly randomised controlled clinical trials, are warranted to better understand their clinical efficacy and potential side effects.
Article
A comprehensive review of molecular mechanisms involved in the promotion and maintenance of distinct microglia phenotypes is provided. The acquisition and perpetuation of predominantly pro-inflammatory microglial phenotypes have been implicated in the pathophysiology of several neuroprogressive diseases and is associated with reduced ATP production via oxidative phosphorylation, increased ATP generation by glycolysis, elevated oxidative and nitrosative stress and other metabolic, inflammatory and hormonal insults. Microglia can also adopt a predominantly anti-inflammatory phenotypes with neuroprotective properties. Strategies that promote and maintain a predominantly anti-inflammatory phenotype may hold promise as novel therapeutic opportunities for neuroprogressive illness. Induced ketosis may promote a transition towards predominantly anti-inflammatory microglial states/phenotypes by several mechanisms, including inhibition of glycolysis and increased NAD+ production; engagement of microglial GPR109A receptors; histone deacetylase inhibition; and elevated n-3 polyunsaturated fatty acids levels. Since microglia activation can now be assessed in vivo, these data provide a clear rationale for the design of transdiagnostic randomized controlled trials of the ketogenic diet and other ketosis-inducing strategies for neuroprogressive diseases, which may also provide mechanistic insights through the assessment of “target engagement”.
Article
It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.
Article
Objective Osteoarthritis is the most prominent form of arthritis, affecting approximately 15% of the population in the United States. Knee osteoarthritis (KOA) has become one of the leading causes of disability in older adults. Besides knee replacement, there are no curative treatments for KOA, so persistent pain is commonly treated with opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs. However, these drugs have many unpleasant side effects, so there is a need for alternative forms of pain management. We sought to test the efficacy of a dietary intervention to reduce KOA. Design A randomized controlled pilot study to test the efficacy of two dietary interventions. Subjects Adults 65–75 years of age with KOA. Methods Participants were asked to follow one of two dietary interventions (low-carbohydrate [LCD], low-fat [LFD]) or continue to eat as usual (control [CTRL]) over 12 weeks. Functional pain, self-reported pain, quality of life, and depression were assessed every three weeks. Serum from before and after the diet intervention was analyzed for oxidative stress. Results Over a period of 12 weeks, the LCD reduced pain intensity and unpleasantness in some functional pain tasks, as well as self-reported pain, compared with the LFD and CTRL. The LCD also significantly reduced oxidative stress and the adipokine leptin compared with the LFD and CTRL. Reduction in oxidative stress was related to reduced functional pain. Conclusions We present evidence suggesting that oxidative stress may be related to functional pain, and lowering it through our LCD intervention could provide relief from pain and be an opioid alternative.
Article
Dietary habits are fundamental issues to assess and modulate health and wellbeing but, furthermore, different nutritional panels may help people in preventing acute and chronic pain. Many substances, known to be active anti-oxidants and anti-inflammatory compounds, should serve this fundamental task. Anti-nociceptive and analgesic natural compounds include flavonoids, terumbone from ginger root, curcuminoids, omega 3-PUFA, and taurine. Furthermore, a correct intake of trace elements and minerals is strategic to reduce inflammation-related pain. This review addresses these items, trying to suggest new criteria for a correct dietary supplementation to prevent pain.
Article
Despite significant advances in pharmacological and non-pharmacological treatments, mood disorders remain a significant source of mental capital loss, with high rates of treatment resistance, requiring a coordinated effort in investigation and development of efficient, tolerable and accessible novel interventions. Ketogenic diet (KD) is a low-carb diet that substantially changes the energetic matrix of the body including the brain. It has been established as an effective anticonvulsant treatment, and more recently, the role of KD for mental disorders has been explored. Ketogenic diet has profound effects in multiple targets implicated in the pathophysiology of mood disorders, including but not limited to, glutamate/GABA transmission, monoamine levels, mitochondrial function and biogenesis, neurotrophism, oxidative stress, insulin dysfunction and inflammation. Preclinical studies, case reports and case series have demonstrated antidepressant and mood stabilizing effects of KD, however, to date, no clinical trials for depression or bipolar disorder have been conducted. Because of its potential pleiotropic benefits, KD should be considered as a promising intervention in research in mood disorder therapeutics, especially in treatment resistant presentations.
Article
Purpose: We evaluated the efficacy and tolerability of the ketogenic diet (KD) on generalised convulsions and status epilepticus (SE) in patients with Dravet syndrome (DS). Methods: Patients with DS having ≥2 generalised convulsions/month despite drug treatment were included in this study and placed on a KD for 6 months. From 3 months before (baseline) to 6 months after KD initiation, caregivers recorded patients' seizure activity, antiepileptic drug use, and adverse events. The KD efficacy was determined by examining the frequency and duration of seizures at 3 and 6 months vs. baseline. Responders were defined as individuals whose generalised convulsions decreased in frequency by ≥50% vs. baseline. Seizures lasting ≥5 min and SE were specifically evaluated. Patients' cognition was also assessed at 3 and 6 months via questionnaire. Results: Twenty patients continued the KD for at least 3 months. Of the 17 responders identified at month 3, seizures decreased by 50-89% and 90-99% in nine and two patients, respectively; six patients were seizure free. The KD was ineffective in three patients, who discontinued the diet. By month 6, seizures decreased by 50-89% and 90-99% in six and one patient(s), respectively; 10 patients were seizure free. The frequency of other seizure types also improved. During all 6 months, neither generalised convulsions lasting ≥5 min nor SE was detected in the 17 responders. The KD also improved patients' cognition. Conclusion: The KD is a good treatment option for medically intractable epilepsy.
Article
Background context: About 85% of the patients with low back pain seeking medical care have nonspecific low back pain (NsLBP), implying that no definitive cause can be identified. NsLBP is defined as LBP and disability which cannot be linked to a underlying pathology, such as cancer, spinal osteomyelitis, fracture, spinal stenosis, cauda equine, ankylosing spondylitis and visceral-referred pain. Many pain conditions are linked with elevated serum levels of pro-inflammatory biomarkers. Outcomes of interest are NsLBP and the level of pro-inflammatory biomarkers. Purpose: To unravel the etiology and get better insight in the prognosis of NsLBP, the aim of this study was to assess the association between proinflammatory biomarkers and the presence and severity of NsLBP. Study design: A systematic literature search was made in Embase, Medline, Cinahl, Webof- science, and Google scholar up to January 19th 2017. Methods: Included were cross-sectional and cohort studies reporting on patients aged over 18 years with NsLBP, in which one or more pro-inflammatory biomarkers were measured in blood plasma. The methodological quality of the included studies was assessed using the Newcastle Ottawa Scale (NOS). A best-evidence synthesis was used to summarize the results from the individual studies, meaning that the included studies were ranked according to the consistency of the findings and according to their methodological quality score using the NOS. Results: Included were 10 studies which assessed 4 different pro-inflammatory biomarkers. For the association between the presence of NsLBP and Creactive protein (CRP), interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α limited, conflicting and moderate evidence, respectively, was found. For the association between the severity of NsLBP and CRP and IL- 6, moderate evidence was found. For the association between the severity of NsLBP and TNF-α and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) conflicting and limited evidence, respectively, was found. Conclusions: This study found moderate evidence for i) a positive association between the pro-inflammatory biomarkers CRP and IL-6 and the severity of NsLBP, and ii) a positive association between TNF-α and the presence of NsLBP. Conflicting and limited evidence was found for the association between TNF-α and RANTES and severity of NsLBP, respectively.
Article
Brain tissue is bioenergetically expensive. In humans, it composes approximately 2% of body weight and accounts for approximately 20% of calorie consumption. The brain consumes energy mostly for ion and neurotransmitter transport, a process that occurs primarily in synapses. Therefore, synapses are expensive for any living creature who has brain. In many brain diseases, synapses are damaged earlier than neurons start dying. Synapses may be considered as vulnerable sites on a neuron. Ischemic stroke, an acute disturbance of blood flow in the brain, is an example of a metabolic disease that affects synapses. The associated excessive glutamate release, called excitotoxicity, is involved in neuronal death in brain ischemia. Another example of a metabolic disease is hypoglycemia, a complication of diabetes mellitus, which leads to neuronal death and brain dysfunction. However, synapse function can be corrected with “bioenergetic medicine”. In this review, a ketogenic diet is discussed as a curative option. In support of a ketogenic diet, whereby carbohydrates are replaced for fats in daily meals, epileptic seizures can be terminated. In this review, we discuss possible metabolic sensors in synapses. These may include molecules that perceive changes in composition of extracellular space, for instance, ketone body and lactate receptors, or molecules reacting to changes in cytosol, for instance, K ATP channels or AMP kinase. Inhibition of endocytosis is believed to be a universal synaptic mechanism of adaptation to metabolic changes.
Article
Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (e.g., microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared to healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18kDa translocator protein (TSPO), in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared to both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared to more superior segments). Furthermore, the neuroforaminal TSPO signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.
Article
The aim of this study is to investigate the effect of ketogenic metabolism, induced by different diet interventions, on histone acetylation and its potential antioxidant capacity to injured spinal cord tissue in rats. 72 male Sprague-Dawley rats were randomly divided into 4 groups, fed with ketogenic diet (KD), every other day fasting (EODF), every other day ketogenic diet (EODKD) and standard diet (SD) respectively for 2 weeks. β-hydroxybutyrate (βOHB) concentration was measured both in serum and cerebrospinal fluid (CSF). C5 spinal cord tissue was harvested before, at 3h and 24h after injury for analysis of HDAC activity, histone acetylation and oxidative makers. All three dietary interventions resulted in significant increase of βOHB level in both serum and CSF, and inhibited HDAC activity by 31%-43% in spinal cord. Moreover, the expressions of acetylated histone AcH3K9 and AcH3K14 were significantly increased. Anti-oxidative stress genes Foxo3a and Mt2 and related proteins, such as Mitochondrial superoxide dismutase (SOD), FOXO3a, catalase were increased in dietary intervention groups. After SCI, high ketogenic metabolism demonstrated significant reduction of the expression of lipid peroxidation factors malondialdehyde (MDA), and this might contribute to the reported neuroprotection of the spinal cord from oxidative damage possibly mediated by increasing SOD. The result of this study suggested that by inhibiting HDAC activity and modifying related gene transcription, ketogenic metabolism, induced by KD, EODF or EODKD, might reduce oxidative damage in spinal cord tissue after acute injury.
Article
Objective: Investigations into the relationship between dietary carbohydrate restriction and health are mixed. Current guidelines for nutrition promote low-fat foods and higher carbohydrate consumption for optimal health and weight loss. However, high-fat, low-carbohydrate diets are revealing both intra- and extracellular adaptations that have been shown to elicit favorable cardiometabolic changes associated with obesity. Moreover, dietary fat is associated with higher satiety levels from the hormones adiponectin, leptin, and cholecystokinin. Additionally, insulin responses from high-glycemic carbohydrates are known to alter these pathways, potentially leading to an increase in energy consumption and a possible mechanism for obesity. Conclusion: There is convincing evidence of beneficial effects of controlled trials implementing high-fat, low-carbohydrate diets in both sedentary and obese individuals, but longer duration clinical trials are required to confirm this hypothesis.
Article
Objectives: To determine the long-term effects of changing the amount or source of dietary carbohydrate on quality of life (QOL), symptoms and dietary satisfaction in people with type 2 diabetes. Methods: Subjects with diabetes treated by diet alone (n=162) were randomly assigned to high-carbohydrate/high-glycemic-index (HGI) diets; high-carbohydrate/low-glycemic-index (LGI) diets; or lower-carbohydrate/high-monounsaturated-fat (LC) diets for 1 year. We measured QOL at baseline and at study's end, and we measured symptoms and dietary satisfaction quarterly. Results: The HGI, LGI and LC diets contained, respectively, 47±1, 52±1 and 40±1% energy carbohydrate; 30±1, 27±1 and 40±1% fat with GI 64±0.4, 55±0.4 and 59±0.4. Significantly more participants reported increased flatulence on LGI than on LC and HGI diets at 3 months (41%, 19%, 14%; p<0.05), but not at 12 months (29%, 17%, 17%; ns). Abdominal distension was more severe (46% vs. 14%, 19%; p<0.05), and headache less severe (8% vs. 22%, 23%; p<0.05) on LGI than on both other diets. Increased appetite was more severe on LC (33%) than on HGI diets (14%, p<0.05). Joint/limb pains were less severe on LGI (16%) than HGI (28%) diets. LC elicited more severe gloomy thoughts (23%) than LGI (4%; p<0.05) but greater dietary-satisfaction (70%; p<0.05) than LGI (40%) and HGI (48%) diets. For all diets, glycated hemoglobin (A1C) levels increased less in those who gained less weight, had less increased appetite and were more satisfied with the enjoyment obtained from eating. Conclusions: Each diet elicited increased severity of 1 or more symptoms than the other diets. Although overall dietary satisfaction was greater on the 40% carbohydrate diet than on the 50% carbohydrate diet, the LGI diet was no less satisfying than the HGI diet. Changes in appetite and dietary satisfaction may influence body weight and glycemic control, or vice-versa.
Article
Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed.
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The high-fat ketogenic diet (KD) is a remarkably effective treatment for medically intractable epilepsy and has been part of the clinical armamentarium for nearly a century. However, the mechanisms underlying the KD's actions have remained elusive. Over the past decade, there has been phenomenal international growth of clinical centers offering metabolism-based therapies for epilepsy, and rapidly expanding research into the cellular and biochemical effects induced by the KD. At present, there are many hypotheses regarding KD action, and while each is uniquely compelling, it is becoming more apparent that the KD likely works through multiple mechanisms that target fundamental biochemical pathways linked to cellular substrates (e.g., ion channels) and mediators responsible for neuronal hyperexcitability. This is not altogether surprising given the complexity of the epileptic brain, and the many different pathophysiologic mechanisms that underlie seizure genesis and epileptogenicity. The scientific literature involving the KD strongly supports the notion that epilepsy may indeed in part represent a "metabolic disease", and that this concept could serve as a novel framework for the development of more effective anti-seizure drugs. Copyright © 2015. Published by Elsevier Ireland Ltd.
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Obesity rates are approaching epidemic proportions and are a significant factor in annual health care costs. In addition to cardiovascular comorbidities, the presence of diabetes and/or chronic pain is extremely high in this population of individuals. It is now well accepted that the cells of the innate (and adaptive) immune system mediate both acute and chronic pain through release of cytokines into the system. In this chapter, we outline the ways in which poor food choices and elevated adipose tissue (body fat) are likely to activate the immune system and increase inflammation and pain. In addition, we explore the ways in which a variety of foods (e.g., broccoli, ginger, grapes, and fish oils) may have anti-inflammatory effects via their direct action on cells in the immune system and on the subsequent release of inflammatory cytokines. Some foods (green tea, ginger, and broccoli) have been found to antagonize specific cell surface receptors, whereas others (grapes, soy proteins, tomatoes and ginseng) appear to reduce nuclear translocation of the major transcription factor NFκB, thereby reducing production of inflammatory cytokines. Together, we provide data in support of the use of diet interventions to reduce pain and inflammation in patients suffering from chronic pain or other inflammation-mediated disorders. © 2015 Elsevier Inc. All rights reserved.
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OA is a degenerative joint disease characterized by articular cartilage degradation, osteophyte formation, synovitis, and subchondral bone sclerosis. One of OAs main risk factors is obesity. To date, it is not fully understood how obesity results in OA. Historically, this link was ascribed to excessive joint loading as a result of increased body weight. However, the association between obesity and OA in non-weight-bearing joints suggests a more complex aetiology for obesity-induced OA. In the present review, the link between obesity and OA is discussed. First, the historical view of altered joint loading leading to wear and tear of the joint is addressed. Subsequently, the effects of a disturbed lipid metabolism, low-grade inflammation, and adipokines on joint tissues are discussed and linked to OA. Taken together, inflamed adipose tissue and dyslipidaemia play pivotal roles in obesity-induced OA. It becomes increasingly clear that the link between obesity and OA transcends excessive loading. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Inflammation is associated with the development of diseases characterized by altered nutrient metabolism. Although an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. The resolution of inflammation involves the termination of neutrophil recruitment, counterregulation of proinflammatory mediators, stimulation of macrophage-mediated clearance, and tissue remodeling. Specialized proresolving lipid mediators (SPMs)-resolvins, protectins, and maresins-are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that the failure of resolution programs contributes to metabolic diseases and that SPMs may play pivotal roles in their resolution.
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The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.