Targeting Central Sensitization With Nutrition: Expert Opinion And Innovations

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Welcome to this episode where we’re discussing expert opinions and innovations on how to target central sensitization through using nutrition and diet and other lifestyle factors. This is a special episode where you can listen, learn and earn continuing education credit. This episode is sponsored by the Integrative Pain Science Institute. The Institute is approved for continuing education for physical therapists. It also meets the standards for the National Board for Certification in Occupational Therapy. The Integrative Pain Science Institute is approved by the American Psychological Association to sponsor getting education credits for psychologists and other mental health providers. Finally, the Institute is recognized by the National Board for Health and Wellness Coaching as an approved continuing education provider. Once you listen to this episode, and you want to rack up some extra continuing education units, all you have to do is go to the, go to the Courses tab, and then scroll down to where it says “Listen and Learn” and click Register to register for episode number 200. This episode is available for two credit hours.

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Targeting Central Sensitization With Nutrition: Expert Opinion And Innovations

Our objective is to describe how poor nutrition upregulates brain glial cell activation and contributes to central sensitization. You’ll be able to identify dietary patterns associated with central nervous system sensitization and chronic pain. Finally, to explain three ways of optimizing nutrition impacts pain and central sensitization. We’ve used the word, central sensitization, probably already about ten times. I think it’s important that we review the working definition that we’re using for this episode and that you use as you go into that CEU approved course. With regards to central nervous system sensitization, the definition we’re following is an amplification of neuronal signaling within the central nervous system that elicits pain hypersensitivity. Each day, the latest pain science explores deeper into exactly what central nervous system sensitization is, what type of conditions this is present in, and of course, how to effectively prevent or treat it.

Chances are if you’re seeing people with chronic low back pain, lumbar radiculopathy, fibromyalgia, migraine-type headaches, pediatric pain and various mood disorders, especially depression, are all associated with signs of central nervous system sensitization. The research points to central nervous system sensitization being a well-established feature in many patients that we’re seeing in the clinic setting today, especially of course those with chronic pain. Over the last couple of years, there have been more and more research papers coming out with regards to how nutrition impacts chronic non-cancer pain.

We’ve had everything from cohort studies to randomized control trials to meta-analyses. There are two meta-analyses that were completed within the last couple of years. The first one was from the Journal of Human Nutrition and Dietetics in 2019. It looked at a systematic review and meta-analysis of nutrition interventions for chronic non-cancer pain. The second one was in the Journal of Clinical Medicine 2020, which asks the question, Do Nutritional Factors Interact with Chronic Musculoskeletal Pain? This is a systematic review. The overarching themes based on these two different meta-analyses and systematic reviews that’s available in the literature is that an altered dietary pattern and altered specific nutrient intake may have analgesic properties for some patients living with chronic pain. That’s the highest level of evidence. That’s level evidence 1A. Further systematic reviews have associated or have a link between nutritional factors and chronic musculoskeletal pain, specifically how plant-based diets have analgesic properties for chronic musculoskeletal pain.

I encourage you to find those papers. Most of them are available publicly through PubMed, where you can read the information about how nutrition impacts chronic pain. On this episode, I want to focus all of our attention on a paper that was published in June of 2020. The title of the paper is Nutritional Intervention in Chronic Pain: An Innovative Way of Targeting Central Nervous System Sensitization. You can find this paper in the Journal of Expert Opinion on Therapeutic Targets. The lead researcher on this paper was Jo Nijs. He is a physiotherapist and a researcher. He’s probably the top five chronic pain researchers in the world. He’s also probably the number one or two researcher with regard to central nervous system sensitization. There were probably about twelve authors who contributed to this paper. I was one of them. It was great to work with all these minds. It’s an interdisciplinary approach to looking at how nutrition, central sensitization, neuroinflammation all contribute to chronic pain.

HPP 200 | Target Central Sensitization
Poor nutrition leads to oxidative stress, necrotic cells, or tissue damage. Poor nutrition can actually damage or kill cells.


This is the focus of our talk and the focus of the CEU activity. I’ll share the methods with you with regard to this paper. As I mentioned before, there have already been two meta-analyses on the impact of nutrition and chronic pain. We probably could have done a third one, there are rooms for more meta-analyses. If you’re a researcher, I encourage you to look at the data and see where the holes are with regard to pulling that research and creating another meta-analysis. We decided to take an umbrella approach where we looked at many different types of evidence, review that evidence, and then of course, based on all the different types of experts on the paper, provide an expert opinion.

It wasn’t just our personal opinion, this opinion used a grading system from the center of evidence-based medicine. That grading system goes from 1A to number 5, and 1A at the top are systematic reviews of randomized controlled trials. Then as you move down from 1A all the way down to 5, you go through randomized controlled trials, cohort studies, individual case controls, case series. Finally, number five is expert opinion with or without a critical appraisal of literature based on physiology. For example, the neurophysiology of how nutrition impacts pain. These are the methods that were used in this paper. It’s an umbrella approach based on review and expert opinion from experts in the field of nutrition, central sensitization and chronic pain.

When we’re talking about central sensitization and nutrition, we’re talking about the neuroimmune mechanisms that link diet to central nervous system sensitization. There are three key neuroimmune mechanisms with regard to central sensitization. The first one is an increase in microglia or just simply glial cell activity in the brain. With that, there’s an increase in neurotrophic factors, for example, brain derived neurotrophic factor. The second is the increase in pro-inflammatory cytokines. Probably the most common one that you’ll see in the literature is tumor necrosis factor alpha and how it can potentiate. Basically those two, the neurotrophic factors and the pro-inflammatory cytokines can enhance or potentiate increase in optic activity. That’s what ultimately leads to pain and central nervous system sensitization. This slide is probably the key slide of the entire presentation. You can see this key slide that looks at the neuroimmune mechanisms that link dietary patterns to central sensitization and activation of a glia in the central nervous system. I’m going through this piece by piece, one by one, I’ll walk you through this.

There’s a lot on this slide. I’m going to start in the centerpiece there. We’re going to talk about poor nutrition. In general, when you look at nutrition research and when they mention the term poor nutrition, you’re looking at a standard Western diet that is high in saturated fat specifically seed oils that are processed, high in carbohydrates, especially highly-processed carbohydrates foods, and then an overall energy dense diet, for example, high calories, high energy. That’s the model of the framework of poor nutrition.

With that, if you follow that down to the center of the slide there, poor nutrition leads to oxidative stress, necrotic cells or tissue damage. Poor nutrition can actually damage cell or kill cells. When that happens, it can activate toll-like receptors. What are toll-like receptors? On the surface of every cell, we have receptors, specifically these toll-like receptors can be found on immune cells, both the innate and the adaptive immune cells. Poor nutrition can activate those toll-like receptors. When that happens, proteins are produced by those immune cells, and those proteins activate the glial cells in the central nervous system, and that’s what leads to central nervous system sensitization. That’s one funnel there you can follow.

The second is that same dietary pattern, high-saturated fat, high-carbohydrate, nutrient poor, energy dense diet can lead to activation of the vagus nerve in your gut. With the activation of the vagus nerve, the vagus nerve runs from many of the organs, specifically the stomach and the small intestine, runs up into the brain. Specifically, you can have inflammation run along the vagus nerve that activates those vagus afferents. Finally, it runs up into the brain, which again activates glial cells in the central nervous system, and then finally assists central nervous system sensitization. There’s more to the picture. Poor nutrition also changes the gut microbiome. With changes in the gut microbiome, you can have inflammation both inside the gut, let’s say inside the stomach, the small intestine and the large intestine. You can also have peripheral inflammation. It’s inflammation that’s traveling in the periphery and your bloodstream, as well as interstitial fluid. That can activate the vagus nerve, but that peripheral inflammation can also travel through the bloodstream. It can pass through the blood brain barrier. It can also pass through the spinal cord barrier. With that, it can activate glial cells in the central nervous system, then finally cause central nervous system sensitization.

Basically, those are the three ways where poor diet can cause this activation of glial cells. You’ll see not only poor nutrition, but you also see three other important factors: opioids, poor sleep and stress. Along with nutrition, opioids, poor sleep and stress can directly impact those toll-like receptors in the immune system. It can also directly impact through the blood brain barrier activation of glial cells, which in turn causes that wind up or that central nervous system sensitization to happen. That’s why we look at an integrative approach where we’re combining changes in someone’s diet and nutrition, along with changes in sleep patterns and stress. Hopefully moving people away or starting to taper them down off of opioids because opioids in effect can lead to opioid-induced hyperalgesia, which is caused by central nervous system sensitization.

Probably the key question with regards to everything we’re speaking about is can nutrition be used to modulate these neuroimmune mechanisms for the modulation of central nervous system sensitization and chronic pain? In this paper, we discuss both animal studies on nutrition and pain, as well as human clinical studies. I don’t have the time to go through all of that on this episode, it would be for a really long detailed episode. I’m going to talk about both. I’m going to talk about animal studies first very briefly. Based on animal studies, we know that the standard American diet, animals specifically, mice or rats are fed a standard American diet, it results in microglial activation of the central nervous system in pain. That is clearly seen in animal studies. We also know that inadequate or poor nutrition contributes to neuroinflammation. Neuro-inflammation is found in many chronic systemic conditions.

Finally, the hot topic of the day is that metabolic ketosis in the studies of mice, favorably impacts both oxidative stress and neuronal excitability. Ketogenic diets in mice and rats have been found to positively alter metabolic ketosis in a way that impacts oxidative stress and neuronal excitability. We don’t have enough human studies with regard to the impact of a ketogenic diet or a ketogenic nutrition on various types of chronic diseases. Specifically, we need more with regard to nutrition and chronic pain. There are definitely good animal models for this with regard to chronic pain. In this paper, there’s an entire page that goes through various animal studies and the impact of nutrition on pain on animals. I’d like to say that there are many poo-poo animal studies that are not being useful. However, I would argue and say that a really good animal study can set the groundwork for good randomized controlled trial that is being done later on humans.

Look at the animal studies, take the information that’s there. Of course, it’s not a randomized controlled clinical trial on humans, but it might set the foundation for later on. Based on human studies on nutrition, we have the highest level of evidence, level 1A. Altered dietary pattern and altered specific nutrients promote analgesia. We also have level five evidence that this analgesia may result from the modulation of central nervous system sensitization, specifically the microglia.

I want to go through some of the studies that we reviewed and covered in this paper, and explain what the study was about and how you can apply this to clinical practice. If you’re watching this slide presentation, in the upper left-hand corner, I’m going to put the level of evidence at this particular study it is valued at, so you can see, “How much can we rely or maybe not rely on this study? Do we need more information with regard to this particular topic?” The first one is a study from 2016 from the Journal of Neuroinflammation. The title of that paper is Targeting Inflammation as a Treatment Modality for Neuropathic Pain and Spinal Cord Injury: A Randomized Control Trial.

Usually RCTs are higher up in the 2 or 1 area. The reason why is this was a very small group. Even though they randomized two different groups, the one group that had the research trial was done on, it was only about twenty participants. Ideally, if this was maybe 100 participants, the level of evidence probably would have been greater, but still there was a control group with this, so it fits into an RCT. This was a twelve-week anti-inflammatory diet intervention for people who had neuropathic pain. They looked at outcomes of inflammation, as well as anti-inflammatory cytokines, as well as looking at pain scores and specifically neuropathic pain scores for this population.

What’s really nice about this paper and most studies don’t do this in such detail. They gave detailed information about what the anti-inflammatory diet intervention consisted of. This anti-inflammatory diet intervention in this study focused on the elimination of common food intolerances and inflammation-inducing foods, as well as the introduction of foods and supplements that were anti-inflammatory. Examples of foods that were removed from the diet included those that were high-glycemic. That includes products that are high in added sugar, as well as products such as wheat. They took out cow’s milk from this as well, and they made sure they took out hydrogenated oils. Many of the seed oils that fall into that Omega-6 category that cause inflammation.

HPP 200 | Target Central Sensitization
Poor nutrition leads to oxidative stress, necrotic cells, or tissue damage. Poor nutrition can actually damage or kill cells.


With that, participants also consumed dietary supplements with established and anti-inflammatory benefits. What were these supplements? Omega-3 fatty acids, both EPA and DHA at a dose of about three per day. They dosed about 1,000 milligrams of both EPA and DHA three times per day. They also took antioxidants in pill form, specifically coenzyme Q10 and acetyl-cysteine, which has both anti-inflammatory as well as antioxidant and detoxification properties. Mixed tocopherols, which is vitamin E, alpha lipoic acid, extracts of green tea, zinc and selenium, which have been shown to have an effect on pain and muscle relaxation. Then finally, curcumin was taken in pill form about 1,200 milligrams.

They took out inflammatory foods, obviously put in anti-inflammatory foods and as well, they included anti-inflammatory dietary supplements as part of this intervention. If we go back to the conclusion, you’ll see that overall the results of this study demonstrate the efficacy of targeting inflammation as a means of treating chronic neuropathic pain with the potential to impact the mechanisms with regard to pro-inflammatory cytokines specifically PGE2.

The next study, we’ll take a look at 2020 from the Journal of Pain Medicine evidence level of 4. The title of this paper is Dietary Inflammatory Index Scores Are Associated With Pressure Pain Hypersensitivity in Women with Fibromyalgia. The reason why this is a level four is because there wasn’t necessarily an intervention in this study that just looking at the association between an inflammatory dietary index and pain pressure hypersensitivity in women with fibromyalgia, but there were two different groups in this study. The first group were women diagnosed with fibromyalgia. The second group where menopause matched controls. There were two groups, but there wasn’t necessarily intervention. They did find that the group that had a higher dietary inflammatory index score associated was correlated with tender points into women who had fibromyalgia. They also looked at the disease severity, fatigue, sleeping anxiety and central sensitization.

The next study, a recent paper from 2020 from the Journal of Pain Medicine, with much higher on the evidence level. This is evidence level 2B. They compared a twelve-week low carbohydrate diet to a low-fat diet on pain and individuals with knee osteoarthritis. If you’re a low carb advocate, you’re going to enjoy this paper because at the end of this twelve-week period, they found that lowering oxidative stress is related to functional improvements in pain in the group with a lower carbohydrate diet, not necessarily the low-fat diet.

If you’re looking at evidence with regards to a low carbohydrate diet with regard to pain, specifically in individuals with knee osteoarthritis, this is really good and high-quality evidence that a low carbohydrate diet can help people with knee osteoarthritis and pain specifically with regard to reducing oxidative stress. Along the lines of the same topic, looking at nutritional interventions for knee osteoarthritis, this is an older paper from 2013, but higher level of evidence, evidence level 1B. The Effects of Intensive Diet and Exercise on Knee Joint Loads, Inflammation and Clinical Outcomes Among Overweight and Obese Adults with Knee Osteoarthritis. This is a longer study. This study was eighteen months. We’re looking at a deep, intense study for the individuals here.

The conclusion from this study was that among those who are overweight and they have knee osteoarthritis after eighteen months, participants in the diet and exercise group, as well as the diet group, had more weight loss and greater reductions in Interleukin 6, which is an inflammatory cytokine, then the exercise group alone. This study also showed that those in the diet group had greater reductions in knee compressive forces than those in the exercise group alone. It goes to show you that combining diet and exercise is the way to go to help people with both inflammation, as well as their weight, specifically with regard to osteoarthritis. There are some other studies that show this as well, but we have high evidence looking at the expert opinion from this particular study that combining diet and exercise is effective for chronic knee osteoarthritis.

To build out this topic a little bit more, there’s this paper from 2018 from the Journal of Arthritis and Rheumatology, the title of this paper is Diet-Induced Weight Loss Alone or Combined with Exercise and Overweight or Obese People with Knee Pain. There’s a systematic review of meta-analysis. This is evidence 1A. The top of the pyramid with regard to confidence and expert opinion here, that when you combine exercise with nutrition, it has an impact on weight as well as pain scores with regard to osteoarthritis. What’s important about this paper is that the experts report moderate pain relief. That’s really important. Most studies when you look at single interventions like just exercise or just diet or just CBT has small impacts on pain. This combination is moderate impact with regards to pain. Most of the studies show with regard to functional activity as well.

This systematic review and meta-analysis specifically mentioned that the effects on inflammatory biomarkers are questionable. That doesn’t surprise me because biomarkers are like a snapshot in time. Different people, depending where they are along the course of the obesity range, and many of these patients who are obese also have pre-diabetes or diabetes. It doesn’t surprise me that we may or may not be able to rely or with a lot of confidence say that it has an impact on biomarkers. I would question that. I would say let’s look at this a little bit closer. If you look at patients and you’ve placed them on both diet as well as exercise interventions, you will see biomarkers change over the weeks.

We’ve talked a lot about knee osteoarthritis. This is from the Journal of Spine 2011. This was a pilot study, that’s why it only received a level evidence of four. This was a multidisciplinary, medically supervised non-surgical weight loss program for low back pain. This was a 52-week intervention. These people received a lot of care over the course of a year. Most insurance companies, at least in the United States of America do not cover that type of care. We need to take that into consideration. They found at the end of this 52-week trial period that nonsurgical weight loss in obese patients with low back pain, both improved pain as well as function.

We’ve talked a lot about diets so far. I’ve talked a lot about weight loss and looking at pain and looking at inflammatory markers. We talked about oxidative stress. We talked about neuroinflammation. I want to turn your attention to this paper in the Journal of Nutrition. This is from 2017. It’s an evidence level 2B. It looks at the tolerance and efficacy of a polyamine deficient diet for the treatment of perioperative pain. Polyamines occurred naturally in many types of foods. Our body actually needs polyamines, although there’s no nutritional requirement for them. Polyamines can be very high in both red meat, as well as processed foods. If you have someone who has a very high amount of meat in their diet, or high amount of processed foods, which the average American has upwards of 60% of their diet is high in processed foods. Bringing that amount of polyamine down or in effect having a polyamine deficient diet does help with the treatment of pain. This study particularly looked at perioperative pain.

Why does it help? There’s been some research that shows that polyamines have an effect on toll-like receptors. It has an effect of modulating those tall-like receptors, which in turn modulates the immune system and modulates that microglial, and finally that central sensitization. This level of evidence of 2B, the conclusion from this study was that suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction, independent of and complimentary to typical analgesic properties. In essence, this study actually gave them a polyamine deficient drink. That was pretty much all they took in with regards to their diet. Most people aren’t going to tolerate that, but it does show you that if you decrease polyamines in the diet, it may have an impact on analgesia.

In addition to polyamines in the diet, we also want to look at glutamate specifically. Glutamate is common in many packaged products. It’s common in many processed foods. Monosodium glutamate or variations of monosodium glutamate are added to foods to improve their taste. This study from the Journal of Current Developments of Nutrition, this is from June of 2020. It looked at chronic pain in Gulf War veterans. This was a randomized controlled trial, evidence level 2B, looked at the effect of a low glutamate diet and how it can impact pain and other symptoms in veterans with Gulf War illness. They found that a low glutamate diet was effective for the treatment of chronic pain and many other symptoms associated with Gulf War illness.

HPP 200 | Target Central Sensitization
What’s nice about lifestyle interventions is they have very few negative side effects and oftentimes have the most powerful, positive effects on people’s health.


If you’re looking at different types of food additives or a specific element of the diet, low glutamate and low polyamine diets will have an impact according to the highest level of evidence and expert opinion for the impact of chronic pain. I’m going to pop in here with this summary, looking at how nutrition can be used as a target for central sensitization. Obviously, papers like this can both inform dietary or nutrition approaches. When we’re talking about things on a cellular level, it can also be used to develop new pharmaceutical interventions. If you know me, I hope we can keep dialing in the diet and nutrition and lifestyle to help people rather than pharmaceutical interventions. There’s a place for that of course, but what’s nice about lifestyle interventions is they have very few negative side effects and oftentimes have the most powerful, positive effects on people’s health.

There are seven potential therapeutic targets with regards to nutrition, the neuroimmune mechanisms and central sensitization. Those are impacting oxidative stress impacting toll-like receptors, impacting vagal nerves, the microglia, the gut microbiome, polyamines and glutamate, then finally neuro-transmitters specifically as glutamate has an impact on the glutamate balance in the nervous system. This presentation will show you how exercise impacts the gut microbiome, specifically increase the diversity of the gut microbiome. When you combine exercise with a low sugar diet, so obviously we don’t want to have a lot of added sugar to the diet, a diet that’s low in saturated fat from seed oils. When you combine those two, it has an impact on gut microbiome. It has an impact on the vagus nerve. It has an impact on inflammation. All that can normalize glial cell activity in the central nervous system and hopefully modulate or decrease central nervous system sensitization with regard to diet. We’re looking at an anti-inflammatory diet that is high in antioxidants, has the ability to decrease oxidative stress. It has the ability to modulate or prevent the activation of toll-like receptors in both the peripheral and the central nervous system to decrease that central sensitization.

We talked a lot about diet interventions and how to help people with dietary interventions, and how they have an effect on chronic pain. Also in this paper, we looked at how to deliver these interventions. This paper here from 2018 called The Effectiveness of Telephone-Based Interventions for Managing Osteoarthritis and Spinal Pain: A Systematic Review and Meta-analysis, evidence level 1B. From this evidence, they concluded that they are moderately confident that telephone-based interventions can reduce pain intensity, as well as disability in patients with osteoarthritis and spinal pain compared to usual care. This is good information for us right now especially during COVID, when many of us are still relying on or have increased the amount of remote based counseling or interventions for the management of chronic pain.

Then there’s this article from 2017 called Lifestyle Interventions Based on the Diabetes Prevention Program Delivery via eHealth. This is a systematic review and meta-analysis. This is evidence level 1A. It showed that eHealth apps or eHealth interventions are promising and can have an impact on diabetes for people when you combine these eHealth interventions with some counseling. When you combine, let’s say ten weeks of an eHealth intervention, but you also give maybe 1 or 2 counseling interventions that are live, that’s potentially more effective for these types of chronic diseases that we see. Here is your reference. If you want to reference everything I spoke about on this episode, I encourage you to look at this paper, Nutritional Interventions in Chronic Pain: An Innovative Way of Targeting Central Nervous System Sensitization, June 2020, Expert Opinion on Therapeutic Targets, a Journal of Expert Opinion on Therapeutic Targets.

This has been a listen, learn and earn episode. You can earn two CE/CEUs by logging on to the Integrative Pain Science Institute. Once you get to the homepage, you’re going to scroll over to the Courses tab, scroll down to Listen and Learn. Click on the episode to register episode number 200, where you can learn further about nutrition, central sensitization and chronic pain. It’s been great spending this time with you this week. Stay tuned. I’ve got lots of things planned as we head into late 2020. As we change gears and shift into 2021, there are lots of great things. I know it’s been a rough year for some people, but 2021 is going to look good for people living with chronic pain as we help them overcome chronic pain naturally with all the various interventions we’ve been talking about. I’ll see you next time.

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