Anti-Inflammatory Diet:

Dietary Phytonutrients for Pain – a compound based approach

Plant-based nutrients to reduce oxidative stress and inflammation

Plant-based nutrients, or phytonutrients, are natural compounds found in fruits & vegetables, that play vital roles in one’s health and well being. They also offer important benefits in the management of acute and chronic pain.

 

See: Dietary Polyphenols for Pain – Diagnosis Based

For more information, see: clevelandclinic.org

 

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Plant-based Nutrients (Phytonutrients) for Pain

Plant-based nutrients, or phytonutrients, are natural compounds found in fruits, vegetables, dark chocolate, coffee, and tea. These phytonutrients help reduce pain and inflammation in conditions like arthritis, migraines, nerve pain (sciatica, neuropathy, multiple sclerosis, spinal cord and brain injury), Alzheimer’s, and stroke. They include antioxidants that neutralize free-radical molecules to combat oxidation and anti-inflammatories that can ease joint pain, nerve pain, and brain-related symptoms by reducing inflammation.

Oxidative stress (excessive oxidation) and neuro-inflammation (inflammation involving the nervous system) are the fundamental drivers that maintain chronic pain that leads to peripheral and central sensitization and the magnified  experience of pain associated with sensitization.

  • Oxidative stress, caused by an imbalance of reactive oxygen species (ROS) like hydroxyl radicals and reactive nitrogen species (RNS) like peroxynitrite, damage cells, proteins, lipids, and DNA, contributing to systemic inflammation and pain amplification (Rudrapal et al., 2022). In conditions like rheumatoid arthritis and osteoarthritis, ROS & RNS exacerbate joint inflammation, while in neuropathic pain (e.g., sciatica, peripheral neuropathy, multiple sclerosis), oxidative damage to nerves heightens central sensitization and increases pain.
  • Neuroinflammation drives migraines, headaches, and neurodegenerative conditions like Alzheimer’s, while spinal cord injury and stroke involve nerve damage and pain amplification and maintenance.

Regular intake of polyphenol-rich foods or supplements can scavenge ROS, modulate inflammatory pathways, and support pain management, offering a safe, accessible strategy to improve health and reduce pain. Bioavailability of polyphenols varies due to gut metabolism and solubility, but dietary strategies and advanced supplement forms can enhance absorption (Manach et al., 2004; Islam, 2025).

Listed here are powerful phytonutrients called polyphenols and the common polyphenol-rich foods in which they can be found. It is always recommended that one obtain the benefits of these compounds from eating the natural foods that contain them. However, these compounds are also available as dietary supplements that may be recommended by your doctor.

Selected Key Dietary Polyphenols

Below are key dietary polyphenols with strong evidence for reducing oxidative stress and inflammation, particularly in pain-related and neurodegenerative conditions. Each includes:

  • Pain-Related Benefits: listed in order of best evidence first
  • Common Food Sources: listed in order of most abundant amount of compound first
  • Dietary intake: amounts of compound in common food sources/100gm
  • Recommended Daily Intake
  • Bioavailability
  • Absorption Factors
  • Enhancement Strategies:
  • Supplement Recommendations
  • Preferred Supplement Forms: I.e. liposomal vs nano vs liquid etc
  • Suggestion Brands/Products:
  • Special Considerations:
  • Mechanisms of Action:
  • Efficacy in modulating peripheral and central sensitization:
  • Evidence of benefits:
  • Synergies: with other foods/compounds part of anti-inflammatory diet by mechanisms of benefit

How to Add Polyphenols to Your Diet

  • Daily Goal: Eat 2–3 servings of polyphenol-rich foods daily. Try smoothies with berries (cyanidin), salads with red onions (quercetin) and kale (kaempferol), green tea (no milk, EGCG), or turmeric (curcumin) with black pepper.
  • Boost Absorption: Pair with healthy fats (e.g., olive oil, avocado). Add black pepper to turmeric. Avoid milk with green tea (Hollman & Katan, 1999).
  • Supplements: Consider using supplements when the evidence is high for benefit. These phytonutrients are generally considered as safe (GCAS) by the FDA and should be well tolerated. Consider using higher quality brands like Thorne Advanced Nutrients (curcumin, quercetin, EGCG, resveratrol, ~$2.20/day) or Life Extension Two-Per-Day (quercetin, ~$0.80/day). Start with low doses and consult your doctor for drug interactions (e.g., blood thinners, MS drugs like Vumerity).
  • Monitoring: Check inflammation markers (e.g., CRP) after 4–12 weeks.

Key Polyphenols:

Curcumin (Turmeric)

Pain-Related Benefits:

Curcumin, found in turmeric, is a top choice for reducing inflammation and pain in osteoarthritis, with strong clinical evidence showing 30–40% pain reduction and improved joint function in randomized controlled trials (RCTs) (Daily et al., 2016). It also helps with rheumatoid arthritis by easing joint swelling and stiffness, and reduces fibromyalgia and migraine pain by calming inflammation in the body and brain.

For nerve-related pain, such as sciatica, peripheral neuropathy, multiple sclerosis (MS), and spinal cord injury, curcumin lessens burning or tingling sensations by protecting nerves from oxidative damage. It may also support stroke and Alzheimer’s recovery by reducing brain inflammation, making it a versatile option for managing chronic pain and related symptoms.

Curcumin’s pain relief comes from its ability to block inflammation-causing molecules like IL-6 and TNF-α, which are key in arthritis and nerve pain. Studies suggest it reduces cartilage damage in osteoarthritis and may lower migraine frequency by calming brain inflammation. While more research is needed for conditions like MS and stroke, early studies show curcumin protects nerves and reduces pain amplification, offering hope for patients with complex pain conditions.

  • Common Food Sources: Turmeric root (100–200 mg/g, dried), curry powders, mango ginger.
  • Dietary Intake: Turmeric (100–200 mg curcumin/100 g dried root; 1 tsp ~2 g, provides ~200–400 mg curcumin); curry powders (~50–100 mg/100 g); mango ginger (~20–50 mg/100 g).
  • Recommended Daily Intake: 500–1,500 mg/day (supplements); 1–2 tsp turmeric (~200–400 mg curcumin) with black pepper for dietary intake (Rudrapal et al., 2022).
  • Bioavailability: Curcumin has very low bioavailability (<1%) due to poor solubility and rapid metabolism in the gut and liver, where it is conjugated to glucuronides (Manach et al., 2004).
  • Absorption Factors: Absorbed in the small intestine, curcumin is quickly metabolized, limiting plasma levels. Poor water solubility reduces uptake unless enhanced (Scalbert et al., 2005).
  • Enhancement Strategies: Dietary fats (e.g., olive oil, coconut milk) improve solubility and absorption (Zheng et al., 2015). Co-administration with piperine (black pepper) increases bioavailability by up to 2000% by inhibiting glucuronidation metabolism of cur cumin.However,  Nanoparticles consistently achieve higher bioavailability enhancements (15.6- to 55.4-fold) compared to piperine’s 20-fold increase, with sustained plasma levels (up to 24 hours vs. 1–2 hours for piperine). This makes nanoparticles more effective for therapeutic applications requiring systemic exposure, such as pain management in arthritis or neuroinflammation in Alzheimer’s.
  • Supplement Recommendations: Use liposomal or nanoformulated curcumin for better absorption. Start with 500 mg/day, increasing to 1,500 mg/day if tolerated, under medical supervision.
  • Preferred Supplement Forms: Both Liposomal and Nanoparticle-based products offer superior bioavailability without piperine’s drug interaction risks.
  • Liposomal curcumin (e.g., Meriva) or micellar curcumin enhances solubility and cellular uptake (Zheng et al., 2015).
  • Nanoparticle formulations of curcumin achieve significantly higher bioavailability (15.6- to 55.4-fold) compared to unformulated curcumin, surpassing the up to 20-fold increase seen with piperine. These formulations offer sustained release, higher plasma concentrations, and reduced risk of drug interactions, making them a safer and more effective option. While piperine is a dietary enhancer, its potential for drug interactions and inconsistent efficacy at lower doses (e.g., 5 mg) coupled with the low dosage of curcumin associated with usual dietary intake makes nanoparticles the preferred choice for clinical applications.
  • Suggested Brands/Products:.
  • Liposomal products include Thorne Meriva-SF (~$2.20/day, 150 mg/4 capsules) and  Life Extension Super Bio-Curcumin (~$1.50/day).
  • Nanoparticle-based products like Theracurmin (available from Thorne, ~$2.20/day for 180 mg) or Meriva (liposomal, ~$1.50/day for 500 mg)
  • Patient Safety: For patients with chronic pain conditions on medications (e.g., blood thinners), nanoparticle formulations are preferable to avoid piperine’s potential to alter drug metabolism, ensuring safer integration into treatment plans.
  • Special Considerations: Avoid with blood thinners (e.g., warfarin) due to potential interactions. Monitor for GI upset at high doses (>2 g/day) (Daily et al., 2016).
  • Mechanisms of Action (Patient-Friendly): Curcumin acts like a shield, stopping harmful molecules that damage joints and nerves, which helps reduce pain in arthritis and nerve conditions. It also calms inflammation in the body and brain, easing swelling, stiffness, and even migraine pain (Aggarwal & Harikumar, 2009).
  • Mechanisms of Action (Physician-Directed): Curcumin scavenges reactive oxygen species (ROS) like hydroxyl radicals and peroxynitrite, preventing lipid peroxidation and oxidative damage to neurons and joint tissues. It inhibits NF-κB, COX-2, and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), reducing inflammation in osteoarthritis, rheumatoid arthritis, and neuroinflammation in Alzheimer’s and stroke (Aggarwal & Harikumar, 2009; Daily et al., 2016).
  • Efficacy in modulating peripheral and central sensitization: Strong preclinical evidence for suppressing peripheral (TRPV1, COX-2 inhibition) and central sensitization (glial inhibition, NMDA receptor downregulation) in chronic constriction injury (CCI) and spinal cord injury (SCI) models. Limited clinical data suggest peripheral inflammation reduction (Nakagawa et al., 2014).

Preclinical Evidence in modulating sensitization:

    • Neuropathic Pain Models: In a 2016 study in Neuroscience Letters, curcumin (50–200 mg/kg, oral, 7 days) attenuated mechanical allodynia and thermal hyperalgesia in a chronic constriction injury (CCI) model of neuropathic pain in rats. It reduced central sensitization by decreasing spinal expression of pro-inflammatory cytokines (TNF-α, IL-1β) and glial fibrillary acidic protein (GFAP, a marker of astrocyte activation), suggesting modulation of spinal glial activity and neuroinflammation. Curcumin also downregulated phosphorylated NR2B (NMDA receptor subunit), a key mediator of central sensitization.
    • Spinal Cord Injury (SCI): A 2020 study in Molecular Pain showed that curcumin (100 mg/kg, intraperitoneal, 14 days) reduced mechanical allodynia and thermal hyperalgesia in a rat SCI model. It suppressed central sensitization by decreasing microglial activation and CX3CL1/CX3CR1 signaling in the spinal dorsal horn, critical pathways for pain amplification.
    • Mechanisms: Curcumin inhibits NF-κB signaling, reducing pro-inflammatory cytokine release, and enhances antioxidant defenses (e.g., superoxide dismutase, catalase), mitigating oxidative stress-induced sensitization. It also modulates TRPV1 channels, reducing peripheral nociceptor sensitivity. Nanoparticle formulations (e.g., Theracurmin) enhance bioavailability, achieving up to 27-fold higher AUC compared to unformulated curcumin, potentially amplifying these effects (Sasaki et al., 2011,).

Clinical Evidence in modulating sensitization:

Limited direct evidence exists for curcumin’s effect on sensitization in humans. A 2014 study in Journal of Pain Research found that curcumin (400 mg/day, 8 weeks) reduced pain scores in osteoarthritis patients, possibly by suppressing peripheral inflammation (e.g., IL-6, CRP), which could indirectly reduce peripheral sensitization. However, no studies directly measured central sensitization markers (e.g., spinal or supraspinal activity) in humans.

Summary of Evidence in modulating sensitization:

Curcumin shows robust preclinical evidence for suppressing both peripheral (via TRPV1 and cytokine modulation) and central sensitization (via glial inhibition and NMDA receptor downregulation). Nanoparticle formulations enhance its efficacy, but clinical studies are needed to confirm effects on sensitization in humans.

  • Evidence of Benefits: Strong RCTs show 30–40% pain reduction in osteoarthritis (Daily et al., 2016); preclinical studies support benefits for fibromyalgia, migraines, neuropathy, MS, spinal cord injury, and stroke (Aziz et al., 2018).
  • Synergies:
  • Combining with berries (cyanidin) or green tea (EGCG) boosts antioxidant effects, protecting nerves in MS and stroke (Wen Deng et al., 2023).
  • Pairs well with omega-3 fatty acids (e.g., fish oil, 1–2 g/day EPA+DHA) to enhance anti-inflammatory effects. EPA and DHA can inhibit COX-2  (cyclooxygenase-2) by interfering with the COX-2 pathway through multiple mechanisms.

Resveratrol

Pain-Related Benefits:

Resveratrol shows moderate clinical evidence for reducing pain in arthritis, particularly rheumatoid arthritis, by decreasing joint swelling and tenderness (Khojah et al., 2018). It may also help with neuropathic pain in conditions like peripheral neuropathy, MS, spinal cord injury, and stroke by protecting nerves from oxidative stress.

Evidence for pain relief in migraines and fibromyalgia is less robust and relies on preclinical studies. For Alzheimer’s, resveratrol supports brain health by reducing inflammation and may ease related discomfort.

While human studies are limited for nerve pain, animal models suggest resveratrol reduces pain amplification in sciatica and MS, making it a promising option for patients seeking complementary pain relief.

  • Common Food Sources: Red grapes (skin, 1–2 mg/100 g), red wine (1–10 mg/L), blueberries, cranberries, peanuts, dark chocolate.
  • Dietary Intake: Red grapes (1–2 mg/100 g; 1 cup ~1–2 mg); red wine (1–10 mg/L; 150 mL glass ~1–1.5 mg); blueberries (~0.5–1 mg/100 gm).
  • Recommended Daily Intake: 100–500 mg/day (supplements); 1–2 glasses red wine or 1 cup grapes (~1–5 mg) for dietary intake (Rudrapal et al., 2022).
  • Bioavailability: Low (~1–5%) due to rapid gut/liver metabolism into glucuronides and sulfates (Manach et al., 2004).
  • Absorption Factors: Absorbed in the small intestine, peaks in plasma within 30–60 minutes, but rapid conjugation reduces effectiveness (Scalbert et al., 2005).
  • Enhancement Strategies: Consume with dietary fats (e.g., olive oil, avocado) to enhance solubility. Piperine may inhibit glucuronidation (Vestergaard & Ingmer, 2019).
  • Supplement Recommendations: Use liposomal resveratrol, starting at 100 mg/day, increasing to 500 mg/day if needed, with medical guidance.
  • Preferred Supplement Forms: Liposomal or nanoemulsion resveratrol for better absorption (Vestergaard & Ingmer, 2019).
  • Suggested Brands/Products: Thorne ResveraCel (~$2.20/day, 25 mg/4 capsules), Life Extension Optimized Resveratrol (~$1.00/day).
  • Special Considerations: Avoid high doses (>1 g/day) due to GI upset. Caution with anticoagulants due to platelet inhibition (Bonnefont-Rousselot, 2016).
  • Mechanisms of Action: Patient-Friendly: Resveratrol protects joints and nerves by stopping harmful molecules that cause damage and pain. It also reduces swelling in arthritis and supports brain health, helping with pain in conditions like stroke or Alzheimer’s (Rahman et al., 2020).
  • Mechanisms of Action: Physician-Directed: I Resveratrol’s benefits stem from reducing inflammation markers like IL-6 and CRP, which drive joint pain, and protecting neurons via SIRT1 and AMPK pathways. Resveratrol scavenges ROS (e.g., superoxide, hydroxyl radicals), reducing oxidative damage to neurons and tissues. It inhibits COX-1, decreasing thromboxane A2 and inflammation, and activates SIRT1 and AMPK pathways, promoting neuroprotection in Alzheimer’s, stroke, and neuropathic pain (Rahman et al., 2020; Meng et al., 2021).
  • Efficacy in modulating peripheral and central sensitization: Suppresses central sensitization via NMDA receptor and microglial inhibition (Cady et al., 2010). Clinical data are limited to cognitive benefits (Turner et al., 2014).

Preclinical Evidence in modulating sensitization:

    • Neuropathic Pain: A 2010 study in Molecular Pain demonstrated that resveratrol (30 µg, intrathecal, single dose) reversed morphine-resistant neuropathic pain in rats by reducing spinal NR1 and NR2B NMDA receptor subunit expression, key mediators of central sensitization. It also suppressed microglial activation and pro-inflammatory cytokine release (IL-1β, IL-6) in the spinal cord (Cady et al., 2010,).
    • Chronic Stress and Pain: A 2023 study in Cell Death & Disease showed that a bioactive dietary polyphenol preparation (BDPP) containing resveratrol (400 mg/kg, oral, via drinking water) reduced depression-like and anxiety-like behaviors in mice by reversing microglial activation in the amygdala and hippocampus. This suggests suppression of central sensitization in supraspinal pain-related regions (e.g., amygdala), mediated by the HMGB1-RAGE signaling pathway (Wang et al., 2023,).
    • Mechanisms: Resveratrol activates SIRT1, a protein that inhibits NF-κB and promotes M2 (anti-inflammatory) microglial polarization, reducing neuroinflammation and central sensitization. It also modulates the gut-brain axis, enhancing metabolite bioavailability to suppress inflammation (Yan et al., 2022,).

Clinical Evidence in modulating sensitization:

A 2014 randomized controlled trial (RCT) in Journal of Alzheimer’s Disease found that resveratrol (200 mg/day, 26 weeks) improved memory and hippocampal connectivity in older adults, suggesting modulation of supraspinal plasticity, though direct pain sensitization was not assessed. Co-administration with piperine (20 mg) enhanced bioavailability, supporting its use in pain contexts (Turner et al., 2014,).

Summary of Evidence in modulating sensitization:

Resveratrol suppresses central sensitization by inhibiting NMDA receptors, microglial activation, and HMGB1-RAGE signaling in preclinical models. Its effects on supraspinal regions suggest potential for modulating central pain pathways, but clinical evidence specific to sensitization is lacking.

  • Evidence of Benefits: RCTs show reduced inflammation in rheumatoid arthritis (Khojah et al., 2018); preclinical data support neuropathy, MS, spinal cord injury, and stroke (Meng et al., 2021).
  • Synergies: Combines with omega-3s (1–2 g/day) to enhance anti-inflammatory effects via COX-1 inhibition. Pairs with berries (cyanidin) for antioxidant synergy in neuroprotection (Wen Deng et al., 2023).

Cyanidin (Anthocyanin)

Pain-Related Benefits:

Cyanidin, an anthocyanin, is found in various fruits and vegetables with red, purple, or blue hues. It has emerging clinical evidence for reducing joint pain and inflammation in osteoarthritis and rheumatoid arthritis, helping ease stiffness and swelling (Khoo et al., 2017). It also shows promise for neuropathic pain in sciatica, peripheral neuropathy, MS, and spinal cord injury by reducing oxidative stress on nerves (based on preclinical studies).

For migraines and Alzheimer’s, cyanidin may decrease inflammation-related discomfort, though human data are limited.

Its ability to block COX-1 and COX-2 enzymes reduces inflammation in joints and nerves, while its antioxidant properties protect against cell damage in stroke and Alzheimer’s. Though less studied than curcumin, cyanidin’s benefits in arthritis and potential in neuropathic pain make it a valuable addition to an anti-inflammatory diet.

Common Food Sources: Blackberries (100–200 mg/100 g), blueberries, black chokeberries, red and black grapes, raspberries, and elderberries are excellent sources. Other good sources include cherries, plums, apples, red cabbage, and red onions and other various fruits and vegetables with red, purple, or blue hues.

Dietary Intake: Blackberries (100–200 mg/100 g; 1 cup ~100–200 mg); blueberries (~50–100 mg/100 g); red cabbage (~20–50 mg/100 g).

Recommended Daily Intake: 50–100 mg/day (supplements); 1 cup blackberries or blueberries (~100–200 mg) for dietary intake (Rudrapal et al., 2022).

  • Bioavailability: Low (~1–2%) due to rapid metabolism to phenolic acids in the gut and colon (Manach et al., 2004).
  • Absorption Factors: Glycosylated forms (e.g., cyanidin-3-glucoside) are absorbed intact in the small intestine, but microbial metabolism reduces plasma levels (Khoo et al., 2017).
  • Enhancement Strategies: Consume with dietary fats (e.g., yogurt, avocado) to enhance absorption. Fermentable fibers (e.g., from berries) support gut microbial metabolism (Reis et al., 2016).
  • Supplement Recommendations: Use standardized berry extracts (20–30% anthocyanins), starting at 50 mg/day, with medical advice.
  • Preferred Supplement Forms: Liposomal or microencapsulated anthocyanin extracts for stability and absorption (Reis et al., 2016).
  • Suggested Brands/Products: Vitacost Bilberry Extract (~$0.50/day), Life Extension Blueberry Extract (~$0.80/day).
  • Special Considerations: Monitor for rare allergic reactions. Limited safety data for high doses (>200 mg/day) (Khoo et al., 2017).
  • Mechanisms of Action: Patient-Friendly: Cyanidin fights harmful molecules that hurt joints and nerves, reducing pain and swelling in arthritis. It also protects the brain, which may help with migraine or Alzheimer’s discomfort (Reis et al., 2016).
  • Mechanisms of Action: Physician-Directed: Cyanidin scavenges ROS, inhibiting lipid peroxidation in nerves and joints. It inhibits COX-1 and COX-2, reducing prostaglandin synthesis, which decreases inflammation in arthritis and neuroinflammation in Alzheimer’s and migraines. Its ability to block COX-1 and COX-2 enzymes reduces inflammation in joints and nerves, while its antioxidant properties protect against cell damage in stroke and Alzheimer’s(Reis et al., 2016; Khoo et al., 2017).
  • Efficacy in modulating peripheral and central sensitization:

Preclinical Evidence in modulating sensitization:

A 2017 study in Food & Nutrition Research found cyanidin (20–50 mg/kg, oral, 10 days) reduced inflammatory pain in mice by inhibiting COX-2 and prostaglandin E2, mitigating peripheral sensitization. A 2021 study in Molecular Pain showed cyanidin (30 mg/kg, oral, 14 days) reduced spinal TNF-α and glial activation in a rat CCI model, suggesting central sensitization suppression (Khoo et al., 2017; Li et al., 2021).

Mechanisms: Scavenges ROS, inhibits COX-1/COX-2, and reduces neuroinflammation via NF-κB suppression. Limited BBB crossing restricts direct CNS effects.

Clinical Evidence in modulating sensitization:

Limited to anti-inflammatory effects in arthritis (Khoo et al., 2017), with no direct sensitization studies.

Summary of Evidence in modulating sensitization:

Cyanidin suppresses peripheral sensitization via COX inhibition and shows moderate central sensitization effects in preclinical models. Clinical data are needed.

  • Evidence of Benefits: Clinical studies show reduced inflammation in arthritis; preclinical data support neuropathic pain, MS, stroke, and Alzheimer’s (Khoo et al., 2017).
  • Synergies: Pairs with omega-3s (1–2 g/day) to enhance COX inhibition. Combines with turmeric (curcumin) or green tea (EGCG) for antioxidant synergy in nerve protection (Wen Deng et al., 2023).

 

Quercetin

Pain-Related Benefits:

Quercetin reduces joint pain and stiffness in rheumatoid arthritis, with RCTs showing significant relief in morning stiffness and inflammation (Javadi et al., 2017). It also helps neuropathic pain in sciatica, peripheral neuropathy, and MS by protecting nerves from oxidative damage, with preclinical studies supporting its role in spinal cord injury and stroke. For migraines, quercetin may reduce severity by stabilizing mast cells and calming brain inflammation, though human evidence is limited.

Preclinical data suggest quercetin supports Alzheimer’s recovery by reducing neuroinflammation, making it a versatile option for patients with joint and nerve-related pain conditions.

  • Common Food Sources: Red onions (20–32 mg/100 g), capers, kale, apples, berries (e.g., cranberries, blueberries), also including  broccoli, citrus fruits, cherries, green tea, coffee, and red wine.
  • Dietary Intake: Red onions (20–32 mg/100 g; 1 medium onion ~10–30 mg); kale (~10–20 mg/100 g); apples (~4–8 mg/100 g).
  • Recommended Daily Intake: 500–1,000 mg/day (supplements); 1–2 cups onions or kale (~10–30 mg) for dietary intake (Rudrapal et al., 2022).
  • Bioavailability: Low (~2–10%) due to glucuronidation and sulfation. Glycosides (e.g., quercetin-3-glucoside in onions) are better absorbed (Hollman & Katan, 1999).
  • Absorption Factors: Absorbed in the small intestine, with peak plasma levels at 1–2 hours. Glycosides enhance uptake compared to aglycones (Manach et al., 2004).
  • Enhancement Strategies: Consume with dietary fats (e.g., olive oil, nuts). Vitamin C may stabilize quercetin and reduce oxidation (Pérez-Jiménez et al., 2010).
  • Supplement Recommendations: Use liposomal quercetin, starting at 500 mg/day, increasing to 1,000 mg/day if tolerated, with medical supervision.
  • Preferred Supplement Forms: Liposomal or phytosome quercetin for improved absorption (Shi et al., 2019).
  • Suggested Brands/Products: Thorne Vitamin C with Quercetin (~$2.20/day, 50 mg/4 capsules), Life Extension Two-Per-Day (~$0.80/day, 5 mg/2 capsules).
  • Special Considerations: Caution with blood thinners or kidney issues due to CYP2D6 inhibition at high doses (>1.5 g/day) (Javadi et al., 2017).
  • Mechanisms of Action: Patient-Friendly: Quercetin protects joints and nerves by stopping harmful molecules that cause pain and damage. It reduces swelling in arthritis and calms brain inflammation, which may help with migraines or Alzheimer’s (Pandey & Rizvi, 2009).
  • Mechanisms of Action: Physician-Directed: Quercetin scavenges ROS, reducing lipid peroxidation in nerves and tissues. It inhibits NF-κB, AP-1, and lipoxygenase, lowering IL-6, TNF-α, and leukotriene production. Its anti-inflammatory effects target cytokines like IL-6 and TNF-α, easing arthritis and systemic inflammation. It activates Nrf2, similar to VUMERITY, supporting neuroprotection in MS, Alzheimer’s, and stroke (Javadi et al., 2017; Middleton et al., 2000).
  • Efficacy in modulating peripheral and central sensitization: Suppresses peripheral sensitization (TRPV1, COX-2) and moderate central effects (microglial inhibition). Clinical data support anti-inflammatory effects (Javadi et al., 2017).

Preclinical Evidence in modulating sensitization:

    • Neuropathic Pain: A 2017 study in Neuropharmacology found that quercetin (100 mg/kg, oral, 14 days) reduced mechanical allodynia and thermal hyperalgesia in a rat sciatic nerve injury model. It suppressed peripheral sensitization by inhibiting TRPV1 channel activity in dorsal root ganglia (DRG) neurons and central sensitization by reducing spinal microglial activation and IL-1β expression.
    • Inflammatory Pain: A 2022 review in Frontiers in Pharmacology noted that quercetin (50–200 mg/kg, oral) reduced inflammatory pain in mice by inhibiting COX-2 and prostaglandin production, key mediators of peripheral sensitization (Khan et al., 2021,).
    • Mechanisms: Quercetin inhibits pro-inflammatory pathways (e.g., NF-κB, COX-2) and enhances Nrf2-mediated antioxidant responses, reducing oxidative stress in peripheral and central tissues. Its moderate BBB permeability limits direct CNS effects, but gut microbiota-derived metabolites (e.g., 3,4-dihydroxyphenylacetic acid) may enhance CNS bioavailability (Ma et al., 2020,).

Clinical Evidence in modulating sensitization:

A 2020 RCT in Journal of Clinical Nutrition found that quercetin (500 mg/day, 8 weeks) reduced CRP and IL-6 in patients with rheumatoid arthritis, suggesting suppression of peripheral inflammation that could mitigate sensitization. No direct studies on central sensitization were found.

Summary of Evidence in modulating sensitization:

Quercetin effectively suppresses peripheral sensitization via TRPV1 and COX-2 inhibition and shows moderate effects on central sensitization through microglial modulation. Clinical evidence supports its anti-inflammatory role, but direct sensitization studies are needed.

  • Evidence of Benefits: RCTs show pain reduction in rheumatoid arthritis (Javadi et al., 2017); preclinical data support neuropathy, MS, migraines, spinal cord injury, stroke, and Alzheimer’s (Ahmed et al., 2006).
  • Synergies: Combines with vitamin C (500–1,000 mg/day) to enhance antioxidant effects. Pairs with omega-3s or berries (cyanidin) for anti-inflammatory and neuroprotective benefits (Wen Deng et al., 2023).

 

Kaempferol

Pain-Related Benefits:

Kaempferol shows preclinical evidence for reducing joint pain and inflammation in rheumatoid arthritis and osteoarthritis by decreasing cartilage damage and swelling (Lee et al., 2018). It may help neuropathic pain in sciatica, peripheral neuropathy, MS, and spinal cord injury by protecting nerves from oxidative stress, though human studies are limited. For Alzheimer’s and migraines, kaempferol may reduce neuroinflammation, but evidence is primarily from animal models.

While clinical trials are needed, kaempferol’s antioxidant properties make it a promising addition for patients managing arthritis or nerve-related pain through diet or supplements.

  • Common Food Sources: Kale (47 mg/100 g), spinach, broccoli, capers, green tea (no milk).
  • Dietary Intake: Kale (47 mg/100 g; 1 cup ~20–50 mg); spinach (~20–30 mg/100 g); green tea (~5–10 mg/100 mL).
  • Recommended Daily Intake: 50–100 mg/day (supplements); 1 cup kale or spinach (~20–50 mg) for dietary intake (Rudrapal et al., 2022).
  • Bioavailability: Low (~2–5%) due to glucuronidation and sulfation. Glycosides are hydrolyzed in the intestine, improving absorption (Manach et al., 2004).
  • Absorption Factors: Absorbed in the small intestine, with peak plasma levels at 1–2 hours. Glycosides enhance uptake (Hollman & Katan, 1999).
  • Enhancement Strategies: Consume with dietary fats (e.g., olive oil, nuts). Avoid milk with green tea to improve absorption (Pérez-Jiménez et al., 2010).
  • Supplement Recommendations: Use standardized kaempferol extracts, starting at 50 mg/day, with medical advice.
  • Preferred Supplement Forms: Liposomal or nanoparticle kaempferol for better absorption (Lee et al., 2018).
  • Suggested Brands/Products: Life Extension Kale Extract (~$0.60/day), Vitacost Spinach Extract (~$0.50/day).
  • Special Considerations: Limited safety data for doses >200 mg/day. Monitor for mild GI upset (Lee et al., 2018).
  • Mechanisms of Action: Patient-Friendly: Kaempferol shields joints and nerves from damage by harmful molecules, reducing pain and swelling in arthritis. It may also calm brain inflammation, helping with migraines or Alzheimer’s discomfort (Pandey & Rizvi, 2009).
  • Mechanisms of Action: Physician-Directed: Kaempferol scavenges ROS, enhancing glutathione levels and inhibiting lipid peroxidation. It suppresses NF-κB and lipoxygenase, reducing IL-6 and TNF-α production, mitigating inflammation in arthritis and neuroinflammation in Alzheimer’s and migraines (Lee et al., 2018; Pandey & Rizvi, 2009). Its anti-inflammatory effects target NF-κB and lipoxygenase, reducing cytokines that drive joint and nerve pain.
  • Efficacy in modulating peripheral and central sensitization:

Preclinical Evidence in modulating sensitization:

    • A 2018 study in Nutrients showed kaempferol (30–100 mg/kg, oral, 14 days) reduced mechanical allodynia and thermal hyperalgesia in a rat arthritis model by inhibiting COX-2 and iNOS, reducing peripheral sensitization. A 2020 study in Journal of Neuroinflammation found kaempferol (50 mg/kg, intraperitoneal, 7 days) suppressed central sensitization in a neuropathic pain model by reducing spinal microglial activation and IL-1β expression (Lee et al., 2018; Yang et al., 2020).
    • Mechanisms: Inhibits NF-κB and MAPK pathways, reducing cytokine production and glial activation. Moderate BBB permeability limits direct CNS effects, but gut metabolites enhance systemic activity.

Clinical Evidence in modulating sensitization:

No direct studies on sensitization. Anti-inflammatory effects in humans suggest potential peripheral sensitization suppression.

Summary of Evidence in modulating sensitization:

Kaempferol shows preclinical promise for suppressing peripheral and central sensitization, but clinical data are lacking.

  • Evidence of Benefits: Preclinical studies show reduced joint inflammation in arthritis and neuroprotection in Alzheimer’s, stroke, MS, and neuropathy (Lee et al., 2018).
  • Synergies: Pairs with green tea (EGCG) for antioxidant synergy. Combines with omega-3s (1–2 g/day) to enhance anti-inflammatory effects in arthritis and nerve pain (Wen Deng et al., 2023).

 

EGCG (Green Tea)

Pain-Related Benefits:

EGCG has emerging RCT evidence for reducing neuropathic pain in MS, with 600–800 mg/day improving symptoms and biomarkers (Islam et al., 2025). It also helps osteoarthritis and rheumatoid arthritis by reducing joint pain and inflammation, and may decrease migraine frequency by calming brain inflammation. Preclinical studies support its role in sciatica, peripheral neuropathy, spinal cord injury, and stroke by protecting nerves from oxidative damage and reducing pain amplification.

EGCG’s benefits come from blocking inflammation pathways like JAK/STAT and NF-κB, which drive pain in arthritis and MS. In Alzheimer’s, it reduces brain plaques (60% in frontal cortex) and supports recovery, making it a promising option for patients with nerve pain or neurodegenerative conditions, though more human studies are needed for migraines and fibromyalgia.

Common Food Sources: Green tea and matcha green tea (50–100 mg/100 mL), cocoa powder (use unsweetened), dark chocolate, carob, blackberries apples, strawberries.

Dietary Intake: Green tea (50–100 mg/100 mL; 1 cup 240 mL ~100–300 mg); matcha (~100–150 mg/100 g); Black tea, white tea, and oolong tea contain significant amounts of EGCG, though generally less than green tea), apples (~2–5 mg/100 gm).

Recommended Daily Intake: 300–800 mg/day (supplements); 2–3 cups green tea (~100–300 mg) for dietary intake (Rudrapal et al., 2022).

  • Bioavailability: Moderate (~1–10%) due to poor intestinal absorption and glucuronidation in the liver (Manach et al., 2004).
  • Absorption Factors: Absorbed in the small intestine, peaks at 1–2 hours. Milk proteins (e.g., casein) reduce absorption (Hollman & Katan, 1999).
  • Enhancement Strategies: Consume with dietary fats (e.g., coconut oil). Avoid adding milk, its proteins will bind to the EGCG and prevent absorption.
  • Tips to maximize EGCG intake
  • Do not allow your tea to be exposed to boiling water, which is too hot and will destroy the EGCG.
  • Steep green tea for longer: Research suggests that increasing the brewing time for green tea can maximize EGCG content.
  • Consume green tea between meals: EGCG binds to proteins and minerals in food, reducing its absorption. Drinking tea between meals or on an empty stomach may improve bioavailability.
  • Opt for high-quality brewed teas: Avoid bottled, sweetened teas and premixed green teas, as they tend to be lower in antioxidants and may contain high amounts of sugar.
  • Supplement Recommendations: Use liposomal EGCG, starting at 300 mg/day, increasing to 800 mg/day with medical supervision.
  • Preferred Supplement Forms: Liposomal or nanoparticle EGCG for improved absorption (Rossi et al., 2008).
  • Suggested Brands/Products: Thorne Green Tea Phytosome (~$2.20/day, 50 mg/4 capsules), Life Extension Mega Green Tea Extract (~$1.00/day).
  • Special Considerations: Avoid >1,000 mg/day due to hepatotoxicity risks. Monitor for dizziness or liver issues (Steinmann et al., 2013).
  • Mechanisms of Action: Patient-Friendly: EGCG protects nerves and joints by stopping harmful molecules that cause pain and damage. It reduces swelling in arthritis and calms brain inflammation, helping with MS, migraines, or Alzheimer’s (Islam et al., 2025).
  • Mechanisms of Action: Physician-Directed: EGCG scavenges ROS, inhibits lipid peroxidation, and activates Nrf2, paralleling Vumerity’s mechanism (an MS medication). It suppresses COX-2, NF-κB, AP-1, and JAK/STAT pathways, reducing IL-1β, IL-6, and TNF-α production, mitigating inflammation in arthritis, MS, and neuroinflammation in Alzheimer’s and migraines (Islam et al., 2025; Jin et al., 2020).
  • Efficacy in modulating peripheral and central sensitization: Strong preclinical evidence for central sensitization suppression via MAPK and glial inhibition, enhanced by BBB penetrability (Xifró et al., 2015). Limited clinical data on sleep quality (Mähler et al., 2021).

Preclinical Evidence in modulating sensitization:

    • Neuropathic Pain: A 2019 study in Brain Research Bulletin showed that EGCG (50 mg/kg, intraperitoneal, 7 days) reduced mechanical allodynia and thermal hyperalgesia in a rat CCI model. It suppressed central sensitization by decreasing spinal p38 MAPK phosphorylation and microglial activation, reducing pro-inflammatory cytokines (TNF-α, IL-1β).
    • Cognitive Impairment: A 2020 study in Nutrients found that EGCG (10–50 mg/kg, oral, 4 weeks) improved memory in ethanol-induced cognitive impairment models in rats by increasing NR1 subunit expression in hippocampal neurons, suggesting modulation of synaptic plasticity relevant to central sensitization (Fila et al., 2020,).
    • Mechanisms: EGCG crosses the blood-brain barrier (BBB) more effectively than curcumin due to its lower molecular weight and higher lipophilicity, enabling direct CNS effects. It inhibits NF-κB and MAPK pathways, reducing glial activation and cytokine release, and enhances antioxidant defenses, mitigating peripheral and central sensitization (Perry et al., 2018,).

Clinical Evidence in modulating sensitization:

A 2021 RCT in Nutrients reported that EGCG (150 mg/day, 12 weeks) improved sleep quality in humans, potentially by reducing neuroinflammation, which could indirectly modulate central sensitization. No direct studies on pain sensitization were identified.

Summary of Evidence in modulating sensitization:

EGCG shows strong preclinical evidence for suppressing central sensitization via glial inhibition and MAPK modulation, with potential peripheral effects through antioxidant activity. Its BBB penetrability enhances its CNS efficacy, but clinical data on pain sensitization are limited.

  • Evidence of Benefits: RCTs for MS (600–800 mg/day) and Alzheimer’s; preclinical data for arthritis, neuropathy, migraines, spinal cord injury, and stroke (Islam et al., 2025).
  • Synergies: Combines with omega-3s (1–2 g/day) for enhanced anti-inflammatory effects. Pairs with berries (cyanidin) or turmeric (curcumin) for antioxidant synergy in MS and Alzheimer’s (Wen Deng et al., 2023).

 

Comparative Analysis of Compounds for Peripheral & Central Sensitization:

Peripheral Sensitization

Strongest Evidence: Curcumin and quercetin effectively suppress peripheral sensitization by inhibiting TRPV1 channels and COX-2-mediated prostaglandin production in DRG neurons, reducing nociceptor hyperexcitability.

    • Moderate Evidence: EGCG and myricetin show anti-inflammatory effects that may reduce peripheral inflammation, but direct evidence on nociceptor modulation is limited.
    • Limited Evidence: Resveratrol and chrysin have less direct evidence for peripheral sensitization, primarily acting through systemic anti-inflammatory mechanisms.

Central Sensitization:

    • Strongest Evidence: Curcumin, resveratrol, and EGCG robustly suppress central sensitization by inhibiting spinal and supraspinal glial activation (microglia, astrocytes), NMDA receptor activity, and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Curcumin and EGCG also modulate MAPK pathways, while resveratrol targets SIRT1 and HMGB1-RAGE signaling.
    • Moderate Evidence: Myricetin and chrysin reduce glial activation and cytokine release in preclinical models, but their lower BBB permeability limits CNS efficacy compared to EGCG.
    • Limited Evidence: Quercetin’s CNS effects are constrained by moderate BBB crossing, though its metabolites may contribute to central modulation.

Bioavailability Considerations:

    • Nanoparticle formulations significantly enhance curcumin’s bioavailability (9- to 55.4-fold vs. 20-fold with piperine), making it more effective for both peripheral and central effects (Shaikh et al., 2009,; Yallapu et al., 2012,).
    • EGCG’s superior BBB penetrability enhances its CNS efficacy, while resveratrol benefits from piperine co-administration, though this introduces drug interaction risks (Turner et al., 2014,).
    • Quercetin, myricetin, and chrysin have lower bioavailability, but nanoformulations or gut microbiota-derived metabolites may improve their efficacy (Tiwari et al., 2020,).

 

 

References

  • Islam MR, et al. Epigallocatechin 3-gallate-induced neuroprotection in neurodegenerative diseases. Mol Cell Biochem. 2025;480:3363–3383. doi:10.1007/s11010-025-05211-4.
  • VUMERITY® efficacy. https://www.vumerity.com/en_us/home/about/efficacy.html.
  • Daily JW, et al. Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis. J Med Food. 2016;19(8):717-729.
  • Javadi F, et al. The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis. J Am Coll Nutr. 2017;36(1):9-15.
  • Aziz MT, et al. Curcumin: a potential therapeutic agent for neurological disorders. Curr Neuropharmacol. 2018;16(9):1256-1271.
  • Rossi L, et al. Benefits from dietary polyphenols for brain aging and Alzheimer’s disease. Neurochem Res. 2008;33(12):2390-2400.
  • Steinmann J, et al. Effects of green tea catechins on liver health: a review. Molecules. 2013;18(4):4567-4583.
  • Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009;2(5):270-278.
  • Shi J, et al. Enhanced bioavailability of quercetin via nanotechnological approaches. J Control Release. 2019;303:112-124.
  • Zheng B, et al. Novel formulation of curcumin with enhanced bioavailability. J Agric Food Chem. 2015;63(36):8011-8020.
  • Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle. 2008;7(8):1020-1035.
  • Meng X, et al. Resveratrol in the management of chronic inflammatory diseases. Phytother Res. 2021;35(3):1123-1134.
  • Rahman MH, et al. Role of resveratrol in neurodegenerative diseases. Front Biosci (Landmark Ed). 2020;25(4):733-750.
  • Hollman PC, Katan MB. Dietary flavonoids: intake, health effects and bioavailability. Food Chem Toxicol. 1999;37(9-10):937-942.
  • Khoo HE, et al. Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food Nutr Res. 2017;61(1):1361779.
  • Reis JF, et al. Anthocyanins and inflammation: a review of the evidence. Crit Rev Food Sci Nutr. 2016;56(15):2523-2530.
  • Lee CJ, et al. Kaempferol as an anti-inflammatory and antioxidant agent. Nutrients. 2018;10(10):1398.
  • Jin F, et al. The protective effect of EGCG on Alzheimer’s disease: a potential therapeutic agent. Front Neurosci. 2020;14:711.
  • Wen Deng, et al. Omega-3 polyunsaturated fatty acids reduce pain in osteoarthritis. Front Nutr. 2023;10:1233397.

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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