Accurate Education – Omega 3 Fatty Acids (Therapeutic)

Neutraceuticals:

Omega-3 Fatty Acids (Therapeutic)

Omega-3 fatty acids are a type of polyunsaturated fat that are essential for human health but cannot be produced by the body. They must be obtained through diet or supplements. These fatty acids play a crucial role in various bodily functions, including brain and heart health, and they reduce inflammation making them important players in the management of chronic pain.

This treatise explores omega-3s’ therapeutic roles, synergies, dosing, and mechanisms, tailored for pain management. For more in-depth information regarding omega fatty acids including in-depth information on omega-3’s and the foods that contain them, please see Omega Fatty Acids.

See:

• Handout – A Brief Review of Omega-3 Fatty Acids
• Omega Fatty Acids
• Omega-3 Supplements – A Quick Review
• Omega Fatty Acid – Therapeutics
• Omega Supplements –  Blood Thinners

 

Key to Links:

• Grey text – handout
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Definitions and Terms Related to Pain

 

Omega-3 vs Omega-6 Fatty Acids

Diet:

Before evaluating omega-3 fatty acids and their potential for therapeutic benefits, it’s important to gain context with a quick review of omega-3 vs omega-6 fatty acids.

Historic Perspectives

In recent decades, consumption of omega-6 polyunsaturated fatty acids (PUFAs) in Western diets increased dramatically, initially encouraged by aggressive marketing of vegetable oils to replace animal fats based on the belief that vegetable oils were more healthy than animal fats as related to heart disease. It was argued that the high levels of the omega-6 linoleic acid in vegetable oils reduced blood cholesterol and, by extension, reduced heart disease risk. Consequently,, consumption of margarine increased 10-fold while over the same period, consumption of fatty fish, the main dietary source of omega-3s decreased. As a result, the dietary intake of omega-6 to omega-3 fats shifted from an optimal ratio of 5:1, to 20:1, or even higher.

Current Perspectives

Current research, based on the benefits of 20 year hindsight, now recognizes that the ratio of omega-6 to omega-3 is the more important consideration

Health and dietary omega fatty acids

Since the importance of omega-3 fats in the diet has been recognized, diets and supplements with omega-3 fatty acids are encouraged as of means of restoring healthier omega-6 to omega-3 ratios and reducing the development of inflammation-based conditions, including obesity, chronic pain, neuropathic pain, arthritis, inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, cognitive function (memory and thought processing0, depression, fatigue, insomnia, gut health, diabetes and cardiovascular diseases, Multiple Sclerosis and Alzheimer’s disease.

Pain and dietary omega fatty acids

Less commonly appreciated is the fact that higher dietary omega-6 to omega-3 ratios is also associated with overall greater pain intensity, including, headache, low back pain, bodily pain and oral – facial pain.  Of note,  these conditions are not always necessarily tightly associated simply with inflammation, suggesting that the mechanism by which omega.-3s impact pain is likely based on mechanisms not limited to inflammation. Furthermore, the DHA omega-3 fat levels  are more strongly associated with less pain intensity than other omega fat levels, including EPA fats.

 

Supplementing with omega-3 fatty acids

This treatise focuses on the therapeutic benefits of omega-3 fatty acids, particularly EPA and. DHA.  As is the case with many nutritious compounds, it is often advisable to consider the use of nutrition based supplements, nutraceuticals, as an additional tool for the management of chronic pain and other conditions. Nutraceuticals are substances derived generally from food sources, with a focus on providing medicinal benefits for addressing specific health conditions.

When assessing the need for a nutraceutical, it is necessary to understand not just the immediate benefits that may be perceived when taking a supplement, but also to understand the role that a nutraceutical may have in long-term health benefits that may not be directly perceived, yet are still valuable. This is particularly true for omega-3 fatty acids as a nutraceutical supplement with “hidden benefits.”

A brief overreview of therapeutic benefits associated with omega-3 supplementation

1: Mechanisms of Action and Biological Rationale 

 Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert anti-inflammatory, neuroprotective, and analgesic effects through several mechanisms. They incorporate into cell membranes, altering membrane fluidity and lipid raft formation, which modulates early signaling events in immune and neural cells. EPA and DHA competitively inhibit arachidonic acid metabolism, reducing pro-inflammatory prostaglandins and leukotrienes, and serve as precursors for specialized pro-resolving mediators (SPMs) such as resolvins, protectins, and maresins. These SPMs actively resolve inflammation, downregulate cytokine production, and promote tissue repair, with direct relevance to arthritis, migraine, and neuropathy.[1][2][3]

 

2: Evidence for Omega-3 Supplementation in Arthritis 

Meta-analyses and systematic reviews demonstrate that omega-3 supplementation (EPA/DHA) leads to modest but clinically meaningful reductions in pain, tender and swollen joint counts, and disease activity scores in rheumatoid arthritis. Most studies support high-dose animal-derived omega-3 (>2 g/day) for 3–6 months as optimal for symptom improvement.[4][5] In osteoarthritis, omega-3s may moderate low-grade inflammation and cartilage loss, though clinical effects are less robust than in inflammatory arthritis.[6] The overall effect size is small, and the certainty of evidence is low to moderate, but omega-3s are considered a reasonable adjunct to standard therapy.[7]

  

3: Evidence for Omega-3 Supplementation in Migraine and Headache 

Randomized controlled trials and reviews indicate that EPA and DHA supplementation can reduce headache frequency, severity, and migraine days in both episodic and chronic migraine. For example, increasing EPA+DHA intake to 1.5 g/day for 16 weeks reduced headache days and hours, with additional benefit from lowering dietary linoleic acid.[8] High-dose EPA (1.8–2 g/day) as monotherapy or adjunctive therapy has shown significant reductions in monthly migraine days, headache severity, disability, and improved quality of life, particularly in female patients.[9][10] Omega-3s are well tolerated, with few adverse events.[3][9][10]

  

4: Evidence for Omega-3 Supplementation in Peripheral Neuropathy 

Clinical trials and meta-analyses support the use of DHA-rich or combined EPA/DHA supplementation for painful diabetic neuropathy and chemotherapy-induced neuropathy. DHA-rich regimens (1000 mg DHA + 200 mg EPA daily for 3 months) have been shown to decrease neurotoxic lipid mediators, improve pain scores, and upregulate neuroprotective pathways.[11][12] Meta-analysis of RCTs in chemotherapy-induced neuropathy found reduced incidence and severity of neuropathy with omega-3 supplementation.[13] Mechanistic studies in animal models confirm that both EPA and DHA acutely and sub-chronically reverse mechanical allodynia, with effects dependent on central μ-opioid receptor activation.[14][15]

  

5: DHA:EPA Ratio and Nerve-Related Conditions 

Emerging evidence suggests that a higher ratio of DHA to EPA may be advantageous for nerve-related conditions and neuropathic pain. Human studies using DHA-rich supplementation (1000 mg DHA:200 mg EPA) demonstrated greater reductions in neurotoxic lipids and improved pain outcomes in diabetic neuropathy.[11][12] Animal studies show that both EPA and DHA are effective, but DHA may have superior neuroprotective and regenerative effects, accelerating nerve regeneration and preventing neuropathic pain behaviors.[15] However, direct head-to-head trials comparing different DHA:EPA ratios in humans are limited, and optimal ratios remain to be established.[13]

 

6: Application as Adjunctive Therapy for Chronic Pain 

Cohort data and meta-analyses indicate that omega-3 intake is associated with reduced pain incidence and worsening in chronic pain populations. Higher oily fish consumption and marine omega-3 intake (EPA and DHA) are linked to lower odds of pain worsening over five years (reduced central sensitization).[16] Systematic review and meta-analysis of intervention studies show moderate improvement in chronic pain with omega-3 supplementation .[17] Omega-3s are safe, with minimal adverse effects, and should be considered as adjunctive therapy for chronic pain, typically at doses of 1–2 g/day of combined EPA/DHA, with higher DHA ratios potentially preferred for neuropathic pain.[4][11][17]

References

1. N-3 PUFA and Inflammation: From Membrane to Nucleus and From Bench to Bedside. Calder PC. The Proceedings of the Nutrition Society. 2020;:1-13. doi:10.1017/S0029665120007077.

2. Implications for Eicosapentaenoic Acid- And Docosahexaenoic Acid-Derived Resolvins as Therapeutics for Arthritis. Souza PR, Norling LV. European Journal of Pharmacology. 2016;785:165-173. doi:10.1016/j.ejphar.2015.05.072.

3. Neuroimmunological Effects of Omega-3 Fatty Acids on Migraine: A Review. Chen TB, Yang CC, Tsai IJ, et al. Frontiers in Neurology. 2024;15:1366372. doi:10.3389/fneur.2024.1366372.

4. Impact of Type and Dose of Oral Polyunsaturated Fatty Acid Supplementation on Disease Activity in Inflammatory Rheumatic Diseases: A Systematic Literature Review and Meta-Analysis. Sigaux J, Mathieu S, Nguyen Y, et al. Arthritis Research & Therapy. 2022;24(1):100. doi:10.1186/s13075-022-02781-2.

5. Dietary Omega-3 Polyunsaturated Fatty-Acid Supplementation Upregulates Protective Cellular Pathways in Patients With Type 2 Diabetes Exhibiting Improvement in Painful Diabetic Neuropathy. Durán AM, Beeson WL, Firek A, Cordero-MacIntyre Z, De León M. Nutrients. 2022;14(4):761. doi:10.3390/nu14040761.

6. Efficacy of N-3 Fatty Acid Supplementation on Rheumatoid Arthritis’ Disease Activity Indicators: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. Gkiouras K, Grammatikopoulou MG, Myrogiannis I, et al. Critical Reviews in Food Science and Nutrition. 2024;64(1):16-30. doi:10.1080/10408398.2022.2104210.

7. Omega-3 Polyunsaturated Fatty Acid Oral Supplements for Improving Peripheral Nerve Health: A Systematic Review and Meta-Analysis. Zhang AC, De Silva MEH, MacIsaac RJ, et al. Nutrition Reviews. 2020;78(4):323-341. doi:10.1093/nutrit/nuz054.

8. The Role of Marine N-3 Polyunsaturated Fatty Acids in Inflammatory-Based Disease: The Case of Rheumatoid Arthritis. Parolini C. Marine Drugs. 2023;22(1):17. doi:10.3390/md22010017.

9. Omega-3 Fatty Acids for the Management of Osteoarthritis: A Narrative Review. Cordingley DM, Cornish SM. Nutrients. 2022;14(16):3362. doi:10.3390/nu14163362.

10. Dietary Alteration of N-3 and N-6 Fatty Acids for Headache Reduction in Adults With Migraine: Randomized Controlled Trial. Ramsden CE, Zamora D, Faurot KR, et al. BMJ (Clinical Research Ed.). 2021;374:n1448. doi:10.1136/bmj.n1448.

11. A 12-Week Randomized Double-Blind Clinical Trial of Eicosapentaenoic Acid Intervention in Episodic Migraine. Wang HF, Liu WC, Zailani H, et al. Brain, Behavior, and Immunity. 2024;118:459-467. doi:10.1016/j.bbi.2024.03.019.

12. Acute Antinociceptive Effect of Fish Oil or Its Major Compounds, Eicosapentaenoic and Docosahexaenoic Acids on Diabetic Neuropathic Pain Depends on Opioid System Activation. Redivo DDB, Jesus CHA, Sotomaior BB, Gasparin AT, Cunha JM. Behavioural Brain Research. 2019;372:111992. doi:10.1016/j.bbr.2019.111992.

13. Long-Chain Omega-3 Fatty Acids Supplementation Accelerates Nerve Regeneration and Prevents Neuropathic Pain Behavior in Mice. Silva RV, Oliveira JT, Santos BLR, et al. Frontiers in Pharmacology. 2017;8:723. doi:10.3389/fphar.2017.00723.

14. Eicosapentaenoic Acid Versus Placebo as Adjunctive Therapy in Chronic Migraine: A Randomized Controlled Trial. Mohammadnezhad G, Assarzadegan F, Koosha M, Esmaily H. Headache. 2025;65(1):153-163. doi:10.1111/head.14808.

15. Dietary Docosahexaenoic Acid-Rich Supplementation Decreases Neurotoxic Lipid Mediators in Participants With Type 2 Diabetes and Neuropathic Pain. Durán AM, Zamora F, De León M. Nutrients. 2024;16(23):4025. doi:10.3390/nu16234025.

16. Fish Consumption, Omega-3 Fatty Acid Intake, and Risk of Pain: The Seniors-Enrica-1 Cohort. Carballo-Casla A, García-Esquinas E, Banegas JR, Rodríguez-Artalejo F, Ortolá R. Clinical Nutrition (Edinburgh, Scotland). 2022;41(11):2587-2595. doi:10.1016/j.clnu.2022.09.007.

17. Polyunsaturated Fatty Acids and Chronic Pain: A Systematic Review and Meta-Analysis. Prego-Dominguez J, Hadrya F, Takkouche B. Pain Physician. 2016 Nov-Dec;19(8):521-535.

Omega-3 Fatty Acids – Therapeutics

Therapeutic Summary

Omega-3 fatty acids, essential polyunsaturated fats including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), are renowned for their anti-inflammatory, antioxidant, and neuroprotective properties, making them valuable in pain management

Diets rich in omega-3s have been recommended for heart and brain health, including sources like salmon (1,000–2,000 mg EPA/DHA per 3 oz serving). But to obtain their benefits consistently, it requires frequent servings of these omega-3 rich foods which is impractical for many people so supplementation is generally recommended.

Supplements (1,000–3,000 mg EPA/DHA/day) with high-purity formulations are essential to get the most beneficial therapeutic effects. Omega-3s are generally safe, with few of any side effects outside of occasional mild gastrointestinal upset or fishy aftertaste at high doses (>3 g/day).

EPA vs DHA – What is the difference?

EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are both omega-3 fatty acids, but they have distinct roles in the body. EPA is primarily known for its role in reducing inflammation and supporting cardiovascular health, while DHA is crucial for brain, nerve and eye health.

DHA over EPA is beneficial for CNS conditions like stroke, spinal cord injury, neuropathic pain, peripheral neuropathy, and fibromyalgia, while favoring EPA over DHA is warranted for generalized supplementation and inflammatory conditions like arthritis and inflammatory bowel diseases.

Dietary EPA vs DHA

Cold-water oily fish are the most common foods particularly rich in both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), but the relative proportions of these  two fatty acids vary by species. Salmon, mackerel, herring, sardines, and anchovies are among the highest in total EPA and DHA content, with

Fish tending to have a higher proportion of DHA vs EPA:

• Salmon
• Mackerel
• Tuna (especially bluefin and albacore)
• Sardines
• Algal oil  algae-based supplement)

Fish tending to have a more balanced or slightly higher EPA vs DHA -predominant profile:

• Anchovies
• Herring
• Oysters (lower amounts)
• Mussels (lower amounts)

Plant-based foods do not contain appreciable amounts of EPA or DHA, but are sources of alpha-linolenic acid (ALA), which is inefficiently converted to EPA and minimally to DHA. Some specialty oils, such as algal oil, are rich in DHA and are used in fortified foods and supplements.

Dietary/Supplemental DHA is generally emphasized over EPA  for central nervous system (CNS) and nerve-related conditions such as neuropathic pain, peripheral neuropathy, fibromyalgia, stroke, spinal cord injury and multiple sclerosis..

Supplemental EPA is emphasized over DHA for general supplementation and for inflammatory conditions like arthritis and inflammatory bowel diseases.

Combined supplementation of both EPA and DHA should be included in supplemental formulations – but with a higher ratio of EPA to DHA or vice versa – based on one’s diagnostic conditions and other variables. These other variables may include omega-3 blood levels, dietary intake, underlying risks (e.g. cardiovascular diseases, diabetes), age, and pain severity.

EPA Over DHA for General Supplementation and Inflammatory Conditions (Arthritis, IBD)

Favoring EPA for inflammation is sound, as EPA more potently reduces pro-inflammatory cytokines (e.g., IL-6, TNF-α) and eicosanoids in arthritis and IBD. Studies show EPA lowers inflammation in rheumatoid arthritis (RA) and OA, with meta-analyses confirming EPA+DHA (EPA-dominant) reduces joint pain and stiffness. It should be stressed that the benefits for both of these fatty acids is essential for the management of systemic inflammation, neuro-inflammation and oxidative stress.

For IBD, EPA reduces colon inflammation better than DHA. DHA has anti-inflammatory effects but is less effective for peripheral inflammation, making EPA-dominant ratios (e.g., 2:1 EPA:DHA) ideal. For general supplementation, balanced ratios (1:1) are recommended by the American Heart Association (AHA) for cardiovascular disease prevention, but EPA emphasis addresses inflammation without specific diagnostic needs.,Your conclusion is wise, though combined EPA+DHA is often superior to EPA alone.

 

DHA Over EPA for CNS Conditions (Stroke, Spinal Cord Injury, Neuropathic Pain, Peripheral Neuropathy, Fibromyalgia)

DHA is abundant in brain and nerve tissues, supporting neuroprotection, membrane fluidity, and resolution of inflammation in neuropathic pain. Evidence shows DHA reduces neuropathic pain by inhibiting pro inflammatory compounds such as interleukins (ILs) and TNF-α, with case series reporting pain reduction in fibromyalgia and neuropathy at 2-3 g/day DHA. For fibromyalgia, DHA reduces dysmenorrhea-like pain and depression via cytokine modulation. In spinal cord injury and stroke, DHA promotes neuronal repair and reduces oxidative stress. However, EPA also aids neuropathic pain by blocking sodium channels, suggesting combined use (e.g., 1:1 or DHA-dominant) may be optimal. For fibromyalgia, omega-3s (EPA+DHA) reduce symptoms, but DHA’s CNS focus is key. Overall, evidence supports your conclusion, but ratios like 2:1 DHA:EPA are recommended for synergy.

Summary:

Combination EPA+DHA with different ratios based on therapeutic targets are evidence-based and clinically relevant, but optimal outcomes may require personalized ratios (e.g., via OmegaCheck) and combined EPA+DHA, as pure DHA or EPA monotherapy shows limited superiority in trials.

 

 

In order to gain a full understanding of the place that omega-3 fatty acids have in chronic pain and in health in general, one must be familiar with two processes intimately involved in these conditions: systemic inflammation and oxidative stress.

1. Understanding Systemic Inflammation and Oxidative Stress

“Systemic Inflammation” and “Oxidative Stress” are two conditions that contribute to chronic pain by creating a cycle of tissue damage, immune cell activation, and pain amplification. By disrupting normal cellular physiology, these conditions also contribute to the development and progression of chronic diseases, including diabetes, heart disease, stroke, chronic kidney and liver disease, rheumatoid arthritis, cancer and Alzheimer’s [8].

• Systemic inflammation is a widespread inflammatory response throughout the body, triggered by infection, injury, stress, or other conditions. It involves the release of pro-inflammatory molecules and activation of the immune system, contributing to chronic pain and leading to various health issues. Symptoms can include increased pain, fatigue, cognitive problems, depression, decreased motivation for physical activity, and, in severe cases, organ dysfunction. While inflammation is a natural part of the healing process, chronic or excessive systemic inflammation can contribute to the development of diseases like heart disease, diabetes, and autoimmune disorders [7].

Neuroinflammation, a component of systemic inflammation, is inflammation within the central nervous system (brain and spinal cord). Systemic inflammation leads to the release of inflammatory molecules that cross the blood-brain barrier and activate immune cells in the brain, leading to or exacerbating, neuroinflammation.

Neuroinflammation contributes to the progression of acute to chronic pain. It is characterized by activation of immune cells (glial cells and astrocytes) in the nervous system that release various inflammatory chemicals like cytokines, proteases, and free radicals such as reactive oxygen (ROS), and nitrogen species (RNS). When these immune cells remain activated, neuroinflammation persists and drives chronic pain.

• Oxidative stress is an imbalance in the body of excessive “oxidants” (oxidizing or chemically active agents, including free radicals, obtained from the diet or produced by the body) and insufficient “antioxidants” that neutralize oxidants (chemically active agents also obtained from the diet or produced by the body). Oxidative stress and chronic systemic inflammation coexist because they mutually induce each other. Oxidative stress, caused by excessive free radicals and insufficient antioxidant defenses, damages cells and tissues, including nerve cells, which leads to pain. Furthermore, this damage also triggers more inflammation, further exacerbating pain.

3. Supplements and the Anti-Inflammatory Diet

The anti-inflammatory diet emphasized at Accurate Clinic focuses on foods that help reduce inflammation and oxidative stress, potentially reducing chronic pain and the risk of chronic diseases. It emphasizes whole, unprocessed foods like fruits, vegetables, and healthy fats, while limiting or avoiding processed foods, red meat, and sugary drinks [9].

Although the anti-inflammatory diet is certainly of critical importance, even this healthy diet will not provide enough of the anti-inflammatory and antioxidant nutrients to provide the full therapeutic benefits for the many common conditions that plague patients with chronic pain. For this reason, patients are encouraged to consider taking supplements of various nutrients to gain the benefits that taking higher amounts will provide.

Additionally, as is common with many nutrients, the bioavailability of the nutritious compounds found in foods may be severely limited when simply ingested along with the foods they are found in. “Bioavailability” refers to how much of a nutrient is actually available to the body for therapeutic use after consumption.  In the absence of a formulation designed to enhance absorption and penetration into the brain and nervous system, simply eating foods that are rich in a particular nutrient may not be enough in order to gain the nutrient’s full benefits. As such, it is of value to understand the nature of enhanced formulations when considering the purchase of a nutraceutical product. Insights into enhanced formulations of nutritional supplements can be found here.

In summary, for certain nutrients found in foods it may not be enough to obtain them directly from the diet due to the relatively small amounts found in foods or they may need enhanced formulations to improve bioavailability that is not achieved by eating them in food.

4. The Role of Omega-3s in Systemic Inflammation and Oxidative Stress

• Systemic Inflammation: Omega-3 fatty acids, particularly EPA and DHA, exert potent anti-inflammatory effects by modulating eicosanoids (local cellular hormones involved in inflammation) production and resolving inflammation. They compete with omega-6 fatty acids for incorporation into cell membranes, reducing pro-inflammatory arachidonic acid-derived mediators like prostaglandins and leukotrienes. Omega-3s promote specialized pro-resolving mediators (SPMs) such as resolvins, protectins, and maresins, which actively resolve inflammation without immunosuppression. The resolution of acute  inflammation is a critical step in avoiding the transition of acute pain (less than three months duration) associated with a new injury to becoming a chronic source of pain due to prolonged inflammation.

In clinical trials, omega-3 supplementation (1–2 gms EPA/DHA/day) significantly reduces systemic inflammatory biomarkers like CRP, IL-6, and TNF-α in conditions like rheumatoid arthritis and metabolic syndrome. An inflammatory biomarker is a measurable substance that indicates the level of inflammation in the body *systemic inflammation) and can be monitored to assess the response to a treatment. CRP is a biomarker monitored routinely in chronic pain patients at Accurate Clinic while IL-6 and TNF-α are not generally available in private medical practice due to lack of coverage by insurance.

Research

A meta-analysis of 68 random controlled trials (RCTs) showed omega-3s lower CRP by 0.5–1 mg/L, with greater effects in diabetic patients. In cardiovascular disease, omega-3s improve endothelial function by reducing vascular inflammation, lowering risk of atherosclerosis and likelihood of heart attack or stroke. Studies indicate 1 gm/day for 12 weeks decreases IL-6 by ~20% in healthy adults.

Omega-3s’ anti-inflammatory effects extend to gut health, alleviating inflammatory bowel disease (IBD) symptoms by enhancing gut barrier integrity and modulating microbiota, the microorganisms in the intestines that greatly affect chronic pain in many medical condition. 

RCTs show 2–4 gm (2000-4000mg)/day reduces remission rates in ulcerative colitis by ~30%. For pain, reduced inflammation mitigates tissue damage in OA. However, bioavailability varies; algal or fish oil forms are preferred, with enteric-coated capsules enhancing absorption. Preclinical studies suggest benefits for neuropathy by reducing NF-κB in glial cells, but human data are limited. Overall, omega-3s rank highly for systemic inflammation, with high confidence in RA and gut health, moderate for neuropathy.

• Neuro-Inflammation: Neuroinflammation involves inflammatory cells, such as microglial and astrocytic activation in the CNS, releasing cytokines that exacerbate pain and neurodegeneration. Omega-3s, especially DHA, cross the blood-brain barrier and incorporate into neuronal membranes, modulating inflammatory pathways. DHA-derived resolvins (e.g., RvD1) inhibit microglial activation, reducing pro-inflammatory cytokines like IL-1β and TNF-α.

Research

Preclinical animal research shows DHA (100–500 mg/kg) reduces neuroinflammation in diabetic neuropathy by suppressing NF-κB and enhancing SPMs, improving nerve conduction. In DPN rat models, DHA prevents thermal hyperalgesia by reducing oxidative stress in dorsal root ganglia.

Clinical trials in multiple sclerosis (MS) patients (1–2 gm EPA/DHA/day) report reduced brain lesion activity via lowered IL-6.

For migraines, omega-3s reduce neurovascular inflammation, with RCTs showing 1 gm/day decreases frequency by ~30% via CGRP modulation (the same mechanism by which migraine prescription medication, such as Nurtec and Ubrelvy, the commonly used new migraine medication’s that have proven to be greatly effective reducing the frequency and severity of headaches, as well as aborting onset of headaches).

In Alzheimer’s, DHA (800 mg/day) has been proposed to slow cognitive decline by reducing amyloid-induced inflammation.

Bioavailability is key:  phospholipid-bound forms enhance CNS delivery. Overall, omega-3s’ role in neuroinflammation is supported, with:

• • • Moderate confidence for migraines and neuropathy
    • High confidence for MS .

• Oxidative Stress: Oxidative stress arises from excess ROS overwhelming antioxidants, damaging lipids, proteins, and DNA. Omega-3s incorporate into cell membranes, enhancing fluidity and reducing lipid peroxidation. They upregulate Nrf2, boosting SOD, catalase, and glutathione peroxidase.

Research

In diabetic peripheral neuropathy (DPN), DHA reduces ROS in Schwann cells, preventing demyelination. Preclinical studies show DHA (200 mg/kg) lowers malondialdehyde by ~25% in diabetic rats, improving nerve function. RCTs in type 2 diabetes (1 g EPA/DHA/day, 12 weeks) reduce oxidative biomarkers like 8-OHdG by ~20%.

For cardiovascular health, omega-3s lower oxidized LDL, with meta-analyses showing 1–2 gm/day reduces F2-isoprostanes by 10–15%. In OA, they protect cartilage from ROS-induced cell death.

Bioavailability: Krill oil > fish oil for absorption.

Level of Confidence

• • High confidence for metabolic and cardiovascular conditions,
  • Moderate confidence for neuropathy

• Peripheral and Central Sensitization: Mechanisms amplifying chronic pain.

Peripheral sensitization involves nociceptor hyperexcitability due to inflammatory mediators. Omega-3s reduce this by inhibiting TRPV1 and sodium channels in DRG neurons, decreasing excitability. In DPN models, DHA (100 mg/kg) lowers sodium currents, reducing allodynia by ~30%.

Central sensitization amplifies pain via spinal glial activation. Omega-3s suppress microglia, reducing BDNF and glutamate excitotoxicity.

• • • Preclinical data show EPA/DHA (1:1 ratio) attenuates NMDA receptor activity, preventing wind-up.
    • Clinical trials in fibromyalgia (2 gm/day) report reduced tenderness, with higher DHA ratios showing better outcomes in DPN (e.g., 2:1 DHA:EPA reduces symptoms more than 1:1).

Overall, omega-3s reduces sensitization, with:

• • • Moderate confidence for neuropathy
    • Low for fibromyalgia

• Transition Acute to Chronic Pain: Prevention strategies.  Transition to chronic pain involves persistent inflammation post-injury. Omega-3s prevent this by promoting resolution via SPMs. In post-surgical models, DHA (500 mg/kg) reduces IL-6, preventing hyperalgesia chronicity. In DPN, early omega-3 supplementation (1 gm/day) halts nerve damage progression. RCTs in acute injury show 2 gm/day reduces transition risk by ~20%.

Strategies: High DHA formulations (2:1 DHA:EPA) for DPN prevention. Confidence: low-moderate, preclinical dominant

5. Summary of Omega-3s: Conditions with moderate – high levels of confidence:

Neuropathic Pain Conditions

• Peripheral Neuropathy (diabetic, chemotherapy-induced): Moderate; DHA reduces symptoms in DPN (higher DHA:EPA ratios better)
• Fibromyalgia: Moderate; reduces tenderness .
• Multiple Sclerosis: High; reduces lesion activity .

Inflammatory Pain Conditions

• Osteoarthritis: High; pain reduction ~20-30% .
• Rheumatoid Arthritis: High; lowers cytokines .
• Crohn’s Disease/Ulcerative Colitis: Moderate; remission improvement .

Other Pain Conditions

• Migraine Headaches: Moderate; frequency reduction ~30% .

Other Conditions

• Cognitive Function/Enhancement: Moderate; DHA supports memory .

Mental health

• Anxiety: Moderate; reduces symptoms, especially ≥2000 mg/d with higher DHA:EPA ratios
• Alzheimer’s Disease: Moderate; slows decline .

Gut Health: Moderate

Metabolic Health:

• Diabetes: High; insulin sensitivity .

Cardiovascular Health

• Triglyceride regulation: High

6. Therapeutic Roles in Pain Conditions and Other Conditions

6a. Neuropathic Pain Conditions

• Peripheral Neuropathy (diabetic) Omega-3s, especially DHA, show promise in DPN. RCTs (1 g EPA/DHA/day, 12 weeks) reduce pain by ~20%, improving NCV. Higher DHA:EPA ratios (e.g., 2:1) are superior, as per studies preventing neuropathy in diabetic models by reducing oxidative stress and inflammation.

  DHA addresses the multifaceted nature of DPN by modulating lipid profiles, exerting anti-inflammatory effects, directly protecting nerve cells, and influencing pathways involved in pain signaling and nerve repair.

  Moderate confidence.

  Here’s how DHA helps in DPN:

  1. Modulation of lipid profiles

  • DPN is associated with elevated levels of harmful lipids like saturated fatty acids (SFAs) and their derivatives, which can impair nerve function and contribute to inflammation.
  • DHA supplementation can help shift the lipid profile towards a more neuroprotective composition by decreasing levels of neurotoxic lipids (e.g., specific derivatives of palmitic and stearic acid) while increasing levels of beneficial lipids (e.g., DHA-containing phospholipids like DHA-PC).

  • Anti-inflammatory effects

    1. Inflammation plays a crucial role in DPN pathogenesis, with elevated levels of pro-inflammatory cytokines like TNF-α and IL-1β contributing to nerve damage and pain.
    2. DHA possesses anti-inflammatory properties, potentially reducing neuroinflammation and alleviating pain by inhibiting the production of these cytokines and modulating immune responses. One study found that DHA reduces mixed lineage kinase domain-like protein (MLKL) levels, a marker of necrosis, while increasing autophagy protein 5 (ATG5) and fatty acid-binding protein 5 (FABP5), involved in cell maintenance and repair.

  • Neuroprotection and nerve repair

    1. DHA may directly protect nerve cells from damage and improve their function.
    2. DHA can enhance nerve regeneration and functional recovery by mitigating oxidative stress, a key factor in DPN progression, according to the National Institutes of Health (NIH).
    3. DHA can interact with proteins like FABP5, which plays a role in neuronal survival and repair mechanisms, says the National Institutes of Health (NIH).

  • Modulation of excitotoxicity

    1. Overactivation of NMDA receptors by glutamate can contribute to neuropathic pain and neuronal death.
    2. DHA may help modulate the glutamatergic system towards a more neuroprotective state by decreasing glutamate levels and potentially inhibiting NMDA receptor activity.

 

• Peripheral Neuropathy (chemotherapy-induced) For CIPN, omega-3s protect against paclitaxel damage
• Sciatica Limited data; theoretical anti-inflammatory benefit.
• Fibromyalgia RCTs (2 g/day) reduce tenderness via inflammation reduction. Moderate confidence .
• Multiple Sclerosis High confidence; reduces neuroinflammation, lesion activity .

 

6b Inflammatory Pain Conditions

• Osteoarthritis High confidence; 1–2 g/day reduces pain ~20-30% via cytokine lowering .
• Rheumatoid Arthritis High; reduces swelling, cytokines .
• Crohn’s Disease/Ulcerative Colitis Moderate; improves remission .

 

6c. Other Pain Conditions

• Migraine Headaches Moderate; 1 g/day reduces frequency ~30% .

6d. Other Conditions

• Cognitive Function/Enhancement DHA (800 mg/day) improves memory in aging. Moderate .
• Insomnia Low; theoretical.
• Fatigue Low.
• Mental health
  • Anxiety: Moderate.
  • Stress: Low.
  • Depression: Low.
  • Alzheimer’s Disease: Moderate; DHA slows decline .
• Gut Health Moderate; supports barrier in IBD .
• Metabolic Health High; improves insulin sensitivity in diabetes .
• Cardiovascular Health High; regulates lipids .
• Other pertinent relevant conditions Cancer prevention: Low

7. Synergies

• Prescription Medications: Omega-3s enhance
  1. NSAIDs in OA (1 g/day + ibuprofen, better pain relief).
  2. Gabapentin in neuropathy, may reduce oxidative stress.
  3. Caution with anticoagulants (increased bleeding at high doses)
• Nutraceuticals:
  1. Curcumin: reduces inflammation in gut.
  2. ALA: enhances neuroprotection in DPN.
  3. Vitamin D: synergizes for metabolic health .
• Adaptogens:
  1. Ashwagandha + omega-3s for anxiety reduction.
• Cannabinoids:
  1. THC/CBD + omega-3s for pain via CB2.
• Terpenes:
  1. Beta-caryophyllene enhances anti-inflammation.

• Acupuncture:
  1. May improve OA pain.

8. Recommended Dosing

• Dietary sources:

Dietary sources rich in the omega-3’s fatty acids, EPA and DHA (1,000–2,000 mg EPA/DHA/3 oz), are generally limited to cold water fatty fish, including sardines, salmon , mackerel, tuna, herring, and oysters. Current recommended daily intakes of EPA and DHA/day to achieve the best therapeutic benefits are in the neighborhood of 1,000 to 3,000 mg/day. This amount is rarely provided in the typical American diet, so dietary supplements are recommended.  (See: Omega Fatty Acids)

 

Dosing Recommendations

General Guidelines

Dosing:

• 250–500 mg/day EPA+DHA for general health (AHA);
• 1–2 g/day for inflammation/pain;
• 2–4 g/day for cardiovascular disease or elevated triglycerides.

Ratios of EPA & DHA:

• General health (1:1).
• CNS/nerve pain – (DHA-dominant, 2:1 DHA:EPA);
• Inflammation – (EPA-dominant, 2:1 EPA:DHA);

Dosing modifications should prioritize variables in this order:

1. Omega-3 Status (OmegaCheck/Omega-3 Index): Primary determinant; low levels (<4%) require higher doses to reach 8% O3I equivalent (~5.5% OmegaCheck).
2. Dietary Intake: Low intake (<250 mg/day EPA+DHA) warrants higher supplementation; high intake (e.g., 2–3 fish servings/week) reduces need.
3. Underlying Risks (CVD, Diabetes): EPA-dominant for CVD/TG reduction; monitor LDL in diabetes, as DHA may raise LDL modestly.
4. Age and Age-Related Diseases: Older adults (>65) may need 1–2 g/day for CNS/inflammatory risks; adjust for frailty or comorbidities.
5. Pain Severity: Severe pain  justifies 2–3 g/day; mild-moderate suffices with 1–2 g/day.

 

Condition	Recommended Ratio	Base Dose (EPA+DHA)	Adjustments by Variables
CNS (Stroke, Spinal Cord Injury, Neuropathic Pain, Neuropathy, Fibromyalgia)	DHA-dominant (2:1 DHA:EPA)	1–3 g/day	– Low OmegaCheck (<4%): 2–3 g/day. – Low Diet: +500 mg. – CVD/Diabetes Risk: Monitor LDL, prefer 1:1 if high LDL. – Older Age: 1.5–2.5 g/day. – Severe Pain: 2–3 g/day.
Inflammatory (Arthritis, IBD)	EPA-dominant (2:1 EPA:DHA)	1–2.7 g/day	– Low OmegaCheck: 2–2.7 g/day. – Low Diet: +500–1000 mg. – CVD/Diabetes: 2–4 g/day EPA focus for TG reduction. – Older Age: 1.5–2.5 g/day. – Severe Pain: 2–2.7 g/day.
General Supplementation	Balanced (1:1 EPA:DHA)	250–500 mg/day	– Low OmegaCheck: 500–1000 mg/day. – Low Diet: +250 mg. – CVD/Diabetes: EPA-dominant 1–2 g/day. – Older Age: 500–1000 mg/day. – Mild Pain: 250–500 mg/day.

Forms: Triglyceride (TAG) preferred for bioavailability; ethyl ester (EE) requires 25–50% higher dose. Safety: ≤3 g/day safe with Eliquis; monitor bleeding in CVD/diabetes.

Supplement forms:

OTC forms of omega-3 supplements come in a variety of ways. First, it’s important to understand that supplementing with omega-3 fatty acids should be focused on EPA and DHA specifically, although some products may also include DPA, another omega-3 that gets converted to EPA in the body. But it is the EPA and DHA that provides the primary therapeutic benefits directed at pain, anxiety, and cardiovascular health.

Read the label carefully!

Product labeling can be very misleading. For example, the label may simply identify the product as “1,000 mg fish oil” or “1000 mg omega 3.” This amount does not necessarily represent the amount of EPA and DHA specifically present in the capsule product. Also, the product may imply an amount per capsule, but upon closer reading of the label one may discover the serving size to be two capsules that is required to deliver the milligram amount presented on the label.

Read carefully as recommended dosing of omega-3’s is based ONLY on EPA and DHA, no other omega fatty acids.

Furthermore, the ratio of EPA to DHA in the product is important. The ratio of these two omega-3’s in the product may be approximately equal or there may be significantly more EPA than DHA or vice versa.

Current recommendations regarding EPA and DHA ratios suggest that when treating inflammatory conditions including arthritis and inflammatory bowel disease diseases, one should use a product with a ratio of EPA > DHA.

However, when treating the brain, central nervous system conditions or nerve conditions, including neuropathy, post-stroke, spinal cord injury, migraine headaches or anxiety, a ratio of DHA > EPA should be selected.

 

Product Sources

Krill oil: For vegetarians. EPA and DHA omega-3’s can be sourced from krill oil as opposed to fish oil. Krill oil forms may provide greater bioavailability and may avoid fishy taste

Fish oil: 1,000–2,000 mg EPA/DHA/day.

 

Higher DHA (e.g., 2:1 DHA:EPA) for DPN and anxiety (anxiolytic effects stronger with DHA-favoring ratios ≥2000 mg/d, paralleling DPN benefits). Fish/algal oil capsules.

Safety:

1. 1. Safe at 1–3 g/day;
   2. Fishy taste,
   3. Bleeding risk with high doses. For Eliquis (apixaban), doses ≤3 g/day EPA + DHA pose minimal bleeding risk per reviews and trials (e.g., REDUCE-IT), with slight increase in minor events (bruising) but no major bleeding. Use TAG forms ≤2 g/day or EE ≤3 g/day for safety; monitor for epistaxis. Avoid >3 g/day without supervision.

 

DHA Ingestion and LDL-Cholesterol Levels

DHA ingestion can modestly raise LDL-C at higher doses (>2 g/day), but this is often accompanied by favorable lipid changes like reduced triglycerides (TG), increased HDL, and larger LDL particles, reducing overall atherogenicity. Evidence from meta-analyses and RCTs supports minimal concern for most individuals, though monitoring is advised for high-risk patients. In pain management, DHA’s benefits for OA outweigh potential LDL-C effects, aligning with dietary and supplemental strategies.

Mechanisms

DHA’s LDL-C-raising effect may stem from altered lipoprotein metabolism. It increases LDL particle size and turnover rate, potentially reducing atherogenicity despite higher levels. DHA inhibits hepatic VLDL secretion less effectively than EPA, leading to more LDL production, but larger particles are cleared faster and less prone to oxidation. At high doses, DHA may shift lipid profiles toward increased HDL and LDL while decreasing TG, a trade-off that benefits overall cardiovascular risk.

Evidence on DHA and LDL-C Levels

Meta-analyses indicate that DHA tends to raise LDL-C more than EPA, but the increase is small and dose-dependent. A meta-analysis of 11 RCTs involving 485 healthy participants found that algal DHA (median dose 1.68 g/day) increased LDL-C by 0.23 mmol/L while reducing TG by 0.20 mmol/L and increasing HDL-C by 0.07 mmol/L. Another meta-analysis of RCTs on omega-3 supplementation in metabolic syndrome patients showed no significant overall effect on LDL-C, but subgroup analyses suggested DHA may contribute to slight elevations compared to EPA. A dose-response meta-analysis of omega-3 intake found near-linear reductions in TG and non-HDL-C, but DHA was noted to modestly increase LDL-C, particularly at doses >2 g/day. Reviews differentiate EPA and DHA: EPA often reduces or has no effect on LDL-C, while DHA increases it by 5–10% at 3–4 g/day, though this is balanced by larger LDL particles and reduced TG.

RCTs provide direct evidence. In a trial of high-dose DHA (3 g/day) versus EPA, DHA increased LDL-C and TG more than EPA, but also enlarged LDL particles, making them less atherogenic. A large observational study of 9,253 patients found no association between erythrocyte DHA increases and LDL-C rises, suggesting real-world effects may be minimal. In hypertriglyceridemia patients, DHA modestly increased LDL-C more than EPA, but reduced TG significantly. Trials in postmenopausal women showed omega-3s (including DHA) elevated LDL-C modestly while reducing TG. Overall, LDL-C increases are ~5–10% at doses >2 g/day DHA, but not usually clinically significant.

Clinical Implications

The concern that DHA raises LDL-C is valid but often overstated for doses <2 g/day, where increases are minimal (~0.23 mmol/L). Benefits like TG reduction (15–30%) and HDL increase outweigh risks for most, especially in pain management for OA, where 1–2.7 g/day EPA + DHA reduces symptoms. Monitor LDL-C in patients with high baseline levels or CVD risk, preferring EPA-dominant supplements if needed. For your patient, algal DHA (e.g., 1.68 g/day) balances benefits with modest LDL-C effects, safe with Eliquis at ≤3 g/day.

 

 

When purchasing an Omega-3, Fish or Krill Oil supplement, pay careful attention to identify the total amount of EPA + DHA  per serving (not the total Omega-3 amount).

EPA+DHA dosing to reach recommended level Omega-Check of 5.5% (or Omega-Index of 8%):

1. Diet-based recommended intakes of EPA+DHA:

• Very low dietary intake of omega-rich foods (<3 servings/week):  
  • • Consume 3000 mg/da (EPA+DHA) for12-16 weeks to correct deficiency
    • (EPA:DHA ratio ___ 1:1  or 2:1 for inflammatory pain;  ___ 1:2 for neuropathic/nerve pain or anxiety)
• Low to moderate dietary intake of omega-rich foods (3-4 servings/week): 
  • • Consume 2000 mg/day y (EPA+DHA) for12-16 weeks to correct deficiency
    • (EPA:DHA ratio ___ 1:1  or 2:1 for inflammatory pain;  ___ 1:2 for neuropathic/central pain or anxiety).

2. Omega-Check (or Omega-3 Index) -based recommended intakes of EPA + DHA:

• Omega-Check of <3.8% (or Omega-3 of <4%):  
  • • Consume 3000 mg/day (EPA+DHA) for12-16 weeks to correct deficiency
    • (EPA:DHA ratio:  ___ 1:1 or 2:1 for inflammatory pain;  ___ 1:2 for neuropathic/nerve pain or anxiety)
• Omega-Check of 3.8-5.4% (or Omega-3 Index of 4-8%): 
  • • Consume 2000 mg/day (EPA+DHA) for12-16 weeks to correct deficiency.
    • (EPA:DHA ratio: ___ 1:1 or 2:1 for inflammatory pain;  ___ 1:2 for neuropathic/nerve pain or anxiety)

Notes:

• It may require >12-16 weeks to reach an Omega-Check of 5.5% (or an Omega-Index of 8%)
• A dose of 1 gram/day EPA+DHA lowers serum triglycerides by about 7-10% in 2-3 weeks
• When Omega-Check reaches  ≥5.5%  (or Omega-3 Index reaches ≥8%), dosing may be reduced to a maintenance level based also on clinical response that should be reviewed with your physician:

   Maintenance supplement dosing:

• 1,000-1,500 mg/day (EPA+DHA) to sustain levels (may vary by body weight and diet)

Supplemental Sources Emphasizing DHA>EPA

Prescription – EPA>DHA:: 

1. Lovaza  (EPA-465mg / DHA-375mg) [EE] /capsule
   • Rx:  #120 tabs.  1-4 caps/day

Over the counter (OTC) – EPA>DHA:

1. Nature Made Minis  (EPA-680mg / DHA-250mg) / 2 caps
   • Target:  $12
   • Dose: 1-6/caps/day

1. Ocean Blue 2100  (EPA-1350mg/DHA-600mg /DPA-150mg) 1000mg/cap

• • Rodriguez: #120 $46
  • Dose: 1-3 caps/day

OTC Dietary and Supplemental Sources Emphasizing DHA>EPA

Marine algae, particularly Schizochytrium sp., are rich sources of DHA with minimal EPA (~10:1 DHA/EPA ratio), making them ideal for boosting HA>EPA levels in patients with chronic pain conditions like peripheral neuropathy.

Commercial Supplements

• Thorne Advanced  DHA (EPA-200mg / DHA-650mg)/ 2 caps
  • Doctor Supplement Store (DSS): 60 tabs) $22
  • Dose: 2-6/caps/Day

• Nordic Naturals Algae Omega: ~500–600 mg DHA per 2 softgels (minimal EPA, <50 mg). Triglyceride form, vegan, non-GMO, third-party tested.
  1. Web Retailers: Amazon ($29.95 for 60 softgels), iHerb ($28.50), Nordic Naturals website ($30.95);
  2. Physical Retailers Whole Foods, Sprouts Farmers Market, The Vitamin Shoppe (~$30–$32).

• iwi Life Omega-3: ~250–350 mg DHA per 2 softgels (minimal EPA, <30 mg). Triglyceride form, vegan, sustainably sourced.
  1. Web Retailers: Amazon ($34.99 for 60 softgels), iwi Life website ($35.99), Walmart.com ($33.50);
  2. Physical Retailers Target, GNC (~$35–$38).

• Nested Naturals Vegan Omega-3: ~300 mg DHA per 1 softgel (minimal EPA, <20 mg). Triglyceride form, vegan, non-GMO.
  1. Web Retailers: Amazon ($19.95 for 60 softgels), Nested Naturals website ($20.99), Vitacost ($18.50);
  2. Physical Retailers: Primarily online.

• DSM Ovega-3: ~320 mg DHA and ~130 mg EPA per 1 softgel (DHA/EPA ratio ~2.5:1). Triglyceride form, vegan.
  1. Web Retailers: Amazon ($39.99 for 60 softgels), Ovega website ($41.99), Walgreens.com ($40.50);
  2. Physical Retailers: CVS, Walgreens (~$40–$43).

Fortified Foods

• Horizon Organic DHA Omega-3 Milk: ~32–50 mg DHA per 8 oz serving (negligible EPA). Organic, non-GMO.
  1. Web Retailers: Walmart.com ($4.99 per half-gallon), Instacart ($5.29), Amazon Fresh ($5.50);
  2. Physical Retailers: Walmart, Kroger, Whole Foods (~$4.50–$5.50).

• Silk DHA Omega-3 Plant-Based Milk (Soy or Almond): ~32 mg DHA per 8 oz serving. Vegan, non-GMO.
  1. Web Retailers: Amazon ($3.99 per half-gallon), Target.com ($4.29), Instacart ($4.50);
  2. Physical Retailers: Target, Walmart, Safeway (~$3.50–$4.50).

• Stonyfield Organic DHA-Fortified Yogurt: ~20–40 mg DHA per 6 oz serving. Organic, non-GMO.
  1. Web Retailers: Amazon Fresh ($1.50 per 6 oz), Instacart ($1.75), Stonyfield website ($1.80);
  2. Physical Retailers Whole Foods, Trader Joe’s, Kroger (~$1.25–$2).

• Tropicana Healthy Kids DHA-Fortified Orange Juice: ~40 mg DHA per 8 oz serving. Non-GMO.
  1. Web Retailers: Amazon ($4.29 per 59 oz), Walmart.com ($4.50), Instacart ($4.75);
  2. Physical Retailers: Publix, Kroger, Target (~$4–$5).

1. Thorne Advanced  DHA (EPA-200mg / DHA-650mg)/ 2 caps
   • Doctor Supplement Store (DSS): 60 tabs) $22
   • Dose: 2-6/caps/Day

9. Bioavailability and Recommended Formulations

• Bioavailability: High for EPA/DHA (~90%); ALA converts poorly (~5–10%) .
• Formulations: Fish oil (more affordable), krill oil (better absorption), algal (vegan).
• Practical tips: Take with meals; refrigerate to prevent oxidation.

10a. Mechanisms of Action (Patient-Friendly Explanation)

Omega-3s reduce swelling, protect nerves from damage, and balance brain chemicals, easing pain and improving health.

10b Detailed Mechanisms of Action 

Omega-3s incorporate into membranes, reducing arachidonic acid-derived mediators. DHA in DPN: Reduces sodium currents, increases potassium currents in DRG neurons; generates resolvins for inflammation resolution

11. Levels of Confidence 

Determining Levels of Confidence

Levels of confidence are determined by the hierarchy of research study designs:

• Randomized Controlled Trials (RCTs): High confidence (e.g., a drug for diabetic neuropathy [1]). Randomized Controlled Trials (RCTs) involve human participants who are randomly assigned to different groups (treatment or control) to test the effectiveness of an intervention.Limitations: Short duration.
• Systematic Reviews/Meta-Analyses: Highest confidence (e.g., diabetic neuropathy meta-analysis [1]).
• Cochrane Reviews: Gold-standard systematic reviews.
• Other Studies: Observational, preclinical; lower confidence (e.g., acute pain [4]). Confidence is rated High (robust RCTs, meta-analyses), Moderate (small RCTs, observational), or Low (preclinical, case reports).

Levels of Confidence in Omega-3s research

• Systemic Inflammation: High; lowers CRP/IL-6 .
• Neuro-Inflammation: Moderate; reduces glial activation .
• Oxidative Stress: High; boosts antioxidants .
• Peripheral/Central Sensitization: Moderate; modulates ion channels .
• Transition Acute to Chronic Pain: Moderate; resolves inflammation .
• Other conditions: As in section 5.

12. Chemistry and Sources (up to 200 words per subsection)

• Chemical structure: EPA (C20:5 n-3), DHA (C22:6 n-3); long-chain PUFAs.
• Primary dietary sources: Salmon (1–2 g/3 oz), flaxseeds (ALA 2 g/Tbsp).

13. References

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC10324313/
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC5875591/
3. https://www.medcentral.com/pain/chronic/omega-3-fatty-acids-neuropathic-pain
4. https://www.mdpi.com/2227-9059/13/7/1607
5. https://www.dovepress.com/omega-3-polyunsaturated-fatty-acids-effect-on-neuropathy-of-the-periph-peer-reviewed-fulltext-article-DMSO
6. https://www.sciencedirect.com/science/article/pii/S0952327822000680
7. https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-12-355
8. https://www.sciencedirect.com/science/article/pii/S0005273617301566
9. https://www.ahajournals.org/doi/10.1161/cir.0000000000000482
10. https://www.dovepress.com/effects-of-omega-3-polyunsaturated-fatty-acid-supplementation-on-neuro-peer-reviewed-fulltext-article-DMSO
11. https://www.researchgate.net/publication/393191161_Omega-3_Polyunsaturated_Fatty_Acids_PUFAs_and_Diabetic_Peripheral_Neuropathy_A_Pre-Clinical_Study_Examining_the_Effect_of_Omega-3_PUFAs_from_Fish_Oil_Krill_Oil_Algae_or_Pharmaceutical-derived_Ethyl_Es
12. https://www.droracle.ai/articles/32703/if-a-fish-oil-supplement-reports-3600-mg-fish-oil-1296-mg-epa-and-864dha-would-it-be-ok-for-a-person-with-peripheral-neuropathy-to-take-two-of-these-a-day-or-is-that-too-high-of-a-dose-and-if-it-is-too-high-of-a-dose-what-would-be-expected-in-terms-of-side-effects
13. https://www.researchgate.net/figure/Effect-of-omega-6-and-omega-3-PUFA-on-diabetic-peripheral-neuropathy_fig1_327227653
14. https://www.lifeextension.com/magazine/2020/3/new-hope-for-diabetic-neuropathy
15. https://pubmed.ncbi.nlm.nih.gov/40015508/
16. https://ascopubs.org/doi/10.1200/jco.2014.32.15_suppl.5019
17. https://pubmed.ncbi.nlm.nih.gov/22894640/
18. https://www.clinicaltrials.gov/study/NCT01049295
19. https://onf.ons.org/sites/default/files/2025-05/pn-evaluation-table_omega-3-2025.pdf
20. https://ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.tps9643
21. https://journals.lww.com/md-journal/fulltext/2020/12110/prevention_of_oxaliplatin_related_neurotoxicity_by.93.aspx
22. https://research.bond.edu.au/en/publications/the-effect-of-oral-omega-3-polyunsaturated-fatty-acid-supplementa-2
23. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00723/full
24. https://www.pmc.ncbi.nlm.nih.gov/articles/PMC5875591/
25. Circulating polyunsaturated fatty acids and pain intensity in five chronic pain conditions – 2022

14. Patient Handout

Omega-3 Fatty Acids: Your Natural Pain and Inflammation Reliever

What are Omega-3s?Omega-3s are healthy fats in fish, seeds, and algae, helping reduce swelling and protect nerves.

How Do They Help? (List pain conditions, pain-related conditions, other conditions, including cognitive function, fatigue, gut health, metabolic health, cardiovascular health.) (up to 500 words)

• Joint Pain: Reduces osteoarthritis pain.
• Nerve Pain: Improves diabetic neuropathy, especially DHA; protects against chemotherapy-induced neuropathy; may benefit idiopathic neuropathy.
• Headaches: Lowers migraine frequency.
• Mood: Eases anxiety/depression.
• Brain Health: Boosts memory, slows Alzheimer’s.
• Gut Health: Supports microbiome and inflammatory bowel diseases.
• Heart Health: Lowers cholesterol/blood pressure.
• Metabolic Health: Improves blood sugar.
• Fatigue: May boost energy.

How to Get Them? (Dietary sources, supplements, preparation, dosage.)

• Diet: Salmon (1–2 g/3 oz), flaxseeds (2 g ALA/Tbsp).
• Supplements: 1,000–2,000 mg EPA/DHA/day; higher DHA for neuropathy.
• Safety and side effects.Mild stomach upset; check with doctor if on blood thinners.

Tips for best results (e.g., food synergies, acupuncture).Take with meals; combine with curcumin; try acupuncture for OA.

www.accurateclinic.com

 

References

1. Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome – 2019
2. Impact of Omega-3 Polyunsaturated Fatty Acids on Alcohol Use and Negative Consequences- A Systematic Review – 2025
3. Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids – 2017
4. Analgesia enhancement and prevention of tolerance to morphine_ beneficial effects of combined therapy with omega-3 fatty acids – PubMed – 2015

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.

 

Supplements recommended by Dr. Ehlenberger may be purchased commercially online

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

 

 

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