Accurate Education – Pain Processing

Neurobiology of Pain:

Pain Processing

Simply put, pain processing refers to how tissue damage is first detected by specialized nerves, which then send signals via peripheral nerves to the spinal cord and then to the brain where it is then processed into the awareness and experience of pain.

Pain processing is complex and subject to modification at every level in ways that can reduce or increase the severity of how pain is perceived. In chronic pain, these modifications can contribute to an abnormal sensitivity to pain, magnifying the severity of the pain experience, referred to as “Sensitization.”

Understanding the processes and conditions that lead to sensitization provides an important tool to counter them in order to reduce the severity of chronic pain.

See:  

• Pain Processing

       How Nutraceuticals Impact Pain Processing

1. How Acetyl-L-Carnitine (ALC) Impacts Pain Processing
2. How Alpha-Lipoic Acid (ALA) impacts pain processing
3. How Boswellia Impacts Pain Processing
4. How CoQ10 Impacts Pain Processing
5. How Curcumin Impacts Pain Processing
6. How Magnesium Impacts Pain Processing
7. How Melatonin Impacts Pain Processing
8. How Omega-3 fatty acids (EPA and DHA) Impact Pain Processing
9. How N-Acetyl Cysteine (NAC) Impacts Pain Processing
10. How Nicotinamide Riboside (NR) Impacts Pain Processing
11. How PEA (Palmitoylethanolamide) Impacts Pain Processing
12. How Quercetin Impacts Pain Processing
13. How Resveratrol Impacts Pain Processing
14. How Sulforaphane (SFN): Impacts Pain Processing
15. How Taurine Impacts Pain Processing

Key to Links:

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Definitions and Terms Related to Pain

Understanding How Your Body Processes Pain

THE PAIN PATHWAY: A STEP-BY-STEP JOURNEY

Pain processing refers to how pain signals are processed from the initial damaged tissue source of pain through the nerves and spinal cord to the brain and then down the spinal cord again. Nutraceuticals offer potential benefit for reducing the severity of the pain experience by acting at various levels of pain processing. These benefits are independent of the benefits the nutraceutical offers at the source of pain.

See the links above for how various nutraceuticals impact pain processing

Introduction

Nutraceuticals offer a broad spectrum of pharmacological actions relevant to the process of sending pain signals from an area of injury to the brain, resulting in the experience of pain. Nutraceuticals impact the processing of pain signaling based on its different properties, including anti-inflammatory, antioxidant, and neuroprotective properties.

   Pain Processing involves complex nerve interactions that:

1. Starts with the detection of damaged tissues by specialized pain receptors,
2. Followed by sending pain signals to the spinal cord through peripheral nerves, then
3. Processing of the signals in the spinal cord, then
4. Forwarding the signals up ascending pain pathways to various parts of the brain, then
5. Processing of the pain signals in the brain (supraspinal integration)
6. Followed, finally, by the brain sending pain signals back down descending pain pathways in the spinal cord to impact the pain signal processing in the spinal cord (descending pain modulation).

At each of these stages, or levels, of pain processing, the pain signaling can be modified referred to as pain modulation.  Pain modulation can result in the pain experience being magnified or suppressed, temporarily or in some cases permanently. There are many situations and processes that modulate the pain experience, but the focus here is limited to the magnification of pain that occurs in the pathologic processing of pain signals in nerves in the peripheral nervous system and/or the spinal cord and brain (the central nervous system).

This pathologic pain processing that results in heightened sensitivity and magnification of the pain experience, it is referred to as “Sensitization) which  can originate in peripheral and or central nervous system, termed “Peripheral Sensitization” and “Central Sensitization.”

Central to the pathophysiology of pain processing leading to Peripheral Sensitization and Central Sensitization are 4 interconnected conditions, sometimes referred to as “the 4 Demons of Pain:”

1. Systemic Inflammation
2. Neuroinflammation’ below
3. Oxidative Stress
4. Mitochondrial Dysfunction.

(See “Combating the 4 Demons” below)

The Levels of Pain Processing can be organized as follows:

• Level 1: Peripheral Nociception (Pain Receptor Transduction)
• Level 2: Primary Afferent Transmission to Spinal Cord
• Level 3: Spinal Cord Dorsal Horn Processing (First Synapse)
• Level 4: Ascending Spinal Pathways and Supraspinal Processing
• Level 5: Thalamic and Cortical Brain Processing and Pain Perception
• Level 6: Descending Pain Modulation

Think of pain signals traveling through your body like a message being passed along a relay race. Here’s how it works:

Level 1: Peripheral Nociception (Pain Receptor Transduction) – Detection (The Alarm Goes Off)

Your body has millions of tiny specialized nerve sensors called “nociceptors” (no-see-SEP-tors)  or “pain receptors,” in your skin, muscles, joints, and organs. These pain receptors can detect potentially harmful conditions such as:

• Extreme heat or cold
• Strong pressure or stretching
• Tissue Damage which release chemicals

When these sensors detect something potentially harmful, they send a nerve impulse, or pain signal, along a peripheral nerve towards the spinal cord.

Level 2: Primary Afferent Transmission to Spinal Cord – (Sending the Message)

When the pain receptor is triggered, the signal travels along nerve fibers to the spinal cord. There are two types of nerve fibers that carry pain signals:

• Fast fibers (A-delta fibers): These carry sharp, immediate pain—like when you stub your toe. You feel it right away and know exactly where it hurts.
• Slow fibers (C fibers): These carry dull, aching pain that comes a few seconds later and feels more spread out.[3]

Level 3: Spinal Cord Dorsal Horn Processing – (First Synapse) – (or Checkpoint)

The spinal cord is like a relay station where pain signals are processed before going to the brain. It is an important checkpoint because:

• At the spinal cord the pain signal can be suppressed or magnified
• Other signals (like touch or pressure) can interact with the pain signal to modify it—this is why rubbing a sore spot can help it feel better
• This is where many pain medications work[4]

Level 4: Ascending Spinal Pathways and Supraspinal Processing – (Traveling to the Brain – The Highway)

From the spinal cord, pain signals travel up through pathways in your spine to reach your brain. Different pathways carry different types of information:

• One pathway tells your brain WHERE the pain is and HOW INTENSE it is
• Another pathway connects to emotional centers, which is why pain can make you feel anxious, upset, or afraid[5]

Level 5: Thalamic and Cortical Brain Processing and Pain Perception – (The Brain Making Sense of Pain)

Pain isn’t truly “felt” until the signal reaches your brain. Multiple brain areas work together to create your complete pain experience:

• Sensory brain areas: Figure out the location, intensity, and type of pain (sharp, burning, aching)
• Emotional brain areas: Create the unpleasant feelings that come with pain
• Thinking brain areas: Help you evaluate the pain and decide what to do about it thank you
• Memory brain areas: Compare this pain to past experiences

Level 6: Descending Pain Modulation – (the brain sending signals back to the spinal cord to modify processing of the spinal cord)

Understanding the Pain Experience

The actual experience of pain can be influenced by many factors. Most importantly, the brain processes pain information coming from nerves and the spinal cord and can modify the pain experience in a number of ways, resulting in suppression or magnification of pain severity.

Key Brain Areas Involved in Pain Processing:

The Brain

THE VOLUME CONTROL: THE BODY’S BUILT-IN PAIN MANAGEMENT

The brain doesn’t just passively receive pain signals from a site of injury—it can actively controls how much pain one feels. The brain has a “volume control” system that can turn pain up or down.

Turning Pain DOWN:

The brain can send signals back down the spinal cord to reduce pain. This explains why:

• 1. Athletes and soldiers sometimes don’t feel injuries when actively engaged
  2. You might not notice a cut until you see it
  3. Distraction, relaxation, and positive emotions can reduce pain
  4. Some medications (like certain antidepressants) help pain by boosting these “turn it down” signals

Turning Pain UP:

Unfortunately, the brain can also increase pain sensitivity. This can happen when:

• 1. One is stressed, anxious, or depressed
  2. One is sleep deprived
  3. One focuses intensely on their pain
  4. Pain becomes chronic after it has been present for a long time

However, the experience of pain can also be influenced by modifications of the pain signaling system, which starts at a site of injury and progresses to the spinal cord and then up to the brain. After the brain has processed the signals coming from spinal cord, it then turn may send signals back down the spinal cord to modify further pain signaling coming back up to the brain.

To fully understand pain processing, then requires not just how the brain itself may modify the experience, but also how the pain signaling process can be modified before and after reaching the brain.

The Pain Signaling System

The experience of pain begins at the source of tissue damage or malfunction when signals are sent from the area of injury ultimately reaching the brain where signals are interpreted and ultimately experienced as pain.

Pain Processing

The Details: Facets of Pain Processing

1. Transduction: Tissue damage (mechanical, thermal, chemical) activates specialized nerve endings called nociceptors (pain receptors), converting the stimulus into electrical pain signals.
2. Transmission: Pain signals travel along periheral sensory nerves (A-delta for sharp pain, C-fibers for dull pain) to the spinal cord in the central nervous system, then cross over and ascend to the brain via different pathways (including the spinothalamic tract). This signaling can be modified with the use of medications like gabapentin (Neurontin) and pregabalin (Lyrica).
3. Modulation: The brain can either amplify or inhibit pain signals through descending pathways from the brainstem to the dorsal horn in the spinal cord, using neurotransmitters and endogenous opioids (endorphins).

   The dorsal horn contains a complex balance of circuitry of excitatory and inhibitory nerves that modulate signal transmission. Under pathological conditions, this balance shifts toward excitation, producing central sensitization characterized by hyperalgesia (the magnified pain response to painful stimulation)and allodynia (when normally non-painful stimulation is perceived as painfula0.

   These pathways are targeted by analgesic medications like duloxetine (Cymbalta) as well as behaviors like meditation and hypnosis.

4. Perception: The brain integrates these signals with information including location, intensity and emotional conetnt, creating the conscious, subjective experience of pain.

The 4 Pathologic Processes/Conditions That Impact Pain Processing and Contribute to Sensitization

1. Systemic Inflammation
2. Neuroinflammation
3. Oxidative Stress
4. Mitochondrial Dysfunction

These 4 pathologic processes/conditions above play important roles in magnifying pain experience and sensitization in pain processing –  the 4 Demons of Pain.

“Systemic Inflammation” and “Oxidative Stress” are two processes/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.

•  Systemic inflammation (SI) is a widespread inflammatory response throughout the body, triggered by infection, injury, stress and other conditions. It involves activation of the immune system with the release of pro-inflammatory compounds that contribute to chronic pain and lead to other health issues. Symptoms of SI 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 SI contributes to the development of heart disease, diabetes, and autoimmune disorders like rheumatoid arthritis.

•  Neuroinflammation (NI), a component of systemic inflammation, is inflammation within the central nervous system (brain and spinal cord). SI releases inflammatory compounds that cross into the brain and spinal cord that activate immune cells causing NI and contributes to the progression of acute to chronic pain. NI is characterized by activation of immune cells (glial cells and astrocytes) in the nervous system that release 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 (OS) is an imbalance of excessive “oxidants” (“oxidizing” or chemically active agents (including ROS and NOS) obtained from the diet or produced by the body coupled with insufficient “antioxidants,” the compounds that neutralize oxidants. Excessive oxidants damage nerve cells and other tissues causing and maintaining pain. Antioxidants are manufactured by the body, but sufficient dietary intake of antioxidants is critical for good health. OS and chronic SI co-exist and feed each other, damaging tissues in a vicious cycle that further worsens pain.

•  Mitochondrial Dysfunction (MD). Mitochondria are organelles found in cells that function as the “powerhouses” of cells in that they process food into energy. In addition to providing energy, they play a major role in maintaining antioxidants to combat OS and SI. Because mitochondria impact the metabolism of all cells, they play a huge role in general health. Impairment of mitochondrial function (dysfunction) contributes to many conditions including chronic pain, obesity, migraines, fibromyalgia, diabetes, heart disease and neurodegenerative diseases like Alzheimers.In MD, energy production goes down and fatigue develops along with impaired physical functioning, even if more calories are ingested. MD is the hallmark of conditions such as obesity and fibromyalgia. Mitochondrial dysfunction leads to the metabolic impairment that is found in many chronic diseases including depression, bipolar disorders and premature aging.

Combating these 4 Demons

Combating these four demons of pain involves lifestyle factors, including sleep, exercise, reducing stress and maintaining a healthy diet, particularly the Anti-Inflammatory Diet (AID)

These compounds impact pain processing at all levels in ways to prevent or reverse the damages driven by the four demons. In many cases, the use of multiple nutraceuticals provide synergistic benefits that enhance their therapeutic benefits. Links to many of these nutraceuticals are provided at the top of this page and offer information regarding how they can improve pain processing via the different pain processing pathways.

Pain Processing Pathways in Review:

Pain processing involves a sophisticated multi-level pathway that transforms tissue damage into the conscious experience of pain, with both ascending (sensory) and descending (modulatory) components that determine the ultimate pain experience.

The stages, or Levels, of Pain Processing can be organized as follows:

• Level 1: Peripheral Nociception (Pain Receptor Transduction): Activation and Sensitization
• Level 2: Primary Afferent Transmission to Spinal Cord
• Level 3: Spinal Cord Dorsal Horn Processing (First Synapse)
• Level 4: Ascending Spinal Pathways and Supraspinal Processing
• Level 5: Thalamic and Cortical Processing and Pain Perception
• Level 6: Descending Pain Modulation

Level 1: Peripheral Nociception (Pain Receptor Transduction): Activation and Sensitization

Pain begins when nociceptors—specialized free nerve endings in skin, muscle, viscera, and other tissues—detect potentially harmful stimuli (mechanical, thermal, or chemical). These receptors express ion channels (TRPV1, Nav1.7, Nav1.8) that convert noxious stimuli into electrical signals. Tissue damage releases inflammatory mediators (prostaglandins, bradykinin, substance P, CGRP) that sensitize nociceptors, lowering their activation threshold—a process called peripheral sensitization.[1][2]

Level 2: Transmission via Primary Afferents

Nociceptive signals travel via two primary afferent fiber types: Aδ fibers (myelinated, fast-conducting, sharp/localized pain) and C fibers (unmyelinated, slow-conducting, dull/diffuse pain). These fibers have cell bodies in the dorsal root ganglia (DRG) and terminate in the spinal cord dorsal horn, primarily in laminae I, II, and V.[1][3]

Level 3: Spinal Cord Dorsal Horn Processing (First Synapse)

The dorsal horn serves as the first critical integration site for nociceptive information.[3] Here, primary afferents synapse with secondary neurons, releasing glutamate (primary neurotransmitter) and neuropeptides (substance P, CGRP) during intense stimulation.[2] The dorsal horn contains complex circuitry of excitatory and inhibitory interneurons that modulate signal transmission according to gate control theory—innocuous touch (Aβ fibers) can activate inhibitory interneurons that reduce pain transmission.[4][3] Under pathological conditions, this balance shifts toward excitation, producing central sensitization characterized by hyperalgesia and allodynia.[3][5]

Level 4: Ascending Spinal Pathways

Projection neurons in the dorsal horn send axons across the midline and ascend via several tracts:[6][1]

• Spinothalamic tract (lateral): Primary pathway for pain and temperature; projects to the ventral posterolateral (VPL) thalamus, then to somatosensory cortex for sensory-discriminative aspects (location, intensity, quality)
• Spinoreticular tract: Projects to brainstem reticular formation; involved in arousal and autonomic responses
• Spinomesencephalic tract: Projects to periaqueductal gray (PAG) and other midbrain structures; activates descending modulation
• Spinoparabrachial tract: Projects to parabrachial nucleus then amygdala; mediates emotional/affective aspects of pain[7]

Level 5: Thalamic Relay and Cortical Processing

The thalamus serves as the central relay station, with two parallel pathways:[6]

• Lateral thalamocortical pathway (VPL → primary/secondary somatosensory cortex): Encodes sensory-discriminative aspects—where the pain is, how intense, what quality
• Medial thalamocortical pathway (medial thalamic nuclei → anterior cingulate cortex, insula, prefrontal cortex): Encodes emotional-motivational aspects—the unpleasantness and suffering

The anterior insula appears to be a critical convergence zone where sensory and limbic information integrate to produce the conscious perception of pain, with responses occurring within ~700 ms of stimulus.[7] Multiple cortical regions contribute to the complete pain experience, including somatosensory cortices (S1, S2), anterior cingulate cortex (ACC), insular cortex, and prefrontal cortex.[8]

Level 6: Descending Pain Modulation

Pain is not simply a one-way transmission—descending pathways from the brainstem powerfully modify spinal cord processing, either inhibiting or facilitating pain.[9][10] The key structures include:

• Periaqueductal gray (PAG): Receives input from cortex, hypothalamus, and amygdala; integrates cognitive and emotional influences on pain
• Rostral ventromedial medulla (RVM): Contains functionally distinct cell populations—OFF-cells that inhibit pain and ON-cells that facilitate pain[9]
• Locus coeruleus (LC): Provides descending noradrenergic inhibition to the spinal cord[11]

These descending pathways release serotonin and norepinephrine at the dorsal horn, which can either inhibit or facilitate nociceptive transmission depending on the receptor subtypes activated.[10] This system underlies phenomena such as stress-induced analgesia, placebo analgesia, and the analgesic effects of SNRIs (duloxetine / Cymbalta) and TCAs (amitriptyline / Elavil and doxepin).[12]

References through Level 1-6

Table 1  Comparison of Levels of Impact of Pain-Modulating Nutraceuticals

Legend: +++ = Strong effect; ++ = Moderate effect; + = Weak/indirect effect.   

Summary of Evidence for Original Nutraceuticals:

Taurine acts as a glycine receptor agonist and GABA-A modulator, with intrathecal studies demonstrating antinociceptive effects mediated through strychnine-sensitive glycinergic neurotransmission.[4] It also corrects abnormal Ca²⁺ signaling in sensory neurons and attenuates hyperalgesia in diabetic models.[3] Peripheral muscarinic receptor activation contributes to its analgesic effects and may reduce opioid tolerance.[1]

Alpha-Lipoic Acid has the strongest human RCT evidence among these nutraceuticals, with the SYDNEY 2 trial demonstrating that 600 mg/day oral dosing significantly reduces Total Symptom Score in diabetic polyneuropathy.[10] A recent meta-analysis confirmed improvements in paresthesia, numbness, and burning sensations, though effects on nerve conduction velocity remain inconclusive.[8] A Cochrane review noted moderate-certainty evidence for symptom improvement at 6 months.[7]

Acetyl-L-Carnitine exerts long-lasting analgesic effects through epigenetic upregulation of mGlu2 receptors via acetylation of histone H3 bound to the Grm2 gene promoter.[17] Meta-analysis of RCTs showed moderate pain reduction (MD 1.20 on VAS) with greater efficacy in diabetic vs. non-diabetic neuropathy.[13] Its effects persist beyond treatment cessation due to epigenetic mechanisms.[17]

Magnesium functions as a physiological NMDA receptor antagonist, blocking the receptor ion channel and reducing central sensitization.[19] It attenuates spinal cord NR1 subunit phosphorylation in diabetic neuropathy models and prevents chronic postsurgical pain development.[23][24] Clinical evidence supports perioperative use for opioid-sparing effects.[20]

Omega-3 fatty acids (EPA/DHA) reduce inflammation through multiple mechanisms: replacing arachidonic acid as an eicosanoid substrate, generating specialized pro-resolving mediators (resolvins, protectins, maresins), and inhibiting NF-κB activation.[25][26] Strong clinical evidence exists for rheumatoid arthritis pain reduction.[25]

Palmitoylethanolamide (PEA) activates PPAR-α receptors and down-modulates mast cell and glial cell activation.[33] Meta-analysis of 18 RCTs (1196 patients) demonstrated significant pain reduction across nociceptive, neuropathic, and nociplastic pain types, with effects evident by 4-6 weeks.[31] Ultramicronized formulations show enhanced bioavailability and blood-brain barrier penetration.[32]

Curcumin inhibits NF-κB signaling through oxidative metabolites that adduct to IKKβ.[37] It alleviates chemotherapy-induced neuropathic pain by reducing oxidative stress and neuroinflammation.[40] However, low bioavailability limits clinical translation, though nano-emulsion formulations show improved efficacy.[39]

CoQ10 prevents diabetic neuropathic pain development through antioxidant effects, reducing lipid peroxidation in dorsal root ganglia, sciatic nerve, and spinal cord.[43] A placebo-controlled RCT demonstrated that CoQ10 (300 mg/day) added to pregabalin significantly improved pain scores and sleep interference in painful diabetic neuropathy.[44] Long-term supplementation attenuates neuronal loss in DRG and preserves nerve conduction velocity.[48]

References for Table 1

1. Comparative Investigation of Analgesic Tolerance to Taurine, Sodium Salicylate and Morphine: Involvement of Peripheral Muscarinic Receptors. Akbari E, Beheshti F, Zarmehri HA, et al. Neuroscience Letters. 2023;795:137041. doi:10.1016/j.neulet.2022.137041.
2. Taurine and Its Analogs in Neurological Disorders: Focus on Therapeutic Potential and Molecular Mechanisms. Jakaria M, Azam S, Haque ME, et al. Redox Biology. 2019;24:101223. doi:10.1016/j.redox.2019.101223.
3. Taurine Replacement Attenuates Hyperalgesia and Abnormal Calcium Signaling in Sensory Neurons of STZ-D Rats. Li F, Obrosova IG, Abatan O, et al. American Journal of Physiology. Endocrinology and Metabolism. 2005;288(1):E29-36. doi:10.1152/ajpendo.00168.2004.
4. Antinociceptive Effect of Intrathecal Administration of Taurine in Rat Models of Neuropathic Pain. Terada T, Hara K, Haranishi Y, Sata T. Canadian Journal of Anaesthesia = Journal Canadien d’Anesthesie. 2011;58(7):630-637. doi:10.1007/s12630-011-9504-8.
5. Neuropsychopharmacological Actions of Taurine. Banerjee SP, Ragnauth A, Chan CY, et al. Advances in Experimental Medicine and Biology. 2013;775:3-18. doi:10.1007/978-1-4614-6130-2_1.
6. Taurine in the Anterior Cingulate Cortex Diminishes Neuropathic Nociception: A Possible Interaction With the Glycine(A) Receptor. Pellicer F, López-Avila A, Coffeen U, Manuel Ortega-Legaspi J, Angel RD. European Journal of Pain (London, England). 2007;11(4):444-51. doi:10.1016/j.ejpain.2006.06.003.
7. Alpha-Lipoic Acid for Diabetic Peripheral Neuropathy. Baicus C, Purcarea A, von Elm E, Delcea C, Furtunescu FL. The Cochrane Database of Systematic Reviews. 2024;1:CD012967. doi:10.1002/14651858.CD012967.pub2.
8. Effectiveness of Alpha Lipoic Acid Supplementation on Biochemical, Clinical, and Inflammatory Parameters in Patients With Diabetic Polyneuropathy: A Systematic Review and Meta-Analysis. Salinas AV, Caroca TM, Santibáñez FP, et al. Diabetes & Metabolic Syndrome. 2026;20(2):103374. doi:10.1016/j.dsx.2026.103374.
9. Evaluation of the Analgesic Effect of Ɑ-Lipoic Acid in Treating Pain Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cassanego G, Rodrigues P, De Freitas Bauermann L, Trevisan G. Pharmacological Research. 2022;177:106075. doi:10.1016/j.phrs.2022.106075.
10. Oral Treatment With Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy: The SYDNEY 2 Trial. Ziegler D, Ametov A, Barinov A, et al. Diabetes Care. 2006;29(11):2365-70. doi:10.2337/dc06-1216.
11. Efficacy of Α-Lipoic Acid in Diabetic Neuropathy. Papanas N, Ziegler D. Expert Opinion on Pharmacotherapy. 2014;15(18):2721-31. doi:10.1517/14656566.2014.972935.
12. A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy. Nguyen N, Takemoto JK. Journal of Pharmacy & Pharmaceutical Sciences : A Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques. 2018;21(1s):177s-191s. doi:10.18433/jpps30100.
13. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Li S, Li Q, Li Y, et al. PloS One. 2015;10(3):e0119479. doi:10.1371/journal.pone.0119479.
14. Acetyl-L-Carnitine in Chronic Pain: A Narrative Review. Sarzi-Puttini P, Giorgi V, Di Lascio S, Fornasari D. Pharmacological Research. 2021;173:105874. doi:10.1016/j.phrs.2021.105874.
15. Acetyl-L-Carnitine for the Treatment of Diabetic Peripheral Neuropathy. Rolim LC, da Silva EM, Flumignan RL, Abreu MM, Dib SA. The Cochrane Database of Systematic Reviews. 2019;6:CD011265. doi:10.1002/14651858.CD011265.pub2.
16. Acetyl-L-Carnitine: From a Biological Curiosity to a Drug for the Peripheral Nervous System and Beyond. Onofrj M, Ciccocioppo F, Varanese S, et al. Expert Review of Neurotherapeutics. 2013;13(8):925-36. doi:10.1586/14737175.2013.814930.
17. Analgesia Induced by the Epigenetic Drug, L-Acetylcarnitine, Outlasts the End of Treatment in Mouse Models of Chronic Inflammatory and Neuropathic Pain. Notartomaso S, Mascio G, Bernabucci M, et al. Molecular Pain. 2017;13:1744806917697009. doi:10.1177/1744806917697009.
18. The Neurobiology of Acetyl-L-Carnitine. Traina G. Frontiers in Bioscience (Landmark Edition). 2016;21(7):1314-29. doi:10.2741/4459.
19. Magnesium in Pain Research: State of the Art. Srebro D, Vuckovic S, Milovanovic A, et al. Current Medicinal Chemistry. 2017;24(4):424-434. doi:10.2174/0929867323666161213101744.
20. Clinical Efficacy of Magnesium in Perioperative Pain Management: A Narrative Review. Ahmadzadeh S, Wentling JG, Ford BM, et al. Current Pain and Headache Reports. 2025;29(1):117. doi:10.1007/s11916-025-01422-y.
21. Intravenous Magnesium for the Management of Chronic Pain:An Updated Review of the Literature. Onyeaka H, Adeola J, Xu R, et al. Psychopharmacology Bulletin. 2024;54(4):81-105.
22. Local Magnesium Sulfate Administration Ameliorates Nociception, Peripheral Inflammation, and Spinal Sensitization in a Rat Model of Incisional Pain. Wen ZH, Wu ZS, Huang SY, et al. Neuroscience. 2024;547:98-107. doi:10.1016/j.neuroscience.2024.03.033.
23. Effects of Magnesium Sulfate Administration in Attenuating Chronic Postsurgical Pain in Rats. Kido K, Katagiri N, Kawana H, et al. Biochemical and Biophysical Research Communications. 2021;534:395-400. doi:10.1016/j.bbrc.2020.11.069.
24. Magnesium Attenuates Chronic Hypersensitivity and Spinal Cord NMDA Receptor Phosphorylation in a Rat Model of Diabetic Neuropathic Pain. Rondón LJ, Privat AM, Daulhac L, et al. The Journal of Physiology. 2010;588(Pt 21):4205-15. doi:10.1113/jphysiol.2010.197004.
25. 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.
26. Omega-3 Fatty Acids and Inflammatory Processes: From Molecules to Man. Calder PC. Biochemical Society Transactions. 2017;45(5):1105-1115. doi:10.1042/BST20160474.
27. Dietary Ω-3 Fatty Acids and Their Influence on Inflammation via Toll-Like Receptor Pathways. Jalili M, Hekmatdoost A. Nutrition (Burbank, Los Angeles County, Calif.). 2021;85:111070. doi:10.1016/j.nut.2020.111070.
28. N-3 Polyunsaturated Fatty Acids, Inflammation, and Inflammatory Diseases. Calder PC. The American Journal of Clinical Nutrition. 2006;83(6 Suppl):1505S-1519S. doi:10.1093/ajcn/83.6.1505S.
29. Immunomodulatory Effects of Omega-3 Fatty Acids: Mechanistic Insights and Health Implications. Bodur M, Yilmaz B, Ağagündüz D, Ozogul Y. Molecular Nutrition & Food Research. 2025;69(10):e202400752. doi:10.1002/mnfr.202400752.
30. Omega-3 Pleiad: The Multipoint Anti-Inflammatory Strategy. da Silva Batista E, Nakandakari SCBR, Ramos da Silva AS, et al. Critical Reviews in Food Science and Nutrition. 2024;64(14):4817-4832. doi:10.1080/10408398.2022.2146044.
31. Meta-Analysis of Palmitoylethanolamide in Pain Management: Addressing Literature Gaps and Enhancing Understanding. Viña I, López-Moreno M. Nutrition Reviews. 2025;83(7):e1604-e1618. doi:10.1093/nutrit/nuae203.
32. Ultramicronized N-Palmitoylethanolamine Associated With Analgesics: Effects Against Persistent Pain. Nobili S, Micheli L, Lucarini E, et al. Pharmacology & Therapeutics. 2024;258:108649. doi:10.1016/j.pharmthera.2024.108649.
33. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-Analysis. Paladini A, Fusco M, Cenacchi T, et al. Pain Physician. 2016;19(2):11-24.
34. Effects of Palmitoylethanolamide (PEA) on Nociceptive, Musculoskeletal and Neuropathic Pain: Systematic Review and Meta-Analysis of Clinical Evidence. Scuteri D, Guida F, Boccella S, et al. Pharmaceutics. 2022;14(8):1672. doi:10.3390/pharmaceutics14081672.
35. The Neuroprotective Effects of Micronized PEA (PEA-m) Formulation on Diabetic Peripheral Neuropathy in Mice. Impellizzeri D, Peritore AF, Cordaro M, et al. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2019;33(10):11364-11380. doi:10.1096/fj.201900538R.
36. The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G. Pain. 2008;139(3):541-550. doi:10.1016/j.pain.2008.06.003.
37. The Anti-Inflammatory Activity of Curcumin Is Mediated by Its Oxidative Metabolites. Edwards RL, Luis PB, Varuzza PV, et al. The Journal of Biological Chemistry. 2017;292(52):21243-21252. doi:10.1074/jbc.RA117.000123.
38. Regulation Mechanism of Curcumin Mediated Inflammatory Pathway and Its Clinical Application: A Review. Liu M, Wang J, Song Z, Pei Y. Frontiers in Pharmacology. 2025;16:1642248. doi:10.3389/fphar.2025.1642248.
39. Oral Administration of Nano-Emulsion Curcumin in Mice Suppresses Inflammatory-Induced NFκB Signaling and Macrophage Migration. Young NA, Bruss MS, Gardner M, et al. PloS One. 2014;9(11):e111559. doi:10.1371/journal.pone.0111559.
40. Curcumin Alleviates Oxaliplatin-Induced Peripheral Neuropathic Pain Through Inhibiting Oxidative Stress-Mediated Activation of NF-κB and Mitigating Inflammation. Zhang X, Guan Z, Wang X, et al. Biological & Pharmaceutical Bulletin. 2020;43(2):348-355. doi:10.1248/bpb.b19-00862.
41. Curcumin: An Inflammasome Silencer. Hasanzadeh S, Read MI, Bland AR, et al. Pharmacological Research. 2020;159:104921. doi:10.1016/j.phrs.2020.104921.
42. Curcumin and Its Multi-Target Function Against Pain and Inflammation: An Update of Pre-Clinical Data. Uddin SJ, Hasan MF, Afroz M, et al. Current Drug Targets. 2021;22(6):656-671. doi:10.2174/1389450121666200925150022.
43. Prophylactic and Antinociceptive Effects of Coenzyme Q10 on Diabetic Neuropathic Pain in a Mouse Model of Type 1 Diabetes. Zhang YP, Eber A, Yuan Y, et al. Anesthesiology. 2013;118(4):945-54. doi:10.1097/ALN.0b013e3182829b7b.
44. Coenzyme Q10 as a Potential Add-on Treatment for Patients Suffering From Painful Diabetic Neuropathy: Results of a Placebo-Controlled Randomized Trial. Amini P, Sajedi F, Mirjalili M, Mohammadi Y, Mehrpooya M. European Journal of Clinical Pharmacology. 2022;78(12):1899-1910. doi:10.1007/s00228-022-03407-x.
45. Diabetic Neuropathic Pain Development in Type 2 Diabetic Mouse Model and the Prophylactic and Therapeutic Effects of Coenzyme Q10. Zhang YP, Song CY, Yuan Y, et al. Neurobiology of Disease. 2013;58:169-78. doi:10.1016/j.nbd.2013.05.003.
46. Neuroprotective Effects of Coenzyme Q10 on Neurological Diseases: A Review Article. Bagheri S, Haddadi R, Saki S, et al. Frontiers in Neuroscience. 2023;17:1188839. doi:10.3389/fnins.2023.1188839.
47. Therapeutic Roles of Coenzyme Q10 in Peripheral Nerve Injury-Induced Neurosensory Disturbances: Mechanistic Insights From Injury to Recovery. Vachirarojpisan T, Srivichit B, Vaseenon S, Powcharoen W, Imerb N. Nutrition Research (New York, N.Y.). 2024;129:55-67. doi:10.1016/j.nutres.2024.07.011.
48. Coenzyme Q10 Prevents Peripheral Neuropathy and Attenuates Neuron Loss in the Db-/Db- Mouse, a Type 2 Diabetes Model. Shi TJ, Zhang MD, Zeberg H, et al. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(2):690-5. doi:10.1073/pnas.1220794110.
49. Efficacy and Safety of Acmella Oleracea and Boswellia Serrata Extract as Add-on Therapy for Chronic Low Back Pain: An Observational, Real-World Cohort Study. Giglio M, Mattia C, Sansone P, et al. Pharmaceuticals (Basel, Switzerland). 2025;18(12):1903. doi:10.3390/ph18121903.
50. 11-Keto-Β-Boswellic Acid and Z-Guggulsterone Suppress HMGB1/TLR4 Pathway Activity and Modulate Microglial Polarization to Remodel Perineuronal Nets After Nerve Injury. Liao Y, Yang L, Ding Y, et al. Journal of Advanced Research. 2025;:S2090-1232(25)00867-7. doi:10.1016/j.jare.2025.10.072.
51. The Biological Activity of 3-O-Acetyl-11-Keto-Β-Boswellic Acid in Nervous System Diseases. Gong Y, Jiang X, Yang S, et al. Neuromolecular Medicine. 2022;24(4):374-384. doi:10.1007/s12017-022-08707-0.
52. Neuronutritional Enhancement of Antioxidant Defense System Through Nrf2/Ho1/Nqo1 Axis in Fibromyalgia. Inferrera F, Tranchida N, Fusco R, et al. Neurochemistry International. 2025;:106057. doi:10.1016/j.neuint.2025.106057.
53. N-Acetyl-Cysteine Attenuates Neuropathic Pain by Suppressing Matrix Metalloproteinases. Li J, Xu L, Deng X, et al. Pain. 2016;157(8):1711-1723. doi:10.1097/j.pain.0000000000000575.
54. Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis. Mohiuddin M, Pivetta B, Gilron I, Khan JS. Pain Medicine (Malden, Mass.). 2021;22(12):2896-2907. doi:10.1093/pm/pnab042.
55. N-Acetyl-Cysteine, a Drug That Enhances the Endogenous Activation of Group-Ii Metabotropic Glutamate Receptors, Inhibits Nociceptive Transmission in Humans. Truini A, Piroso S, Pasquale E, et al. Molecular Pain. 2015;11:14. doi:10.1186/s12990-015-0009-2.
56. Deciphering Resveratrol’s Role in Modulating Pathological Pain: From Molecular Mechanisms to Clinical Relevance. Wang B, Jiang HM, Qi LM, et al. Phytotherapy Research : PTR. 2024;38(1):59-73. doi:10.1002/ptr.8021.
57. Evidence for the Involvement of Opioid and Cannabinoid Systems in the Peripheral Antinociception Mediated by Resveratrol. Oliveira CDC, Castor MGME, Castor CGME, et al. Toxicology and Applied Pharmacology. 2019;369:30-38. doi:10.1016/j.taap.2019.02.004.
58. Antinociceptive Effect of Resveratrol in Carrageenan-Evoked Hyperalgesia in Rats: Prolonged Effect Related to COX-2 Expression Impairment. Pham-Marcou TA, Beloeil H, Sun X, et al. Pain. 2008;140(2):274-283. doi:10.1016/j.pain.2008.08.010.
59. Resveratrol: Harnessing Nature’s Potential for Chronic Pain Relief. Wu H, Wu JY, Gao SJ, et al. Aging and Disease. 2025;:AD.2025.0530. doi:10.14336/AD.2025.0530.
60. Nicotinamide Riboside, a Form of Vitamin B3 and NAD+ Precursor, Relieves the Nociceptive and Aversive Dimensions of Paclitaxel-Induced Peripheral Neuropathy in Female Rats. Hamity MV, White SR, Walder RY, et al. Pain. 2017;158(5):962-972. doi:10.1097/j.pain.0000000000000862.
61. NAD Metabolism in Peripheral Neuropathic Pain. Dai Y, Lin J, Ren J, et al. Neurochemistry International. 2022;161:105435. doi:10.1016/j.neuint.2022.105435.
62. Vitamin D3 Attenuates Neuropathic Pain via Suppression of Mitochondria-Associated Ferroptosis by Inhibiting PKCα/NOX4 Signaling Pathway. Zhang W, Yu S, Jiao B, et al. CNS Neuroscience & Therapeutics. 2024;30(9):e70067. doi:10.1111/cns.70067.
63. A Systematic Review on the Efficacy of Vitamin D Supplementation on Diabetic Peripheral Neuropathy. Yammine K, Wehbe R, Assi C. Clinical Nutrition (Edinburgh, Scotland). 2020;39(10):2970-2974. doi:10.1016/j.clnu.2020.01.022.
64. Cholecalciferol (Vitamin D) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling. Poisbeau P, Aouad M, Gazzo G, et al. Molecular Neurobiology. 2019;56(10):7208-7221. doi:10.1007/s12035-019-1582-6.
65. Melatonin Improves Mitochondrial Dysfunction and Attenuates Neuropathic Pain by Regulating SIRT1 in Dorsal Root Ganglions. Zeng Y, Fang Q, Chen J, et al. Neuroscience. 2023;534:29-40. doi:10.1016/j.neuroscience.2023.10.005.
66. Targeting Melatonin MT2 Receptors: A Novel Pharmacological Avenue for Inflammatory and Neuropathic Pain. Posa L, De Gregorio D, Gobbi G, Comai S. Current Medicinal Chemistry. 2018;25(32):3866-3882. doi:10.2174/0929867324666170209104926.
67. Exogenous Melatonin in the Treatment of Pain: A Systematic Review and Meta-Analysis. Zhu C, Xu Y, Duan Y, et al. Oncotarget. 2017;8(59):100582-100592. doi:10.18632/oncotarget.21504.
68. Supraspinal Melatonin MT Receptor Agonism Alleviates Pain via a Neural Circuit That Recruits Mu Opioid Receptors. Posa L, De Gregorio D, Lopez-Canul M, et al. Journal of Pineal Research. 2022;73(4):e12825. doi:10.1111/jpi.12825.
69. Emerging Promise of Sulforaphane-Mediated Nrf2 Signaling Cascade Against Neurological Disorders. Uddin MS, Mamun AA, Jakaria M, et al. The Science of the Total Environment. 2020;707:135624. doi:10.1016/j.scitotenv.2019.135624.
70. Sulforaphane: An Emerging Star in Neuroprotection and Neurological Disease Prevention. Wu N, Luo Z, Deng R, et al. Biochemical Pharmacology. 2025;233:116797. doi:10.1016/j.bcp.2025.116797.
71. Effects of Sulforaphane in the Central Nervous System. Huang C, Wu J, Chen D, et al. European Journal of Pharmacology. 2019;853:153-168. doi:10.1016/j.ejphar.2019.03.010.
72. The Phytoprotective Agent Sulforaphane Prevents Inflammatory Degenerative Diseases and Age-Related Pathologies via Nrf2-Mediated Hormesis. Calabrese EJ, Kozumbo WJ. Pharmacological Research. 2021;163:105283. doi:10.1016/j.phrs.2020.105283.
73. Quercetin Attenuates Diabetic Neuropathic Pain by Inhibiting mTOR/p70S6K Pathway-Mediated Changes of Synaptic Morphology and Synaptic Protein Levels in Spinal Dorsal Horn of Db/Db Mice. Wang R, Qiu Z, Wang G, et al. European Journal of Pharmacology. 2020;882:173266. doi:10.1016/j.ejphar.2020.173266.
74. The Emerging Role of Quercetin in the Treatment of Chronic Pain. Liu C, Liu DQ, Tian YK, et al. Current Neuropharmacology. 2022;20(12):2346-2353. doi:10.2174/1570159X20666220812122437.
75. Quercetin Reduces Inflammation in a Rat Model of Diabetic Peripheral Neuropathy by Regulating the TLR4/MyD88/NF-κB Signalling Pathway. Zhao B, Zhang Q, Liang X, Xie J, Sun Q. European Journal of Pharmacology. 2021;912:174607. doi:10.1016/j.ejphar.2021.174607. 
76. Quercetin Alleviates Thermal and Cold Hyperalgesia in a Rat Neuropathic Pain Model by Inhibiting Toll-Like Receptor Signaling. Ji C, Xu Y, Han F, et al. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2017;94:652-658. doi:10.1016/j.biopha.2017.07.145.

References through Level 1-6

1. Mechanisms of Chronic Pain. Markenson JA. The American Journal of Medicine. 1996;101(1A):6S-18S. doi:10.1016/s0002-9343(96)00133-7.
2. Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons. Antal M. International Journal of Molecular Sciences. 2025;26(5):2356. doi:10.3390/ijms26052356.
3. Spinal Cord Mechanisms of Pain. D’Mello R, Dickenson AH. British Journal of Anaesthesia. 2008;101(1):8-16. doi:10.1093/bja/aen088.
4. Excitatory and Inhibitory Neurons of the Spinal Cord Superficial Dorsal Horn Diverge in Their Somatosensory Responses and Plasticity . Sullivan SJ, Sdrulla AD. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 2022;42(10):1958-1973. doi:10.1523/JNEUROSCI.1860-21.2021.
5. Network Model of Nociceptive Processing in the Superficial Spinal Dorsal Horn Reveals Mechanisms of Hyperalgesia, Allodynia, and Spinal Cord Stimulation. Gilbert JE, Zhang T, Esteller R, Grill WM. Journal of Neurophysiology. 2023;130(5):1103-1117. doi:10.1152/jn.00186.2023.
6. Acute and Chronic Pain Processing in the Thalamocortical System of Humans and Animal Models. Groh A, Krieger P, Mease RA, Henderson L. Neuroscience. 2018;387:58-71. doi:10.1016/j.neuroscience.2017.09.042.
7. Convergence of Sensory and Limbic Noxious Input Into the Anterior Insula and the Emergence of Pain From Nociception. Bastuji H, Frot M, Perchet C, Hagiwara K, Garcia-Larrea L. Scientific Reports. 2018;8(1):13360. doi:10.1038/s41598-018-31781-z.
8. Cortical Modulation of Nociception. Gamal-Eltrabily M, Martínez-Lorenzana G, González-Hernández A, Condés-Lara M. Neuroscience. 2021;458:256-270. doi:10.1016/j.neuroscience.2021.01.001.
9. The ‘In’s and Out’s’ of Descending Pain Modulation From the Rostral Ventromedial Medulla. De Preter CC, Heinricher MM. Trends in Neurosciences. 2024;47(6):447-460. doi:10.1016/j.tins.2024.04.006.
10. The Plasticity of Descending Controls in Pain: Translational Probing. Bannister K, Dickenson AH. The Journal of Physiology. 2017;595(13):4159-4166. doi:10.1113/JP274165.
11. Inputs to the Locus Coeruleus From the Periaqueductal Gray and Rostroventral Medulla Shape Opioid-Mediated Descending Pain Modulation. Lubejko ST, Livrizzi G, Buczynski SA, et al. Science Advances. 2024;10(17):eadj9581. doi:10.1126/sciadv.adj9581.
12. Brainstem Mechanisms of Pain Modulation: A Within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses. Crawford LS, Mills EP, Hanson T, et al. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 2021;41(47):9794-9806. doi:10.1523/JNEUROSCI.0806-21.2021.
13. Nonnarcotic Methods of Pain Management. Finnerup NB. The New England Journal of Medicine. 2019;380(25):2440-2448. doi:10.1056/NEJMra1807061.

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.

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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.

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