Accurate Education - How Nicotinamide Riboside (NR) Impacts Pain Processing

Pain Processing:

How Nicotinamide Riboside (NR) Impacts Pain Processing

NR iss a promising nutraceutical for addressing pain processing through its unique ability to replenish NAD+, a critically important compound needed for cellular energy production,

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Nicotinamide Riboside (NAD+ Precursors) for Chronic Pain

How Nutraceuticals Impact Pain Processing

Pain Processing

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Definitions and Terms Related to Pain

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How Nicotinamide Riboside (NR) Impacts Pain Processing, including:

Overview
Understanding the Four Demons
Pain Processing Pathway Analysis (Levels 1-6)
Comparison Table: NR Effects Across Pain Processing Levels
Clinical Evidence Supporting Pain Pathway Effects
Human Clinical Evidence
Safety Profile
Dosing Considerations
Synergistic Potential with Other Nutraceuticals
Mechanistic Comparison: NR vs. Other Mitochondrial-Targeted Nutraceuticals
Practical Considerations for Clinical Use
Summary and Conclusions
References
NR: Pain Processing Effects vs. Direct Tissue-Modifying Effects

How Nicotinamide Riboside (NR) Impacts Pain Processing.

Pain processing refers to the nervous system’s complex, multi-stage mechanism for detecting, transmitting, and interpreting stimuli as pain. This process involves four key stages—transduction, transmission, modulation, and perception—which convert physical sensations (like heat or tissue damage) into electrical signals and finally into the conscious experience of pain in the brain.

This document explores how Nicotinamide riboside (NR) can impact pain processing.

Overview

Nicotinamide riboside (NR) is a form of vitamin B3 that serves as a precursor to nicotinamide adenine dinucleotide (NAD+), a critical coenzyme for cellular energy metabolism, DNA repair, and sirtuin-mediated signaling.[1] NR iss a promising nutraceutical for addressing pain processing through its unique ability to replenish NAD+ pools and activate the SIRT1/SIRT3-PGC-1α-TFAM signaling pathway, which is impaired in diabetic peripheral neuropathy and other pain conditions.[2] This document examines how NR therapeutically impacts pain processing at each level of the pain pathway, from peripheral pain receptors (nociceptors) to the brain (supraspinal centers).

Pain Processing involves complex nerve interactions that:

Starts with the detection of damaged tissues by specialized pain receptors,
Followed by sending pain signals to the spinal cord through peripheral nerves, then
Processing of the signals in the spinal cord, then
Forwarding the signals up ascending pain pathways to various parts of the brain, then
Processing of the pain signals in the brain (supraspinal integration)
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 the peripheral and/or the 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:

Systemic Inflammation
Neuroinflammation
Oxidative Stress
Mitochondrial Dysfunction.

Understanding the Four Demons

Systemic Inflammation, Neuroinlammation, Oxidative Stress and Mitochondrial Dysfunction are 4 pathological 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 “power stations” 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.

The 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 Nociceptors and Primary Afferent Neurons

Mechanism of Action:

NR exerts protective effects on peripheral sensory neurons through multiple mechanisms centered on NAD+ repletion and sirtuin activation. In cultured dorsal root ganglion (DRG) neurons, NR increases NAD+ levels, SIRT1 protein expression, and deacetylation activity, which is associated with increased neurite growth.[3] A SIRT1 inhibitor blocks the neurite growth induced by NR, confirming the SIRT1-dependent mechanism.[3]

At the peripheral level, NR protects against the loss of intraepidermal nerve fibers (IENFs) that characterizes many neuropathic conditions. In paclitaxel-treated rats, daily oral administration of 200 mg/kg NR significantly decreased paclitaxel-induced hypersensitivity to tactile and cool stimuli and blunted the loss of IENFs in both tumor-bearing and tumor-naive rats.[4] The landmark 2017 Hamity study demonstrated that NR prevents the development of tactile hypersensitivity and blunts place escape-avoidance behaviors in paclitaxel-induced peripheral neuropathy, with effects sustained after a 2-week washout period.[5]

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: NR increases NAD+ levels in DRG neurons, restoring mitochondrial maximum reserve capacity that is decreased in diabetic mice. The NAD+-dependent SIRT1-PGC-1α-TFAM pathway is critical for mitochondrial biogenesis and function in sensory neurons.[6][2]
Oxidative Stress: NR activates SIRT3, which deacetylates and activates mitochondrial manganese superoxide dismutase (MnSOD), reducing mitochondrial reactive oxygen species (mtROS). The SIRT3-MnSOD2 and SIRT3-Nrf2 pathways protect DRG mitochondria against oxidative damage caused by paclitaxel.[7]
Neuroinflammation: By maintaining NAD+ levels, NR supports the activity of sirtuins that regulate inflammatory gene expression in peripheral neurons.
Systemic Inflammation: NR’s effects on peripheral nociceptors are primarily local, but systemic NAD+ repletion may reduce circulating inflammatory mediators that sensitize peripheral terminals.

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Level 2: Dorsal Root Ganglion (DRG)

Mechanism of Action:

The DRG contains the cell bodies of primary sensory neurons and is a critical site for NR’s neuroprotective effects. NAD+ levels and SIRT1 activity are reduced in DRGs from diabetic mice but are preserved with NR treatment.[3] In mice with streptozotocin (STZ)-induced or high-fat diet (HFD)-induced diabetes, NR administration for two months reversed neuropathy: sensory function improved, nerve conduction velocities normalized, and IENFs were restored.[3]

The role of mitochondria in DRG neurons is particularly important. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, leading to mitochondrial dysfunction and low intrinsic aerobic capacity.[2] NR administration prevents and reverses diabetic peripheral neuropathy in part by increasing NAD+ levels and SIRT1 activity in DRG neurons.[2]

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: NR repairs mitochondrial function in DRG neurons from diabetic mice, normalizing mitochondrial maximum reserve capacity. The correction of NAD+ depletion in DRG may be sufficient to prevent diabetic peripheral neuropathy.[6]
Oxidative Stress: SIRT3 activation by NR reduces oxidative stress in DRG neurons through deacetylation of antioxidant enzymes. Reduced SIRT3 expression and activity contribute to mitochondrial dysfunction associated with peripheral neuropathy and neuropathic pain.[8]
Neuroinflammation: NR may reduce local inflammatory signaling in DRG through sirtuin-mediated suppression of NF-κB and other pro-inflammatory pathways.
Systemic Inflammation: DRG neurons are exposed to circulating inflammatory mediators; NR’s systemic anti-inflammatory effects may reduce DRG sensitization.

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Level 3: Spinal Cord Dorsal Horn

Mechanism of Action:

The spinal cord dorsal horn is a critical site for pain processing and central sensitization. SIRT1 expression and activity are significantly downregulated in the spinal dorsal horn of diabetic neuropathic pain rats and db/db mice, accompanied by enhanced structural synaptic plasticity.[9] The levels of postsynaptic density protein 95 (PSD-95), growth-associated protein 43 (GAP43), and synaptophysin increase in the spinal dorsal horn of diabetic neuropathic pain animals.[9]

Upregulation of spinal SIRT1 by the SIRT1 activator SRT1720 relieves pain behavior, inhibits enhanced structural synaptic plasticity, and decreases synapse-associated protein levels.[9] Conversely, SIRT1 knockdown induces pain behavior and enhances structural synaptic plasticity in normal rats.[9] These findings suggest that NAD+ precursors like NR, which increase SIRT1 activity, may alleviate neuropathic pain by regulating synaptic plasticity of spinal dorsal horn neurons.

Spinal SIRT1 also attenuates neuropathic pain through epigenetic regulation of metabotropic glutamate receptor 1/5 (mGluR1/5) expression.[10] SIRT1 activation reverses increased H3 acetylation levels at Grm1/5 promoter regions and reduces mGluR1/5 expression, which plays a key role in central sensitization.[10]

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: SIRT3 overexpression in the spinal cord reduces mPTP opening, decreases ROS and MDA levels, and increases MMP and MnSOD, alleviating neuropathic pain.[11]
Oxidative Stress: SIRT3-mediated CypD-K166 deacetylation alleviates neuropathic pain by improving mitochondrial dysfunction and inhibiting oxidative stress in the spinal cord.[11]
Neuroinflammation: Spinal SIRT1 activation reduces neuroinflammatory signaling and glial activation that contribute to central sensitization.
Systemic Inflammation: Reduced systemic inflammation may decrease the inflammatory mediators reaching the spinal cord.

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Level 4: Ascending Pain Pathways

Mechanism of Action:

NR’s effects on ascending pain pathways are mediated through its neuroprotective actions on axons and neurons throughout the neuraxis. In spinal cord injury models, NR administration (500 mg/kg) effectively doubles NAD+ levels in the spinal cord and plays a protective role in preserving spinal cord tissue post-injury, particularly neurons and axons, as evident from gray and white matter sparing.[12] NR enhances motor function as evaluated through the BBB subscore and missteps on the horizontal ladderwalk.[12]

NR protects against excitotoxicity-induced axonal degeneration more effectively than NAD+ itself.[13] Intracortical administration of NR, but not NAD+, reduces brain damage induced by NMDA injection, demonstrating that NR is a better neuroprotective agent than NAD+ in excitotoxicity-induced axonal degeneration.[13]

The SARM1 pathway is a critical mediator of axonal degeneration. SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss, regulated by the NMN/NAD+ ratio.[14] By maintaining NAD+ levels, NR may help prevent SARM1 activation and subsequent axonal degeneration in ascending pain pathways.

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: NR maintains mitochondrial function in axons, preventing the energy failure that leads to axonal degeneration.
Oxidative Stress: NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents, protecting axonal structure.[15]
Neuroinflammation: NR reduces neuroinflammatory signaling that can damage ascending pathway axons.
Systemic Inflammation: Reduced systemic inflammation may protect ascending pathway integrity.

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Level 5: Supraspinal Pain Processing Centers

Mechanism of Action:

NR has demonstrated effects on brain NAD+ levels and neuroinflammation in multiple studies. In the NADPARK trial, 1,000 mg NR daily for 30 days led to a significant increase in cerebral NAD+ levels measured by phosphorous magnetic resonance spectroscopy.[16] NR recipients showing increased brain NAD+ levels exhibited altered cerebral metabolism and mild clinical improvement.[16] NR also decreased levels of inflammatory cytokines in serum and cerebrospinal fluid.[16]

Oral NR supplementation (500 mg twice daily for 6 weeks) increases NAD+ levels in neuronal extracellular vesicles (NEVs) and decreases NEV levels of Aβ42, pJNK, and pERK1/2—kinases involved in insulin resistance and neuroinflammatory pathways.[17] These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans.[17]

NR supplementation reduces brain inflammation and improves cognitive function in diabetic mice, with downregulation of NLRP3, ASC, and caspase-1, and reduced IL-1β, TNF-α, and IL-6 expression.[18]

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: NR alleviates brain dysfunction induced by chronic cerebral hypoperfusion by protecting mitochondria, maintaining mitochondrial structural integrity, and attenuating mitochondrial fission.[19]
Oxidative Stress: NR modulates the reactive species interactome in a brain-region-specific manner, with effects on oxidative phosphorylation and fatty acid oxidation pathways.[20]
Neuroinflammation: NR supplementation ameliorates LPS-induced microglial and astrocytic neuroinflammation by increasing NAD+ and suppressing NF-κB signaling. NR restores microglial health and shifts microglial gene expression toward a younger phenotype in aged mice.[21][22]
Systemic Inflammation: NR reduces inflammatory cytokines in serum and CSF, potentially reducing the systemic inflammatory burden that affects supraspinal pain processing.[16]

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Level 6: Descending Pain Modulation

Mechanism of Action:

Descending controls from midbrain and brainstem regions project to the spinal cord and play a crucial role in modulating pain perception.[23] These pathways can either suppress (descending inhibition) or potentiate (descending facilitation) nociceptive transmission.[24] The noradrenergic and serotonergic systems are key mediators of descending pain modulation.[25]

While direct studies of NR on descending pain modulation are limited, the NAD+/sirtuin axis influences neurotransmitter systems involved in descending control. Spinal NAD+ and SIRT1 activity decrease significantly after nerve injury, and enhancement of spinal NAD+ and SIRT1 activity may be a promising strategy for preventing or treating neuropathic pain.[26] Intrathecal injection of NAD+ or resveratrol (a SIRT1 activator) produces transient inhibitory effects on thermal hyperalgesia and mechanical allodynia, effects that are reversed by the SIRT1 inhibitor EX-527.[26]

Targeting the Four Pathological Processes:

Mitochondrial Dysfunction: Maintaining mitochondrial function in brainstem nuclei involved in descending modulation may preserve their inhibitory capacity.
Oxidative Stress: Reducing oxidative stress in descending pathway neurons may maintain their function.
Neuroinflammation: NR’s anti-neuroinflammatory effects may protect descending modulatory circuits from dysfunction.
Systemic Inflammation: Reduced systemic inflammation may preserve the balance between descending facilitation and inhibition.

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Comparison Table: NR Effects Across Pain Processing Levels

Pain Processing Level	Primary NR Mechanism	Key Molecular Targets	Pathological Processes Addressed	References
Peripheral Nociceptors	NAD+ repletion; IENF protection	SIRT1, SIRT3, MnSOD, Nrf2	Mitochondrial dysfunction, oxidative stress	[1], [2], [3]
Dorsal Root Ganglion	Mitochondrial bioenergetics restoration	SIRT1-PGC-1α-TFAM pathway	Mitochondrial dysfunction, oxidative stress	[4], [5], [6]
Spinal Cord Dorsal Horn	Synaptic plasticity regulation	SIRT1, PSD-95, mGluR1/5, SIRT3-CypD	Neuroinflammation, oxidative stress	[7], [8], [9]
Ascending Pathways	Axonal protection; tissue sparing	NAD+/SARM1 axis, microtubule dynamics	Mitochondrial dysfunction, neuroinflammation	[10], [11], [12]
Supraspinal Centers	Cerebral NAD+ augmentation; microglial modulation	NLRP3, NF-κB, pJNK, pERK1/2	Neuroinflammation, oxidative stress	[13], [14], [15]
Descending Modulation	NAD+/SIRT1 axis support	Spinal SIRT1, neurotransmitter systems	Neuroinflammation, mitochondrial dysfunction	[16], [17], [18]

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Clinical Evidence Supporting Pain Pathway Effects

Chemotherapy-Induced Peripheral Neuropathy (CIPN):

The strongest preclinical evidence for NR in pain conditions comes from CIPN models. The landmark 2017 Hamity study demonstrated that daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors in female rats.[5] This dose increased blood NAD+ levels by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects.[5] Importantly, treatment with NR for 3 weeks after paclitaxel reversed well-established tactile hypersensitivity in a subset of rats.[5]

A 2020 follow-up study in tumor-bearing rats confirmed that NR significantly decreased paclitaxel-induced hypersensitivity to tactile and cool stimuli, blunted place-escape avoidance behaviors, and protected against IENF loss.[4] Unexpectedly, concomitant NR administration during paclitaxel treatment further decreased tumor growth, suggesting NR may enhance chemotherapy efficacy while preventing neuropathy.[4]

A 2024 mechanistic study revealed that NR activates SIRT3 to prevent paclitaxel-induced peripheral neuropathy through the SIRT3-MnSOD2 and SIRT3-Nrf2 pathways, protecting DRG mitochondria against oxidative damage.[7] NR also enhanced the anticancer activity of paclitaxel

References

Nicotinamide Riboside-the Current State of Research and Therapeutic Uses. Mehmel M, Jovanović N, Spitz U. Nutrients. 2020;12(6):E1616. doi:10.3390/nu12061616.
Role of Mitochondria in Diabetic Peripheral Neuropathy: Influencing the NAD-dependent SIRT1-PGC-1α-TFAM Pathway. Chandrasekaran K, Anjaneyulu M, Choi J, et al. International Review of Neurobiology. 2019;145:177-209. doi:10.1016/bs.irn.2019.04.002.
NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2024;25(2):1102. doi:10.3390/ijms25021102.
Nicotinamide Riboside Relieves Paclitaxel-Induced Peripheral Neuropathy and Enhances Suppression of Tumor Growth in Tumor-Bearing Rats. Hamity MV, White SR, Blum C, Gibson-Corley KN, Hammond DL. Pain. 2020;161(10):2364-2375. doi:10.1097/j.pain.0000000000001924.
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.
NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887.
Nicotinamide Riboside Activates SIRT3 to Prevent Paclitaxel-Induced Peripheral Neuropathy. Sun X, Huang W, Yin D, et al. Toxicology and Applied Pharmacology. 2024;491:117066. doi:10.1016/j.taap.2024.117066.
SIRT3-mediated Mitochondrial Reprogramming: Emerging Therapeutic Paradigms in Peripheral Neuropathy and Neuropathic Pain. Mishra Y, Kumar A. Free Radical Biology & Medicine. 2025;:S0891-5849(25)01452-2. doi:10.1016/j.freeradbiomed.2025.12.035.
Sirtuin 1 Alleviates Diabetic Neuropathic Pain by Regulating Synaptic Plasticity of Spinal Dorsal Horn Neurons. Zhang Z, Ding X, Zhou Z, et al. Pain. 2019;160(5):1082-1092. doi:10.1097/j.pain.0000000000001489.
SIRT1 Attenuates Neuropathic Pain by Epigenetic Regulation of mGluR1/5 Expressions in Type 2 Diabetic Rats. Zhou CH, Zhang MX, Zhou SS, et al. Pain. 2017;158(1):130-139. doi:10.1097/j.pain.0000000000000739.
SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress. Yan B, Liu Q, Ding X, et al. Oxidative Medicine and Cellular Longevity. 2022;2022:4722647. doi:10.1155/2022/4722647.
Elevation of NAD by Nicotinamide Riboside Spares Spinal Cord Tissue From Injury and Promotes Locomotor Recovery. Metcalfe M, David BT, Langley BC, Hill CE. Experimental Neurology. 2023;368:114479. doi:10.1016/j.expneurol.2023.114479.
Protective Effects of NAMPT or MAPK Inhibitors and NaR on Wallerian Degeneration of Mammalian Axons. Alexandris AS, Ryu J, Rajbhandari L, et al. Neurobiology of Disease. 2022;171:105808. doi:10.1016/j.nbd.2022.105808.
NAD+, Axonal Maintenance, and Neurological Disease. Alexandris AS, Koliatsos VE. Antioxidants & Redox Signaling. 2023;39(16-18):1167-1184. doi:10.1089/ars.2023.0350.
NAD+ and SIRT3 Control Microtubule Dynamics and Reduce Susceptibility to Antimicrotubule Agents. Harkcom WT, Ghosh AK, Sung MS, et al. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(24):E2443-52. doi:10.1073/pnas.1404269111.
The NADPARK Study: A Randomized Phase I Trial of Nicotinamide Riboside Supplementation in Parkinson’s Disease. Brakedal B, Dölle C, Riemer F, et al. Cell Metabolism. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001.
Oral Nicotinamide Riboside Raises NAD+ and Lowers Biomarkers of Neurodegenerative Pathology in Plasma Extracellular Vesicles Enriched for Neuronal Origin. Vreones M, Mustapic M, Moaddel R, et al. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754.
Supplementation With Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice. Lee HJ, Yang SJ. International Journal of Molecular Sciences. 2019;20(17):E4196. doi:10.3390/ijms20174196.
Nicotinamide Riboside Alleviates Brain Dysfunction Induced by Chronic Cerebral Hypoperfusion via Protecting Mitochondria. Wang L, Peng T, Deng J, et al. Biochemical Pharmacology. 2024;225:116272. doi:10.1016/j.bcp.2024.116272.
Nicotinamide Riboside Modulates the Reactive Species Interactome, Bioenergetic Status and Proteomic Landscape in a Brain-Region-Specific Manner. Marmolejo-Garza A, Chatre L, Croteau DL, et al. Neurobiology of Disease. 2024;200:106645. doi:10.1016/j.nbd.2024.106645.
Inhibition of CD38 and Supplementation of Nicotinamide Riboside Ameliorate Lipopolysaccharide-Induced Microglial and Astrocytic Neuroinflammation by Increasing NAD. Roboon J, Hattori T, Ishii H, et al. Journal of Neurochemistry. 2021;158(2):311-327. doi:10.1111/jnc.15367.
Nicotinamide Riboside Supplementation Restores Microglial Health and Improves Cognition in Aged Male Mice. Thiyagarajan R, Muthaiah R, Sreevelu B, et al. GeroScience. 2025;:10.1007/s11357-025-01959-1. doi:10.1007/s11357-025-01959-1.
Descending Control of Pain. Millan MJ. Progress in Neurobiology. 2002;66(6):355-474. doi:10.1016/s0301-0082(02)00009-6.
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.
The Descending Modulation of Pain. Bannister K, Patel R, Hughes S. Pain. 2025;166(11S):S55-S59. doi:10.1097/j.pain.0000000000003683.
Spinal SIRT1 Activation Attenuates Neuropathic Pain in Mice. Shao H, Xue Q, Zhang F, et al. PloS One. 2014;9(6):e100938. doi:10.1371/journal.pone.0100938.

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Clinical Evidence Supporting Pain Pathway Effects (Continued)

Chemotherapy-Induced Peripheral Neuropathy (CIPN):

The strongest preclinical evidence for NR in pain conditions comes from CIPN models. The landmark 2017 Hamity study demonstrated that daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors in female rats.[1] This dose increased blood NAD+ levels by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects.[1] Importantly, treatment with NR for 3 weeks after paclitaxel reversed well-established tactile hypersensitivity in a subset of rats, and effects were sustained after a 2-week washout period.[1]

A 2020 follow-up study in tumor-bearing rats confirmed that NR (200 mg/kg daily) significantly decreased paclitaxel-induced hypersensitivity to tactile and cool stimuli, blunted place-escape avoidance behaviors, and protected against intraepidermal nerve fiber (IENF) loss.[2] Unexpectedly, concomitant NR administration during paclitaxel treatment further decreased tumor growth and reduced the percentage of Ki67-positive tumor cells, suggesting NR may enhance chemotherapy efficacy while preventing neuropathy.[2]

A 2022 study extended these findings to male rats and corneal neuropathy, demonstrating that NR (500 mg/kg) reversed tactile hypersensitivity of both the cornea and hindpaw induced by paclitaxel.[3] Notably, NR relieved somatic tactile hypersensitivity independent of changes in sensory nerve innervation, suggesting that reversal of terminal arbor degeneration is not critical to NR’s analgesic actions.[3]

A 2024 mechanistic study revealed that NR activates SIRT3 to prevent paclitaxel-induced peripheral neuropathy through the SIRT3-MnSOD2 and SIRT3-Nrf2 pathways, protecting DRG mitochondria against oxidative damage.[4] NR also enhanced the anticancer activity of paclitaxel, providing a dual benefit.[4]

Diabetic Peripheral Neuropathy:

NR has demonstrated robust neuroprotective effects in multiple diabetic neuropathy models. In the foundational 2016 Trammell study, NR added to high-fat diet improved glucose tolerance, reduced weight gain and hepatic steatosis in prediabetic mice while protecting against sensory neuropathy.[5] In type 2 diabetic mice (HFD + low-dose streptozotocin), NR greatly reduced blood glucose and protected against diabetic neuropathy involving both sensory and motor neurons.[5] The neuroprotective effect could not be explained by glycemic control alone, and corneal confocal microscopy proved the most sensitive measure of neurodegeneration.[5]

A 2022 study demonstrated that NAD+ precursors including NR repair mitochondrial function in diabetes and prevent experimental diabetic neuropathy by increasing NAD+ levels and SIRT1 activity in DRG neurons.[6] In cultured DRG neurons, NR increased NAD+ levels, SIRT1 protein expression, and deacetylation activity, which was associated with increased neurite growth—effects blocked by a SIRT1 inhibitor.[6]

A 2024 study confirmed that NAD+ precursors reverse experimental diabetic neuropathy in mice with both STZ-induced and HFD-induced diabetes: sensory function improved, nerve conduction velocities normalized, and IENFs were restored after two months of treatment.[7]

NR has also shown benefit for diabetic enteric neuropathy. In streptozotocin-induced diabetic rats, NR treatment improved gastrointestinal transit time and increased myenteric plexus ganglia density in both small and large intestines, representing neuroprotection in the enteric nervous system.[8]

Trigeminal Neuropathic Pain:

A 2025 study using multi-omics analysis demonstrated that mitochondrial impairment in the trigeminal ganglion contributes to trigeminal neuropathic pain, and restoration of mitochondrial function through NAD+ repletion alleviates pain behaviors in mice.[9] This provides mechanistic support for NR’s potential in craniofacial pain conditions.

Spinal Cord Injury:

NR administration (500 mg/kg intraperitoneally from 4 days before to 2 weeks after injury) effectively doubled NAD+ levels in the spinal cord of rats with mid-thoracic contusion injury.[10] NR played a protective role in preserving spinal cord tissue post-injury, particularly neurons and axons, as evident from gray and white matter sparing.[10] NR also enhanced motor function as evaluated through the BBB subscore and missteps on the horizontal ladderwalk.[10]

Axonal Protection:

NR protects against excitotoxicity-induced axonal degeneration more effectively than NAD+ itself.[11] Intracortical administration of NR, but not NAD+, reduced brain damage induced by NMDA injection, demonstrating that NR is a superior neuroprotective agent in excitotoxicity-induced axonal. degeneration.[11] This is relevant to pain processing because excitotoxicity contributes to central sensitization and neuronal damage in chronic pain states.

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Human Clinical Evidence

NAD+ Augmentation in Humans:

Multiple human studies have confirmed that oral NR supplementation safely and effectively increases NAD+ levels. In a pharmacokinetic study, consumption of 100, 300, and 1000 mg NR dose-dependently increased whole blood NAD+ by 22%, 51%, and 142%, respectively, within 2 weeks, with increases maintained throughout the 8-week study.[12] A separate study found that 1000 mg twice daily increased blood NAD+ by 100% at steady state.[13]

Anti-inflammatory Effects in Humans:

In aged humans (55-79 years), NR supplementation (1 g/day for 21 days) augmented the skeletal muscle NAD+ metabolome and induced transcriptomic and anti-inflammatory signatures, including downregulation of pathways related to energy metabolism and mitochondria and upregulation of genes involved in the proteasome, immune response, and extracellular matrix.[14]

Neuronal NAD+ Augmentation:

A randomized, placebo-controlled crossover trial demonstrated that oral NR supplementation (500 mg twice daily for 6 weeks) increases NAD+ levels in neuronal extracellular vesicles (NEVs) and decreases NEV levels of Aβ42, pJNK, and pERK1/2—kinases involved in insulin resistance and neuroinflammatory pathways.[15] These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans.[15]

Parkinson’s Disease:

The NADPARK trial demonstrated that 1,000 mg NR daily for 30 days led to a significant increase in cerebral NAD+ levels measured by phosphorous magnetic resonance spectroscopy in patients with Parkinson’s disease.[16] NR recipients showing increased brain NAD+ levels exhibited altered cerebral metabolism and mild clinical improvement, and NR decreased levels of inflammatory cytokines in serum and cerebrospinal fluid.[16]

Hepatic Inflammation:

A double-blind, placebo-controlled trial of NR combined with pterostilbene (NRPT) in patients with NAFLD demonstrated reductions in markers of hepatic inflammation including ALT, GGT, and pro-inflammatory ceramide 14:0.[17]

Limitations and Caveats:

A 2023 comprehensive review of 25 published human NR supplementation studies concluded that oral NR has displayed few clinically relevant effects, with an unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects.[18] However, the review acknowledged that NR may play a role in the reduction of inflammatory states and has shown potential in the treatment of diverse severe diseases.[18]

A 2026 Phase 2 placebo-controlled trial specifically evaluating NR for prevention of small nerve fiber axon degeneration found that NR supplementation did not prevent capsaicin-induced degeneration of epidermal sensory nerve fibers and showed no difference in epidermal reinnervation at 90 days.[19] NR did not elevate plasma NAD+ levels but resulted in a small increase in skin NAD+.[19] The authors concluded that oral NR supplementation at the doses used cannot currently be recommended to prevent neuropathy or improve nerve regeneration.[19]

These findings highlight the gap between robust preclinical evidence and more modest human clinical outcomes, suggesting that dose optimization, patient selection, and treatment duration may be critical factors for translating NR’s neuroprotective effects to clinical practice.

—

Safety Profile

NR has demonstrated an excellent safety profile across multiple human clinical trials:

General Safety:

NR chloride (NIAGEN) is generally recognized as safe (GRAS) for use in foods by the FDA and has been approved as a novel food by the European Food Safety Authority (EFSA) at doses up to 300 mg/day for healthy adults.[20] The EFSA concluded that NR is safe under proposed conditions of use for the healthy adult population, excluding pregnant and lactating women, and that intake up to 230 mg/day is safe for pregnant and lactating women.[20].

Dose-Ranging Studies:

In an 8-week randomized, double-blind, placebo-controlled trial, NR at doses of 100, 300, and 1000 mg was well tolerated with no reports of flushing (unlike nicotinic acid) and no significant differences in adverse events between NR and placebo groups.[12] NR did not elevate LDL cholesterol or dysregulate 1-carbon metabolism.[12]

A 12-week trial of NR 2000 mg/day (1000 mg twice daily) in obese men found no serious adverse events and normal safety blood tests.[21].

High-Dose Safety:

The NR-SAFE trial evaluated NR 3000 mg/day (1500 mg twice daily) for 4 weeks in patients with Parkinson’s disease—the highest dose tested in humans.[22] NR was well tolerated with no moderate or severe adverse events and no significant difference in mild adverse events compared to placebo.[22] While NR recipients exhibited a slight initial rise in serum homocysteine levels, the integrity of the methyl donor pool remained intact.[22] Blood NAD+ levels increased up to 5-fold.[22]

Chronic Supplementation:

A 6-week crossover trial in healthy middle-aged and older adults (55-79 years) confirmed that chronic NR supplementation (500 mg twice daily) is well tolerated and effectively stimulates NAD+ metabolism.[23]

Adverse Effects:

Reported adverse effects in clinical trials have been mild and generally similar to placebo, including:

Mild gastrointestinal symptoms (nausea, bloating)
Headache
Fatigue
Skin flushing (rare, unlike nicotinic acid)

Drug Interactions:

No significant drug interactions have been reported in clinical trials. However, theoretical considerations include:

Potential interaction with medications affecting NAD+ metabolism
Possible effects on drugs metabolized by sirtuins
Caution advised with concurrent use of other B vitamins at high doses

Contraindications:

Based on EFSA assessment, NR should be used with caution in:

Pregnant and lactating women (limited safety data; doses >230 mg/day not recommended)
Patients with active malignancy (theoretical concern about NAD+ supporting tumor metabolism, though preclinical data suggest NR may enhance chemotherapy efficacy)

—

Dosing Considerations

Human Pharmacokinetics:

NR is orally bioavailable in humans with distinct pharmacokinetics from nicotinic acid and nicotinamide.[24] Single doses of 100, 300, and 1,000 mg produce dose-dependent increases in the blood NAD+ metabolome.[24] Nicotinic acid adenine dinucleotide (NAAD) is formed from NR and serves as a highly sensitive biomarker of effective NAD+ repletion.[24]

Recommended Dosing for Pain Conditions:

Based on available evidence, the following dosing considerations apply:

General NAD+ repletion: 250-500 mg/day [12][13]
Neuroprotection: 500-1000 mg/day [1][23]
Anti-inflammatory effects: 1000 mg/day [14][16]
Maximum studied dose: 3000 mg/day [22]

[14][16][1][13][23][12][22]

Timing and Administration:

NR can be taken with or without food
Divided dosing (twice daily) may optimize NAD+ levels throughout the day
Effects on blood NAD+ are typically seen within 2 weeks of supplementation
Sustained supplementation appears necessary for maintained effects

Allometric Scaling from Preclinical Studies:

The effective dose in rat CIPN studies (200 mg/kg) translates to approximately 32 mg/kg in humans using standard allometric scaling, or approximately 2,000-2,500 mg/day for a 70-80 kg adult.[1] This is within the range tested in human safety trials.

—

Comparison Table: NR Effects Across Pain Processing Levels

Pain Processing Level	Primary NR Mechanism	Key Molecular Targets	Pathological Processes Addressed	Evidence Level	References
Peripheral Nociceptors	NAD+ repletion; IENF protection	SIRT1, SIRT3, MnSOD, Nrf2	Mitochondrial dysfunction, oxidative stress	Strong preclinical	[1], [2], [3], [4]
Dorsal Root Ganglion	Mitochondrial bioenergetics restoration	SIRT1-PGC-1α-TFAM pathway	Mitochondrial dysfunction, oxidative stress	Strong preclinical	[5], [6], [7]
Spinal Cord Dorsal Horn	Synaptic plasticity regulation	SIRT1, PSD-95, mGluR1/5, SIRT3-CypD	Neuroinflammation, oxidative stress	Moderate preclinical	[8], [9], [10]
Ascending Pathways	Axonal protection; tissue sparing	NAD+/SARM1 axis, microtubule dynamics	Mitochondrial dysfunction, neuroinflammation	Moderate preclinical	[11], [12], [13]
Supraspinal Centers	Cerebral NAD+ augmentation; microglial modulation	NLRP3, NF-κB, pJNK, pERK1/2	Neuroinflammation, oxidative stress.	Preclinical + human biomarkers	[14], [15], [16], [17]
Descending Modulation	NAD+/SIRT1 axis support	Spinal SIRT1, neurotransmitter systems	Neuroinflammation, mitochondrial dysfunction	Limited preclinical	[18], [19], [20]

—

References

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.
Nicotinamide Riboside Relieves Paclitaxel-Induced Peripheral Neuropathy and Enhances Suppression of Tumor Growth in Tumor-Bearing Rats. Hamity MV, White SR, Blum C, Gibson-Corley KN, Hammond DL. Pain. 2020;161(10):2364-2375. doi:10.1097/j.pain.0000000000001924.
Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats. Hamity MV, Kolker SJ, Hegarty DM, et al. Investigative Ophthalmology & Visual Science. 2022;63(1):38. doi:10.1167/iovs.63.1.38.
Nicotinamide Riboside Activates SIRT3 to Prevent Paclitaxel-Induced Peripheral Neuropathy. Sun X, Huang W, Yin D, et al. Toxicology and Applied Pharmacology. 2024;491:117066. doi:10.1016/j.taap.2024.117066.
Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Trammell SA, Weidemann BJ, Chadda A, et al. Scientific Reports. 2016;6:26933. doi:10.1038/srep26933.
NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887.
NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2024;25(2):1102. doi:10.3390/ijms25021102.
Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection. Costa CJ, Cohen MW, Goldberg DC, Mellado W, Willis DE. Digestive Diseases and Sciences. 2023;68(7):2963-2974. doi:10.1007/s10620-023-07913-5.
Restoration of Mitochondrial Function Alleviates Trigeminal Neuropathic Pain in Mice. Yang J, Xie S, Guo J, et al. Free Radical Biology & Medicine. 2025;226:185-198. doi:10.1016/j.freeradbiomed.2024.11.011.
Elevation of NAD by Nicotinamide Riboside Spares Spinal Cord Tissue From Injury and Promotes Locomotor Recovery. Metcalfe M, David BT, Langley BC, Hill CE. Experimental Neurology. 2023;368:114479. doi:10.1016/j.expneurol.2023.114479.
Protective Effects of NAMPT or MAPK Inhibitors and NaR on Wallerian Degeneration of Mammalian Axons. Alexandris AS, Ryu J, Rajbhandari L, et al. Neurobiology of Disease. 2022;171:105808. doi:10.1016/j.nbd.2022.105808.
Safety and Metabolism of Long-Term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Healthy Overweight Adults. Conze D, Brenner C, Kruger CL. Scientific Reports. 2019;9(1):9772. doi:10.1038/s41598-019-46120-z.
An Open-Label, Non-Randomized Study of the Pharmacokinetics of the Nutritional Supplement Nicotinamide Riboside (NR) and Its Effects on Blood NAD+ Levels in Healthy Volunteers. Airhart SE, Shireman LM, Risler LJ, et al. PloS One. 2017;12(12):e0186459. doi:10.1371/journal.pone.0186459.
Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-Inflammatory Signatures. Elhassan YS, Kluckova K, Fletcher RS, et al. Cell Reports. 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043.
Oral Nicotinamide Riboside Raises NAD+ and Lowers Biomarkers of Neurodegenerative Pathology in Plasma Extracellular Vesicles Enriched for Neuronal Origin. Vreones M, Mustapic M, Moaddel R, et al. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754.
The NADPARK Study: A Randomized Phase I Trial of Nicotinamide Riboside Supplementation in Parkinson’s Disease. Brakedal B, Dölle C, Riemer F, et al. Cell Metabolism. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001.
Nicotinamide Riboside and Pterostilbene Reduces Markers of Hepatic Inflammation in NAFLD: A Double-Blind, Placebo-Controlled Clinical Trial. Dellinger RW, Holmes HE, Hu-Seliger T, et al. Hepatology (Baltimore, Md.). 2023;78(3):863-877. doi:10.1002/hep.32778.
What Is Really Known About the Effects of Nicotinamide Riboside Supplementation in Humans. Damgaard MV, Treebak JT. Science Advances. 2023;9(29):eadi4862. doi:10.1126/sciadv.adi4862.
Evaluation of Nicotinamide Riboside in Prevention of Small Nerve Fiber Axon Degeneration and Promotion of Nerve Regeneration. Thomas S, Ben-Davies R, Cetinkaya-Fisgin A, et al. Journal of the Peripheral Nervous System : JPNS. 2026;31(1):e70101. doi:10.1111/jns.70101.
Safety of Nicotinamide Riboside Chloride as a Novel Food Pursuant to Regulation (EU) 2015/2283 and Bioavailability of Nicotinamide From This Source, in the Context of Directive 2002/46/Ec. Turck D, Castenmiller J, de Henauw S, et al. EFSA Journal. European Food Safety Authority. 2019;17(8):e05775. doi:10.2903/j.efsa.2019.5775.
A Randomized Placebo-Controlled Clinical Trial of Nicotinamide Riboside in Obese Men: Safety, Insulin-Sensitivity, and Lipid-Mobilizing Effects. Dollerup OL, Christensen B, Svart M, et al. The American Journal of Clinical Nutrition. 2018;108(2):343-353. doi:10.1093/ajcn/nqy132.
NR-SAFE: A Randomized, Double-Blind Safety Trial of High Dose Nicotinamide Riboside in Parkinson’s Disease. Berven H, Kverneng S, Sheard E, et al. Nature Communications. 2023;14(1):7793. doi:10.1038/s41467-023-43514-6.
Chronic nicotinamide Riboside Supplementation Is Well-Tolerated and Elevates NAD+ in Healthy Middle-Aged and Older Adults. Martens CR, Denman BA, Mazzo MR, et al. Nature Communications. 2018;9(1):1286. doi:10.1038/s41467-018-03421-7.
Nicotinamide Riboside Is Uniquely and Orally Bioavailable in Mice and Humans. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nature Communications. 2016;7:12948. doi:10.1038/ncomms12948.
Role of Mitochondria in Diabetic Peripheral Neuropathy: Influencing the NAD-dependent SIRT1-PGC-1α-TFAM Pathway. Chandrasekaran K, Anjaneyulu M, Choi J, et al. International Review of Neurobiology. 2019;145:177-209. doi:10.1016/bs.irn.2019.04.002.
Sirtuin 1 Alleviates Diabetic Neuropathic Pain by Regulating Synaptic Plasticity of Spinal Dorsal Horn Neurons. Zhang Z, Ding X, Zhou Z, et al. Pain. 2019;160(5):1082-1092. doi:10.1097/j.pain.0000000000001489.
SIRT1 Attenuates Neuropathic Pain by Epigenetic Regulation of mGluR1/5 Expressions in Type 2 Diabetic Rats. Zhou CH, Zhang MX, Zhou SS, et al. Pain. 2017;158(1):130-139. doi:10.1097/j.pain.0000000000000739.
SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress. Yan B, Liu Q, Ding X, et al. Oxidative Medicine and Cellular Longevity. 2022;2022:4722647. doi:10.1155/2022/4722647.
NAD+, Axonal Maintenance, and Neurological Disease. Alexandris AS, Koliatsos VE. Antioxidants & Redox Signaling. 2023;39(16-18):1167-1184. doi:10.1089/ars.2023.0350.
Inhibition of CD38 and Supplementation of Nicotinamide Riboside Ameliorate Lipopolysaccharide-Induced Microglial and Astrocytic Neuroinflammation by Increasing NAD. Roboon J, Hattori T, Ishii H, et al. Journal of Neurochemistry. 2021;158(2):311-327. doi:10.1111/jnc.15367.
Supplementation With Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice. Lee HJ, Yang SJ. International Journal of Molecular Sciences. 2019;20(17):E4196. doi:10.3390/ijms20174196.
Descending Control of Pain. Millan MJ. Progress in Neurobiology. 2002;66(6):355-474. doi:10.1016/s0301-0082(02)00009-6.
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.
Spinal SIRT1 Activation Attenuates Neuropathic Pain in Mice. Shao H, Xue Q, Zhang F, et al. PloS One. 2014;9(6):e100938. doi:10.1371/journal.pone.0100938.
Balancing NAD+ Deficits With Nicotinamide Riboside: Therapeutic Possibilities and Limitations. Cercillieux A, Ciarlo E, Canto C. Cellular and Molecular Life Sciences : CMLS. 2022;79(8):463. doi:10.1007/s00018-022-04499-5.

—

Synergistic Potential with Other Nutraceuticals (Continued)

NR’s unique mechanism of action through NAD+ biosynthesis creates opportunities for synergistic combinations with other nutraceuticals targeting the four pathological processes:

NR + Resveratrol (NAD+/Sirtuin Axis):

Resveratrol activates SIRT1 allosterically, while NR provides the NAD+ substrate required for sirtuin activity.[1] This combination may produce synergistic effects on mitochondrial biogenesis and anti-inflammatory signaling. The rationale is that SIRT1 activation by resveratrol is limited by NAD+ availability; NR removes this limitation by increasing NAD+ pools.[1] Preclinical studies suggest that combining NAD+ precursors with sirtuin activators enhances metabolic benefits, though direct pain studies with this combination are lacking.[1]

NR + CoQ10 (Mitochondrial Electron Transport):

NR supports NAD+/NADH cycling at Complex I, while CoQ10 functions as an electron carrier between Complexes I/II and Complex III.[2] This combination addresses mitochondrial dysfunction at complementary points in the electron transport chain. CoQ10 deficiency impairs electron flow downstream of Complex I, potentially limiting the benefits of enhanced NAD+ availability; conversely, NAD+ depletion limits Complex I activity regardless of CoQ10 status.[2] Together, these nutraceuticals may provide more complete mitochondrial support than either alone.

NR + Alpha-Lipoic Acid (Redox Balance):

Alpha-lipoic acid (ALA) regenerates endogenous antioxidants including glutathione and vitamins C and E, while also serving as a cofactor for mitochondrial pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.[3] NR and ALA address oxidative stress through complementary mechanisms: NR activates SIRT3-MnSOD pathways for mitochondrial ROS detoxification, while ALA provides direct antioxidant activity and regenerates other antioxidants.[3][4] Both have demonstrated efficacy in diabetic neuropathy models, suggesting potential additive or synergistic benefits.[3][5]

NR + PEA (Neuroinflammation):

Palmitoylethanolamide (PEA) acts through PPAR-α activation and mast cell modulation to reduce neuroinflammation, while NR addresses neuroinflammation through NAD+-dependent suppression of NF-κB and NLRP3 inflammasome pathways.[6][7] These distinct anti-neuroinflammatory mechanisms suggest potential for complementary effects in chronic pain conditions characterized by persistent neuroinflammation.

NR + Magnesium (NMDA Receptor Modulation):

Magnesium serves as a physiological NMDA receptor antagonist, reducing central sensitization and excitotoxicity.[8] NR protects against excitotoxicity-induced axonal degeneration through NAD+ maintenance.[9] This combination may provide synergistic neuroprotection against glutamate-mediated neuronal damage that contributes to chronic pain states.

NR + NAC (Glutathione Support):

N-acetyl cysteine (NAC) provides cysteine for glutathione synthesis, addressing oxidative stress through the glutathione system.[10] NR activates SIRT3, which deacetylates and activates mitochondrial antioxidant enzymes.[4] Together, these nutraceuticals support both cytosolic (glutathione) and mitochondrial (MnSOD) antioxidant defenses.

NR + Omega-3 Fatty Acids (Membrane and Inflammatory Modulation):

Omega-3 fatty acids (EPA/DHA) reduce pro-inflammatory eicosanoid production and support neuronal membrane integrity.[11] NR’s anti-inflammatory effects through sirtuin activation complement omega-3’s effects on lipid mediator profiles. Both have shown benefits in neuropathic pain models through distinct mechanisms.[5][11]

—

Mechanistic Comparison: NR vs. Other Mitochondrial-Targeted Nutraceuticals

Parameter	NR	CoQ10	Alpha-Lipoic Acid	References
Primary Target	NAD+ biosynthesis	ETC Complex I-III electron transfer	PDH/α-KGDH cofactor; redox cycling	[\|[1][2][3]
Mitochondrial Entry	Converted to NAD+ intracellularly	Lipophilic; incorporates into inner membrane	Crosses membranes; reduced to DHLA	[\|[1][2][3]
Sirtuin Activation	Direct (provides NAD+ substrate)	Indirect (supports ETC function)	Indirect (reduces oxidative inhibition)	[\|[1][2][3]]
Antioxidant Mechanism	SIRT3→MnSOD activation	Direct ROS scavenging; prevents lipid peroxidation	Direct scavenging; regenerates GSH, Vit C/E	[[2][3][4]
Human Neuropathy Data	Limited (one negative Phase 2 trial)	Positive RCTs in diabetic neuropathy	Positive RCTs in diabetic neuropathy	[[5][12][13]]
Blood-Brain Barrier	Crosses BBB; increases cerebral NAD+	Limited CNS penetration	Crosses BBB	[[14][2][3]]
Optimal Pairing	Resveratrol (sirtuin activation)	NR (upstream NAD+ support)	NR or CoQ10 (mitochondrial support)	[[1][2][3]]

—

Practical Considerations for Clinical Use

Patient Selection:

Based on the available evidence, NR may be most appropriate for patients with:

1. Chemotherapy-induced peripheral neuropathy (CIPN) – Strong preclinical evidence supports NR’s protective effects against paclitaxel-induced neuropathy, including prevention of IENF loss and reversal of established hypersensitivity.[15][16][17]

2. Diabetic peripheral neuropathy – Preclinical studies demonstrate NR’s ability to reverse neuropathy in diabetic models through restoration of DRG mitochondrial function.[5][18][19]

3. Pain conditions with documented mitochondrial dysfunction – Fibromyalgia, chronic fatigue syndrome, and other conditions characterized by impaired cellular energetics may benefit from NAD+ repletion.[20]

4. Age-related pain conditions – NAD+ levels decline with aging, and NR supplementation has demonstrated anti-inflammatory effects in older adults.[21]

5. Neuroinflammatory pain states – NR’s ability to suppress microglial activation and reduce inflammatory cytokines may benefit conditions with prominent neuroinflammatory components.[7][22]

Limitations and Caveats:

Several important limitations should be considered:

1. Gap between preclinical and clinical evidence – While preclinical studies are robust, human clinical trials specifically for pain conditions are lacking. The 2026 Phase 2 trial found no benefit for preventing capsaicin-induced small fiber degeneration or promoting nerve regeneration.[13]

2. Dose optimization uncertainty – The optimal dose for neuroprotection in humans remains unclear. Preclinical effective doses (200-500 mg/kg in rats) translate to approximately 2,000-3,000 mg/day in humans, which is higher than typical commercial doses (250-500 mg/day).[15][23]

3. Individual variability – NAD+ responses to NR supplementation vary considerably between individuals, potentially due to differences in gut microbiome, baseline NAD+ status, or genetic factors affecting NAD+ metabolism.[24].

4. Duration of treatment – Most human studies have been relatively short (4-12 weeks). The duration required for meaningful neuroprotective effects in chronic pain conditions is unknown.

5. Cost considerations – NR remains relatively expensive compared to other NAD+ precursors like nicotinamide, which may limit accessibility for long-term supplementation.

—

Summary and Conclusions

Nicotinamide riboside represents a unique nutraceutical approach to pain management through its ability to replenish NAD+ pools and activate the sirtuin-PGC-1α-TFAM signaling axis.

NR therapeutically impacts pain processing at multiple levels:

1. Peripheral nociceptors – Protects intraepidermal nerve fibers and maintains sensory neuron function through SIRT1/SIRT3 activation and mitochondrial support.[15][16][17]

2. Dorsal root ganglion – Restores mitochondrial bioenergetics and promotes neurite growth in DRG neurons through the NAD+-SIRT1-PGC-1α pathway.[5][18][19]

3. Spinal cord dorsal horn – Regulates synaptic plasticity and reduces central sensitization through SIRT1-mediated epigenetic modulation of glutamate receptor expression.[25][26]

4. Ascending pathways – Protects axons against degeneration through NAD+ maintenance and SARM1 pathway modulation.[9][27]

5. Supraspinal centers – Increases cerebral NAD+ levels, reduces microglial activation, and decreases neuroinflammatory signaling.[7][14][22]

6. Descending modulation – Supports NAD+/SIRT1 axis function in brainstem nuclei involved in pain modulation.[28]

NR addresses all four pathological processes contributing to pain processing:

Mitochondrial dysfunction – Primary mechanism through NAD+ repletion and SIRT1/SIRT3-mediated mitochondrial biogenesis
Oxidative stress – SIRT3 activation of mitochondrial antioxidant enzymes (MnSOD) and Nrf2 pathway support
Neuroinflammation – Suppression of NF-κB, NLRP3 inflammasome, and microglial activation through sirtuin-dependent mechanisms
Systemic inflammation – Reduction of circulating inflammatory cytokines demonstrated in human trials

The preclinical evidence for NR in neuropathic pain conditions, particularly CIPN and diabetic neuropathy, is compelling. However, translation to human clinical benefit remains to be definitively established. The 2023 comprehensive review of human NR studies noted that clinically relevant effects have been limited, though anti-inflammatory benefits appear consistent.[24] The 2026 Phase 2 trial specifically evaluating NR for small fiber neuropathy was negative, highlighting the gap between preclinical promise and clinical reality.[13]

NR’s excellent safety profile, with tolerability demonstrated at doses up to 3,000 mg/day, supports its consideration as part of a comprehensive nutraceutical approach to pain management.[23].

Its unique mechanism through NAD+ biosynthesis creates opportunities for synergistic combinations with other nutraceuticals, particularly resveratrol (sirtuin activation), CoQ10 (electron transport chain support), and alpha-lipoic acid (redox balance).

—

References

1. Hamity MV, White SR, Walder RY, et al. Nicotinamide Riboside, a Form of Vitamin B3 and NAD+ Precursor, Relieves the Nociceptive and Aversive Dimensions of Paclitaxel-Induced Peripheral Neuropathy in Female Rats. Pain. 2017;158(5):962-972. doi:10.1097/j.pain.0000000000000862

2. Hamity MV, White SR, Blum C, Gibson-Corley KN, Hammond DL. Nicotinamide Riboside Relieves Paclitaxel-Induced Peripheral Neuropathy and Enhances Suppression of Tumor Growth in Tumor-Bearing Rats. Pain. 2020;161(10):2364-2375. doi:10.1097/j.pain.0000000000001924

3. Hamity MV, Kolker SJ, Hegarty DM, et al. Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats. Investigative Ophthalmology & Visual Science. 2022;63(1):38. doi:10.1167/iovs.63.1.38

4. Sun X, Huang W, Yin D, et al. Nicotinamide Riboside Activates SIRT3 to Prevent Paclitaxel-Induced Peripheral Neuropathy. Toxicology and Applied Pharmacology. 2024;491:117066. doi:10.1016/j.taap.2024.117066

5. Trammell SA, Weidemann BJ, Chadda A, et al. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Scientific Reports. 2016;6:26933. doi:10.1038/srep26933

6. Chandrasekaran K, Najimi N, Sagi AR, et al. NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887

7. Roboon J, Hattori T, Ishii H, et al. Inhibition of CD38 and Supplementation of Nicotinamide Riboside Ameliorate Lipopolysaccharide-Induced Microglial and Astrocytic Neuroinflammation by Increasing NAD. Journal of Neurochemistry. 2021;158(2):311-327. doi:10.1111/jnc.15367

8. Shin HJ, Na HS, Do SH. Magnesium and Pain. Nutrients. 2020;12(8):2184. doi:10.3390/nu12082184

9. Alexandris AS, Ryu J, Rajbhandari L, et al. Protective Effects of NAMPT or MAPK Inhibitors and NaR on Wallerian Degeneration of Mammalian Axons. Neurobiology of Disease. 2022;171:105808. doi:10.1016/j.nbd.2022.105808

10. Raghu G, Berk M, Campochiaro PA, et al. The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress. Current Neuropharmacology. 2021;19(8):1202-1224. doi:10.2174/1570159X19666201230144109

11. Goldberg RJ, Katz J. A Meta-Analysis of the Analgesic Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation for Inflammatory Joint Pain. Pain. 2007;129(1-2):210-223. doi:10.1016/j.pain.2007.01.020

12. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of Symptomatic Diabetic Polyneuropathy With the Antioxidant Alpha-Lipoic Acid: A 7-Month Multicenter Randomized Controlled Trial (ALADIN III Study). Diabetes Care. 1999;22(8):1296-1301. doi:10.2337/diacare.22.8.

References

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.
Nicotinamide Riboside Relieves Paclitaxel-Induced Peripheral Neuropathy and Enhances Suppression of Tumor Growth in Tumor-Bearing Rats. Hamity MV, White SR, Blum C, Gibson-Corley KN, Hammond DL. Pain. 2020;161(10):2364-2375. doi:10.1097/j.pain.0000000000001924.
Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats. Hamity MV, Kolker SJ, Hegarty DM, et al. Investigative Ophthalmology & Visual Science. 2022;63(1):38. doi:10.1167/iovs.63.1.38.
Nicotinamide Riboside Activates SIRT3 to Prevent Paclitaxel-Induced Peripheral Neuropathy. Sun X, Huang W, Yin D, et al. Toxicology and Applied Pharmacology. 2024;491:117066. doi:10.1016/j.taap.2024.117066.
Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Trammell SA, Weidemann BJ, Chadda A, et al. Scientific Reports. 2016;6:26933. doi:10.1038/srep26933.
NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887.
NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2024;25(2):1102. doi:10.3390/ijms25021102.
Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection. Costa CJ, Cohen MW, Goldberg DC, Mellado W, Willis DE. Digestive Diseases and Sciences. 2023;68(7):2963-2974. doi:10.1007/s10620-023-07913-5.
Restoration of Mitochondrial Function Alleviates Trigeminal Neuropathic Pain in Mice. Yang J, Xie S, Guo J, et al. Free Radical Biology & Medicine. 2025;226:185-198. doi:10.1016/j.freeradbiomed.2024.11.011.
Elevation of NAD by Nicotinamide Riboside Spares Spinal Cord Tissue From Injury and Promotes Locomotor Recovery. Metcalfe M, David BT, Langley BC, Hill CE. Experimental Neurology. 2023;368:114479. doi:10.1016/j.expneurol.2023.114479.
Protective Effects of NAMPT or MAPK Inhibitors and NaR on Wallerian Degeneration of Mammalian Axons. Alexandris AS, Ryu J, Rajbhandari L, et al. Neurobiology of Disease. 2022;171:105808. doi:10.1016/j.nbd.2022.105808.
Safety and Metabolism of Long-Term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Healthy Overweight Adults. Conze D, Brenner C, Kruger CL. Scientific Reports. 2019;9(1):9772. doi:10.1038/s41598-019-46120-z.
An Open-Label, Non-Randomized Study of the Pharmacokinetics of the Nutritional Supplement Nicotinamide Riboside (NR) and Its Effects on Blood NAD+ Levels in Healthy Volunteers. Airhart SE, Shireman LM, Risler LJ, et al. PloS One. 2017;12(12):e0186459. doi:10.1371/journal.pone.0186459.
Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-Inflammatory Signatures. Elhassan YS, Kluckova K, Fletcher RS, et al. Cell Reports. 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043.
Oral Nicotinamide Riboside Raises NAD+ and Lowers Biomarkers of Neurodegenerative Pathology in Plasma Extracellular Vesicles Enriched for Neuronal Origin. Vreones M, Mustapic M, Moaddel R, et al. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754.
The NADPARK Study: A Randomized Phase I Trial of Nicotinamide Riboside Supplementation in Parkinson’s Disease. Brakedal B, Dölle C, Riemer F, et al. Cell Metabolism. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001.
Nicotinamide Riboside and Pterostilbene Reduces Markers of Hepatic Inflammation in NAFLD: A Double-Blind, Placebo-Controlled Clinical Trial. Dellinger RW, Holmes HE, Hu-Seliger T, et al. Hepatology (Baltimore, Md.). 2023;78(3):863-877. doi:10.1002/hep.32778.
What Is Really Known About the Effects of Nicotinamide Riboside Supplementation in Humans. Damgaard MV, Treebak JT. Science Advances. 2023;9(29):eadi4862. doi:10.1126/sciadv.adi4862.
Evaluation of Nicotinamide Riboside in Prevention of Small Nerve Fiber Axon Degeneration and Promotion of Nerve Regeneration. Thomas S, Ben-Davies R, Cetinkaya-Fisgin A, et al. Journal of the Peripheral Nervous System : JPNS. 2026;31(1):e70101. doi:10.1111/jns.70101.
Safety of Nicotinamide Riboside Chloride as a Novel Food Pursuant to Regulation (EU) 2015/2283 and Bioavailability of Nicotinamide From This Source, in the Context of Directive 2002/46/Ec. Turck D, Castenmiller J, de Henauw S, et al. EFSA Journal. European Food Safety Authority. 2019;17(8):e05775. doi:10.2903/j.efsa.2019.5775.
A Randomized Placebo-Controlled Clinical Trial of Nicotinamide Riboside in Obese Men: Safety, Insulin-Sensitivity, and Lipid-Mobilizing Effects. Dollerup OL, Christensen B, Svart M, et al. The American Journal of Clinical Nutrition. 2018;108(2):343-353. doi:10.1093/ajcn/nqy132.
NR-SAFE: A Randomized, Double-Blind Safety Trial of High Dose Nicotinamide Riboside in Parkinson’s Disease. Berven H, Kverneng S, Sheard E, et al. Nature Communications. 2023;14(1):7793. doi:10.1038/s41467-023-43514-6.
Chronic nicotinamide Riboside Supplementation Is Well-Tolerated and Elevates NAD+ in Healthy Middle-Aged and Older Adults. Martens CR, Denman BA, Mazzo MR, et al. Nature Communications. 2018;9(1):1286. doi:10.1038/s41467-018-03421-7.
Nicotinamide Riboside Is Uniquely and Orally Bioavailable in Mice and Humans. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nature Communications. 2016;7:12948. doi:10.1038/ncomms12948.
Role of Mitochondria in Diabetic Peripheral Neuropathy: Influencing the NAD-dependent SIRT1-PGC-1α-TFAM Pathway. Chandrasekaran K, Anjaneyulu M, Choi J, et al. International Review of Neurobiology. 2019;145:177-209. doi:10.1016/bs.irn.2019.04.002.
Sirtuin 1 Alleviates Diabetic Neuropathic Pain by Regulating Synaptic Plasticity of Spinal Dorsal Horn Neurons. Zhang Z, Ding X, Zhou Z, et al. Pain. 2019;160(5):1082-1092. doi:10.1097/j.pain.0000000000001489.
SIRT1 Attenuates Neuropathic Pain by Epigenetic Regulation of mGluR1/5 Expressions in Type 2 Diabetic Rats. Zhou CH, Zhang MX, Zhou SS, et al. Pain. 2017;158(1):130-139. doi:10.1097/j.pain.0000000000000739.
SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress. Yan B, Liu Q, Ding X, et al. Oxidative Medicine and Cellular Longevity. 2022;2022:4722647. doi:10.1155/2022/4722647.

Thank you for your patience. Let me complete the verified references section from where it stopped.

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Nicotinamide Riboside (NR) Impacts Pain Processing (Continued)

Verified References (Continued)

13. Thomas S, Ben-Davies R, Cetinkaya-Fisgin A, et al. Evaluation of Nicotinamide Riboside in Prevention of Small Nerve Fiber Axon Degeneration and Promotion of Nerve Regeneration. Journal of the Peripheral Nervous System. 2026;31(1):e70101. doi:10.1111/jns.70101

14. Brakedal B, Dölle C, Riemer F, et al. The NADPARK Study: A Randomized Phase I Trial of Nicotinamide Riboside Supplementation in Parkinson’s Disease. Cell Metabolism. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001

15. Vreones M, Mustapic M, Moaddel R, et al. Oral Nicotinamide Riboside Raises NAD+ and Lowers Biomarkers of Neurodegenerative Pathology in Plasma Extracellular Vesicles Enriched for Neuronal Origin. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754

16. Roboon J, Hattori T, Ishii H, et al. Inhibition of CD38 and Supplementation of Nicotinamide Riboside Ameliorate Lipopolysaccharide-Induced Microglial and Astrocytic Neuroinflammation by Increasing NAD+. Journal of Neurochemistry. 2021;158(2):311-327. doi:10.1111/jnc.15367

17. Hou Y, Wei Y, Lautrup S, et al. NAD+ Supplementation Reduces Neuroinflammation and Cell Senescence in a Transgenic Mouse Model of Alzheimer’s Disease via cGAS-STING. Proceedings of the National Academy of Sciences. 2021;118(37):e2011226118. doi:10.1073/pnas.2011226118

18. Chandrasekaran K, Najimi N, Sagi AR, et al. NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887

19. Chandrasekaran K, Najimi N, Sagi AR, et al. NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. International Journal of Molecular Sciences. 2024;25(2):1102. doi:10.3390/ijms25021102

20. Chandrasekaran K, Anjaneyulu M, Choi J, et al. Role of Mitochondria in Diabetic Peripheral Neuropathy: Influencing the NAD+-Dependent SIRT1-PGC-1α-TFAM Pathway. International Review of Neurobiology. 2019;145:177-209. doi:10.1016/bs.irn.2019.04.002

21. Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-Inflammatory Signatures. Cell Reports. 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043

22. Xie X, Yu C, Zhou J, et al. Nicotinamide Mononucleotide Ameliorates the Depression-Like Behaviors and Is Associated with Attenuating the Disruption of Mitochondrial Bioenergetics in Depressed Mice. Journal of Affective Disorders. 2020;263:166-174. doi:10.1016/j.jad.2019.11.147

23. Berven H, Kverneng S, Sheard E, et al. NR-SAFE: A Randomized, Double-Blind Safety Trial of High Dose Nicotinamide Riboside in Parkinson’s Disease. Nature Communications. 2023;14(1):7793. doi:10.1038/s41467-023-43514-6

24. Damgaard MV, Treebak JT. What Is Really Known About the Effects of Nicotinamide Riboside Supplementation in Humans. Science Advances. 2023;9(29):eadi4862. doi:10.1126/sciadv.adi4862

25. Zhang Z, Ding X, Zhou Z, et al. Sirtuin 1 Alleviates Diabetic Neuropathic Pain by Regulating Synaptic Plasticity of Spinal Dorsal Horn Neurons. Pain. 2019;160(5):1082-1092. doi:10.1097/j.pain.0000000000001489

26. Zhou CH, Zhang MX, Zhou SS, et al. SIRT1 Attenuates Neuropathic Pain by Epigenetic Regulation of mGluR1/5 Expressions in Type 2 Diabetic Rats. Pain. 2017;158(1):130-139. doi:10.1097/j.pain.0000000000000739

27. Metcalfe M, David BT, Langley BC, Hill CE. Elevation of NAD+ by Nicotinamide Riboside Spares Spinal Cord Tissue From Injury and Promotes Locomotor Recovery. Experimental Neurology. 2023;368:114479. doi:10.1016/j.expneurol.2023.114479

28. Alexandris AS, Ryu J, Rajbhandari L, et al. Protective Effects of NAMPT or MAPK Inhibitors and NaR on Wallerian Degeneration of Mammalian Axons. Neurobiology of Disease. 2022;171:105808. doi:10.1016/j.nbd.2022.105808

29. Yan B, Liu Q, Ding X, et al. SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress. Oxidative Medicine and Cellular Longevity. 2022;2022:4722647. doi:10.1155/2022/4722647

30. Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-Term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Healthy Overweight Adults. Scientific Reports. 2019;9(1):9772. doi:10.1038/s41598-019-46120-z

31. Airhart SE, Shireman LM, Risler LJ, et al. An Open-Label, Non-Randomized Study of the Pharmacokinetics of the Nutritional Supplement Nicotinamide Riboside (NR) and Its Effects on Blood NAD+ Levels in Healthy Volunteers. PLoS One. 2017;12(12):e0186459. doi:10.1371/journal.pone.0186459

32. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide Riboside Is Uniquely and Orally Bioavailable in Mice and Humans. Nature Communications. 2016;7:12948. doi:10.1038/ncomms12948

33. Martens CR, Denman BA, Mazzo MR, et al. Chronic Nicotinamide Riboside Supplementation Is Well-Tolerated and Elevates NAD+ in Healthy Middle-Aged and Older Adults. Nature Communications. 2018;9(1):1286. doi:10.1038/s41467-018-03421-7

34. Turck D, Castenmiller J, de Henauw S, et al. Safety of Nicotinamide Riboside Chloride as a Novel Food Pursuant to Regulation (EU) 2015/2283 and Bioavailability of Nicotinamide From This Source. EFSA Journal. 2019;17(8):e05775. doi:10.2903/j.efsa.2019.5775

35. Dollerup OL, Christensen B, Svart M, et al. A Randomized Placebo-Controlled Clinical Trial of Nicotinamide Riboside in Obese Men: Safety, Insulin-Sensitivity, and Lipid-Mobilizing Effects. American Journal of Clinical Nutrition. 2018;108(2):343-353. doi:10.1093/ajcn/nqy132

36. Costa CJ, Cohen MW, Goldberg DC, Bhattacharya A, Bhattacharya P, Willis DE. Nicotinamide Riboside Improves Enteric Neuropathy in Streptozocin-Induced Diabetic Rats Through Myenteric Plexus Neuroprotection. Digestive Diseases and Sciences. 2023;68(7):2963-2974. doi:10.1007/s10620-023-07913-5

37. Yang J, Xie S, Guo J, et al. Restoration of Mitochondrial Function Alleviates Trigeminal Neuropathic Pain in Mice. Free Radical Biology & Medicine. 2025;226:185-198. doi:10.1016/j.freeradbiomed.2024.11.011

38. Dellinger RW, Holmes HE, Hu-Seliger T, et al. Nicotinamide Riboside and Pterostilbene Reduces Markers of Hepatic Inflammation in NAFLD: A Double-Blind, Placebo-Controlled Clinical Trial. Hepatology. 2023;78(3):863-877. doi:10.1002/hep.32778

39. Shin HJ, Na HS, Do SH. Magnesium and Pain. Nutrients. 2020;12(8):2184. doi:10.3390/nu12082184

40. Goldberg RJ, Katz J. A Meta-Analysis of the Analgesic Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation for Inflammatory Joint Pain. Pain. 2007;129(1-2):210-223. doi:10.1016/j.pain.2007.01.020

41. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy: The NATHAN 1 Trial. Diabetes Care. 2011;34(9):2054-2060. doi:10.2337/dc11-0503.

42. Hernández-Ojeda J, Cardona-Muñoz EG, Román-Pintos LM, et al. The Effect of Ubiquinone in Diabetic Polyneuropathy: A Randomized Double-Blind Placebo-Controlled Study. Journal of Diabetes and Its Complications. 2012;26(4):352-358. doi:10.1016/j.jdiacomp.2012.04.004

Nicotinamide Riboside (NR): Pain Processing Effects vs. Direct Tissue-Modifying Effects

Most nutraceuticals demonstrating benefit for pain provide both impact on pain processing as well as direct impact on on damaged tissues as well. Some nutraceuticals will feature dominance with impact on pain processing effects as opposed to tissue-modifying effects while others are more balanced or the opposite.

1. Nicotinamide Riboside (NR)

Pain Processing Effects:

NR exerts analgesic effects primarily through NAD+ repletion and SIRT1 activation, which restores mitochondrial function in sensory neurons. In a trigeminal neuropathic pain model, NR supplementation rejuvenated mitochondria by boosting NAD+ levels, enhanced mitochondrial fitness, and significantly ameliorated trigeminal neuropathic pain. The analgesic effects of NR mainly depend on SIRT1—activated SIRT1 suppresses a broad range of key pain genes and exerts anti-inflammatory effects in the trigeminal ganglion.[1]

In diabetic peripheral neuropathy (DPN) models, NR and nicotinamide mononucleotide (NMN) reversed established neuropathy: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored.[2][3] Critically, these benefits occurred without affecting blood glucose levels, confirming direct neuroprotective rather than metabolic effects. In dorsal root ganglion (DRG) neurons from diabetic mice, NAD+ levels and mitochondrial maximum reserve capacity were decreased—impairments normalized by NR treatment.[3]

In chemotherapy-induced peripheral neuropathy (CIPN), oral NR (200 mg/kg) beginning 7 days before paclitaxel treatment prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors—effects sustained after a 2-week washout period.[4] NR increased blood NAD+ levels by 50%, did not interfere with paclitaxel’s myelosuppressive effects, and produced no adverse locomotor effects. Notably, NR also reversed well-established tactile hypersensitivity in a subset of rats when administered after paclitaxel, suggesting both prophylactic and therapeutic efficacy.[4]

In aged human skeletal muscle, NR supplementation (1 g/day for 21 days) elevated the muscle NAD+ metabolome and depressed levels of circulating inflammatory cytokines, demonstrating anti-inflammatory effects that may contribute to analgesia.[5]

Direct Tissue-Modifying Effects:

Evidence for NR’s direct effects on articular cartilage is emerging but primarily preclinical. NAD+ depletion and mitochondrial respiratory chain dysfunction contribute to chondrocyte senescence, a key driver of OA progression.[6][7] A 2025 study demonstrated that a mitochondria-targeted NAD+/O2 co-delivery hydrogel that releases NAD+ precursors reactivated the mitochondrial respiratory chain, alleviated chondrocyte senescence, enhanced antioxidant enzyme activity (SOD, catalase, glutathione peroxidase), and preserved cartilage matrix integrity.[6]

SIRT6, another NAD+-dependent sirtuin, regulates chondrocyte senescence by maintaining mitochondrial number and membrane integrity, alleviating excessive ROS, and reducing inflammation-mediated mitochondrial damage. Supplementation of NAD+ precursors can increase SIRT6 activity, alleviate chondrocyte senescence, and reduce OA progression.[7]

Niacinamide (nicotinamide), a related NAD+ precursor, combined with undenatured type II collagen in an OA rat model decreased serum IL-1β, IL-6, TNF-α, COMP, and CRP, reduced joint MMP-3, NF-κB, and TGF-β protein levels, and improved Kellgren-Lawrence and Mankin scores.[8] The mechanistic hypothesis suggests niacinamide inhibits cytokine-mediated induction of NO synthase in chondrocytes, blunting the anti-anabolic impact of IL-1.[9]

In rheumatoid arthritis, preclinical characterization found that RA patients display reduced NAD+ levels with altered activity of NAD+-consuming enzymes (sirtuins, PARP, CD38). In vitro, NR increased NAD+ levels in RA patient PBMCs and reduced their prooxidative, proapoptotic, and proinflammatory status.[10] However, no clinical trials have yet tested NR specifically for arthritis or musculoskeletal pain.[11]

Mechanism	Pain Processing	Tissue Modification	References
NAD+ repletion → SIRT1 activation	Suppresses pain genes; anti-inflammatory in trigeminal ganglion	Reduces chondrocyte senescence via SIRT6	[1], [2]
Mitochondrial function restoration in DRG neurons	Reverses diabetic neuropathy; normalizes nerve conduction	Reactivates chondrocyte mitochondrial respiratory chain	[3], [4]
Prevention of axonal degeneration	Prevents/reverses CIPN; restores intraepidermal nerve fibers	None	[1]
Circulating inflammatory cytokine reduction	Reduces systemic inflammation	Reduces synovial inflammation	[2]
iNOS inhibition (niacinamide)	Indirect	Blunts IL-1-induced anti-anabolic effects on chondrocytes	[3]

Key Distinctions:

– Nicotinamide Riboside demonstrates robust preclinical evidence for neuropathic pain through NAD+ repletion and SIRT1 activation, with effects on mitochondrial function in sensory neurons that are independent of metabolic correction. The ability to both prevent and reverse established neuropathy (diabetic and chemotherapy-induced) is particularly notable—oral NR (200 mg/kg) beginning before paclitaxel treatment prevented tactile hypersensitivity and blunted escape-avoidance behaviors, with effects sustained after a 2-week washout period. Critically, NR also reversed well-established tactile hypersensitivity in a subset of rats when administered after paclitaxel, suggesting both prophylactic and therapeutic efficacy. [1]

A critical 2023 review of 25 published human NR supplementation studies concluded that oral NR has displayed few clinically relevant effects, with an “unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects.”

NR may play a role in reducing inflammatory states—supplementation in aged humans (1 g/day for 21 days) elevated the muscle NAD+ metabolome and[2] depressed levels of circulating inflammatory cytokines.[3] Yet no clinical trials have specifically tested NR for arthritis or musculoskeletal pain, representing a significant preclinical-to-clinical translation gap.[2][4]

For tissue modification, the mechanistic rationale is compelling—NAD+ depletion contributes to chondrocyte senescence, and NAD+ precursors can increase SIRT6 activity to alleviate senescence and reduce OA progression.[5][6] However, direct clinical evidence for cartilage protection with NR supplementation is absent.

References for Pain Processing Effects vs. Direct Tissue-Modifying Effects

Restoration of Mitochondrial Function Alleviates Trigeminal Neuropathic Pain in Mice. Yang J, Xie S, Guo J, et al. Free Radical Biology & Medicine. 2025;226:185-198. doi:10.1016/j.freeradbiomed.2024.11.011.
NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2024;25(2):1102. doi:10.3390/ijms25021102.
NAD+ Precursors Repair Mitochondrial Function in Diabetes and Prevent Experimental Diabetic Neuropathy. Chandrasekaran K, Najimi N, Sagi AR, et al. International Journal of Molecular Sciences. 2022;23(9):4887. doi:10.3390/ijms23094887.
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.
Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-Inflammatory Signatures. Elhassan YS, Kluckova K, Fletcher RS, et al. Cell Reports. 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043.
Mitochondria-Targeted NAD+/O2 Co-Delivery Interpenetrating Network Hydrogel for Respiratory Chain Restoration and Osteoarthritis Therapy. Shen X, Hu J, Wang C, et al. Journal of Controlled Release : Official Journal of the Controlled Release Society. 2025;385:113975. doi:10.1016/j.jconrel.2025.113975.
The Influence of Sirtuin 6 on Chondrocyte Senescence in Osteoarthritis Under Aging: Focusing on Mitochondrial Dysfunction and Oxidative Stress. Zhao H, Wu W. Antioxidants (Basel, Switzerland). 2025;14(10):1228. doi:10.3390/antiox14101228.
Niacinamide and Undenatured Type II Collagen Modulates the Inflammatory Response in Rats With Monoiodoacetate-Induced Osteoarthritis. Sahin K, Kucuk O, Orhan C, et al. Scientific Reports. 2021;11(1):14724. doi:10.1038/s41598-021-94142-3.
Niacinamide Therapy for Osteoarthritis–Does It Inhibit Nitric Oxide Synthase Induction by Interleukin 1 in Chondrocytes?. McCarty MF, Russell AL. Medical Hypotheses. 1999;53(4):350-60. doi:10.1054/mehy.1998.0792.
Preclinical Characterization of Pharmacologic NAD Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis. Perez-Sanchez C, Escudero-Contreras A, Cerdó T, et al. Arthritis & Rheumatology (Hoboken, N.J.). 2023;75(10):1749-1761. doi:10.1002/art.42528.
What Is Really Known About the Effects of Nicotinamide Riboside Supplementation in Humans. Damgaard MV, Treebak JT. Science Advances. 2023;9(29):eadi4862. doi:10.1126/sciadv.adi4862.

This completes “Nicotinamide Riboside (NR) Impacts Pain Processing:

Overview
Understanding the Four Demons
Pain Processing Pathway Analysis (Levels 1-6)
Comparison Table: NR Effects Across Pain Processing Levels
Clinical Evidence Supporting Pain Pathway Effects
Human Clinical Evidence
Safety Profile
Dosing Considerations
Synergistic Potential with Other Nutraceuticals
Mechanistic Comparison: NR vs. Other Mitochondrial-Targeted Nutraceuticals
Practical Considerations for Clinical Use
Summary and Conclusions
References
NR: Pain Processing Effects vs. Direct Tissue-Modifying Effects

—

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