LDN and Neuropathy: The Potential Role of Low-Dose Naltrexone (LDN) for Treating Neuropathy "- Integrative Functional Medicine San Antonio
- John Kim
- Dec 29, 2025
- 8 min read
Edited by Yoon Hang Kim MD MPH
About Dr. Kim
Dr. Yoon Hang “John” Kim is a fellowship-trained integrative and functional medicine physician with over 20 years of experience. He completed a residential fellowship in integrative medicine at the University of Arizona under Dr. Andrew Weil and is a 2024 Functional Medicine for All scholarship recipient from the Institute for Functional Medicine.
After serving as Chief Wellness Officer at a rural community hospital in Illinois, Dr. Kim now provides virtual integrative and functional medicine care, expanding access to personalized, evidence-based treatment nationwide. His root-cause approach combines advanced functional lab testing with lifestyle medicine, nutrition, movement, mindfulness, and complementary therapies.
Board-certified in preventive medicine, medical acupuncture, and integrative and holistic medicine, Dr. Kim has been a faculty member, consultant, and founder of an academic integrative health program. His clinical focus includes autoimmune disease, chronic pain, gastrointestinal disorders, integrative oncology, fibromyalgia, chronic fatigue syndrome, long COVID, and mold-related illness. He is the author of two books and more than 20 publications.
Professional Inquiries: www.yoonhangkim.com
Clinical Inquiries: www.directintegrativecare.com
Introduction
Neuropathy—damage or dysfunction of peripheral nerves—represents a significant clinical challenge due to its prevalence and impact on quality of life. Conventional treatments, including anticonvulsants, antidepressants, and opioids, often provide incomplete relief and carry significant side effects. Low-dose naltrexone (LDN), an off-label use of naltrexone at doses typically ranging from 1 to 5 mg daily, has emerged as a promising option within integrative and functional medicine for various chronic pain conditions, including neuropathy. This article examines what LDN is, the pathophysiology of neuropathy with specific examples, the proposed mechanisms by which LDN may alleviate neuropathic symptoms, and evidence from clinical studies and trials.
What is Low-Dose Naltrexone?
Naltrexone is an opioid receptor antagonist approved for treating alcohol and opioid addiction at standard doses of 50 mg or higher. At these doses, it blocks opioid receptors to prevent euphoria and reduce cravings. Low-dose naltrexone refers to administration at significantly reduced doses—generally 1–5 mg per day, and sometimes even lower. This regimen is used off-label for its potential immunomodulatory and anti-inflammatory effects, particularly in chronic pain and inflammatory conditions.
LDN is thought to work through transient opioid receptor blockade, leading to a compensatory increase in endogenous opioid production, and through non-opioid pathways involving glial cell modulation. Because commercial preparations are designed for higher doses, LDN is typically compounded into capsules or liquid formulations. Clinical observations suggest it's well-tolerated, with minimal side effects such as vivid dreams or mild gastrointestinal discomfort—making it an attractive alternative for patients intolerant to standard therapies.
What is Neuropathy?
Neuropathy, or peripheral neuropathy, encompasses a diverse group of disorders involving damage to peripheral nerves, resulting in sensory, motor, or autonomic dysfunction. Symptoms include pain, numbness, tingling, weakness, and autonomic disturbances. The condition arises from many causes: metabolic (diabetes), toxic (chemotherapy), infectious (herpes zoster), traumatic, autoimmune, nutritional deficiencies (particularly B vitamins), and sometimes idiopathic.
Neuropathic pain is often described as burning, stabbing, or electric-shock-like and is mediated by central and peripheral sensitization. Glial cell activation in the central nervous system contributes to neuroinflammation, amplifying pain signals through proinflammatory cytokine release. This chronicity distinguishes neuropathic pain from nociceptive pain and makes it notoriously difficult to treat with conventional analgesics.
Common Types of Neuropathy
Neuropathies are classified by distribution (e.g., distal symmetric polyneuropathy) or underlying cause. Common examples include:
Diabetic peripheral neuropathy is the most prevalent form, affecting up to 50% of individuals with diabetes. It primarily involves sensory nerves in a stocking-glove distribution, leading to painful symptoms and increased risk of foot ulceration.
Chemotherapy-induced peripheral neuropathy results from neurotoxic agents used in cancer therapy, causing sensory loss, burning pain, numbness, and tingling that may persist long after treatment ends.
Trigeminal neuralgia is a cranial neuropathy involving the fifth cranial nerve, characterized by paroxysmal, lancinating facial pain triggered by innocuous stimuli like light touch or chewing. It often stems from vascular compression or demyelination and can be severely debilitating.
Post-herpetic neuralgia is a complication of herpes zoster (shingles), occurring in 10–20% of cases. Persistent pain follows rash resolution due to viral damage to sensory nerves.
Other forms include small-fiber neuropathy (affecting autonomic and pain fibers) and complex regional pain syndrome (CRPS), which involves neuroinflammation and central sensitization.
How LDN May Help Neuropathic Pain
The analgesic effects of LDN in neuropathy are attributed primarily to its antagonism of Toll-like receptor 4 (TLR4) on microglial cells. Microglia, the resident immune cells of the central nervous system, become activated in response to nerve injury. Once activated, they release proinflammatory cytokines (TNF-α, IL-1β) that exacerbate central sensitization and worsen neuropathic pain.
LDN inhibits TLR4 signaling, preventing excessive glial activation and attenuating this inflammatory cascade. This reduces neuroinflammation without fully blocking opioid receptors, allowing endogenous opioids to continue exerting their natural pain-modulating effects. Additionally, the transient opioid receptor blockade may upregulate endorphin production, enhancing the body's own pain control mechanisms.
Preclinical evidence supports TLR4-mediated reversal of allodynia in neuropathic models, while clinical observations link LDN's benefits to reduced glial-driven inflammation in conditions like diabetic neuropathy and CRPS.
Evidence from Studies and Clinical Trials
Research on LDN for neuropathy is growing, though still dominated by small-scale studies, case series, and retrospective reviews. Key findings include:
A randomized, double-blind, crossover trial involving 67 patients with painful diabetic neuropathy compared LDN (2–4 mg) to amitriptyline (10–50 mg). LDN demonstrated comparable pain reduction on visual analog scales with a superior safety profile and fewer adverse events.
Retrospective cohort studies report significant pain relief in various neuropathic conditions. One analysis of chronic pain patients found LDN effective across multiple pain states, with greater benefits in neuropathic versus nociceptive pain—consistent with the TLR4 antagonism mechanism. Another case series noted improved outcomes in CRPS and diabetic neuropathy.
For trigeminal neuralgia, preclinical rat models showed LDN reversing facial allodynia via TLR4 modulation. A retrospective case series in posttraumatic trigeminal neuropathic pain reported LDN as safe and effective.
Post-herpetic neuralgia and related conditions (including neuropathic corneal pain) have shown symptom improvement in observational data, with LDN reducing pain and enhancing quality of life.
Ongoing or completed trials registered on ClinicalTrials.gov include evaluations for painful diabetic neuropathy (NCT04678895) and CRPS (NCT06306157).
The LDN Research Trust has compiled additional clinical and anecdotal reports of benefit in idiopathic, autonomic, and small-fiber neuropathies.
Overall, evidence suggests LDN provides moderate pain relief in neuropathies—particularly those with inflammatory components—with low risk. However, larger randomized controlled trials are needed to establish efficacy more definitively.
LDN Prescription and Administration
LDN is most effectively prescribed by healthcare providers with training in integrative or functional medicine approaches. The process begins with a thorough assessment of the patient's medical history, current symptoms, and treatment goals to ensure LDN is appropriate.
Most patients start at carefully titrated doses between 0.1 and 4.5 mg per day, typically administered at bedtime to minimize potential side effects like vivid dreams. Because standard commercial formulations aren't available at these low doses, LDN must be prepared by compounding pharmacies.
Regular follow-up appointments are essential for assessing response and making dosage adjustments. This personalized approach—fundamental to integrative and functional medicine practice—helps optimize outcomes for patients managing chronic pain and autoimmune conditions.
Comparison to Conventional Treatments
Low-dose naltrexone represents a different approach compared to conventional therapies for chronic pain. While traditional treatments—opioids, anticonvulsants, and immunosuppressive medications—typically focus on symptom suppression and carry substantial side effect profiles, LDN works through immune modulation and inflammatory pathway regulation. This mechanism addresses underlying pathophysiology rather than merely masking symptoms.
LDN's favorable safety profile, combined with its anti-inflammatory properties, makes it a compelling option for patients seeking alternatives to conventional pharmaceutical interventions. What distinguishes LDN in functional medicine practice is its ability to integrate into comprehensive treatment protocols that may also incorporate physical therapy, nutritional interventions, and other complementary modalities.
Patient Experiences
Clinical observations and published case series document that many patients with chronic pain and autoimmune conditions respond well to LDN as part of comprehensive care. Patients with diabetic neuropathy often report reduced pain intensity and improved sensory function. Those with multiple sclerosis have shown improvements in disability scores and reduced fatigue. Patients managing inflammatory bowel disease have demonstrated improvements in inflammatory markers and symptom severity.
Responses to LDN vary considerably between individuals, and not all patients achieve optimal outcomes. However, clinical experience indicates that LDN protocols provide a reasonable therapeutic option for patients when conventional treatments have shown limited efficacy or tolerability.
Future Directions
Future studies are needed to determine optimal dosing strategies, ideal treatment durations, and which patient populations are most likely to benefit from LDN therapy. There's growing interest in exploring how LDN might work synergistically with other interventions—nutritional therapies, mind-body practices, and lifestyle modifications—to enhance outcomes.
Research into the molecular mechanisms behind LDN's anti-inflammatory and immunomodulatory effects could inform development of new treatments for chronic pain and autoimmune diseases. Expanding clinical trials to include pediatric populations and patients with multiple complex conditions will also be important for understanding LDN's safety and efficacy across diverse groups.
As the evidence base grows, low-dose naltrexone may become an increasingly valuable tool in managing chronic and complex conditions.
Conclusion
Low-dose naltrexone offers a non-opioid approach to managing neuropathy by targeting glial-mediated neuroinflammation through TLR4 inhibition. Preliminary evidence supports its use in diabetic neuropathy, trigeminal neuralgia, and post-herpetic neuralgia, with favorable tolerability. Its integration into functional and integrative medicine frameworks highlights its potential as an adjunctive therapy. While promising, LDN should be used under appropriate medical supervision, and more robust trial data will help clarify its role in neuropathy management.
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At Direct Integrative Care, Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.
Yoon Hang Kim MD
Integrative & Functional Medicine Physician
Virtual Practice Serving IA, IL, MO, FL, GA, and TX
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