Low-Dose Naltrexone for Nerve Pain
What the evidence says about CRPS, trigeminal neuralgia, and post-herpetic neuralgia
By Yoon Hang Kim, MD, MPH
Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician
About Dr. Kim
Dr. Kim is board-certified in Preventive Medicine with more than 20 years of experience in integrative and functional medicine. He completed the University of Arizona fellowship under Dr. Andrew Weil, holds UCLA medical acupuncture certification, and has served as Enterprise Medical Director at WellMed/Optum, Medical Director of Integrative Oncology at Miami Cancer Institute, Director of the Integrative Medicine Program at the University of Kansas Medical Center, and Dean at AIMC Berkeley. His focus includes LDN, autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue, MCAS, and mold toxicity. He is the author of 8 books and more than 25 peer-reviewed articles, and he founded the LDN Support Group. Professional: www.yoonhangkim.com | Clinical: www.directintegrativecare.com
Why nerve pain is so hard to treat
Some pain is simple. You twist an ankle, the tissue heals, and the pain fades. Nerve pain doesn't follow that script. Long after the original injury, infection, or inflammation has settled, the nervous system can stay stuck in a high-alert mode. A light touch burns. A breeze on the face sets off lightning. The alarm keeps ringing, even though the fire is out.
Clients living with this kind of pain often hear that it's "all in your head." It isn't. The pain is real, and it's being maintained by real biology: overactive immune cells in the spinal cord and brain, weakened braking signals, and a sensory system that has turned up its own volume. That's the territory where low-dose naltrexone (LDN) has drawn so much interest.
How LDN might work
Naltrexone at standard doses is an opioid blocker. At very low doses, the thinking goes, it does something different. There are two main ideas.
Calming microglia. Microglia are the immune cells of the nervous system. When they stay activated, they release inflammatory signals that amplify pain. Lab and animal work suggests naltrexone can quiet this process through Toll-like receptor 4 (TLR4), partly independent of the opioid receptors [8-10].
Boosting the body's own opioids. A brief nightly blockade may prompt the body to make more endogenous opioids, which could strengthen its natural pain-dampening pathways [8].
A fair caution: the TLR4 story is strongest in cells and animals. Whether ordinary oral LDN doses do this meaningfully in people hasn't been proven. It's a leading hypothesis, not settled fact.
What the human evidence shows
Here is where I want to be careful, because this field attracts more enthusiasm than data. The support varies a lot from one condition to the next.
Painful diabetic neuropathy: This is the best evidence we have. In a randomized, double-blind crossover trial of 67 people, LDN relieved pain about as well as amitriptyline, with far fewer side effects (8 adverse events versus 52) [1]. There was no placebo arm and the treatment periods were short, so it shows LDN is active and well tolerated, not that it's better than standard care.
Mixed neuropathic pain: A matched retrospective cohort found an average pain reduction of about 38% with LDN versus about 4% in controls. Smaller retrospective series, including one in neuropathic corneal pain, point the same direction [4-6]. These are encouraging but nonrandomized, so selection and expectation effects can't be ruled out.
CRPS: The disease-specific evidence is three case reports (two adults, one child) plus subgroup findings from a pain-center series in which 9 of 12 CRPS clients reportedly responded. Every case involved other treatments too [2,4,7,14]. Two placebo-controlled trials, at Stanford and the Hospital for Special Surgery, are underway, but neither has established efficacy yet [23,24].
Trigeminal neuralgia: No completed human randomized trial exists for classical trigeminal neuralgia. Rat studies show LDN reversing facial allodynia [11,12], and a small 2025 human series found lower pain scores in post-traumatic trigeminal neuropathic pain [3]. That is a different condition from classical TN, which is usually driven by blood vessel compression of the nerve. It's an interesting signal, not proof.
Post-herpetic neuralgia (PHN): Honestly, there isn't a persuasive human study. An FDA orphan-drug designation exists [28], but that's a regulatory status, not evidence that it works. Applying LDN to PHN is a reasonable hypothesis, since PHN has burning pain and allodynia, but it remains unproven.
Who might be worth a closer look
No test can predict who will respond. Still, the clients where LDN seems most reasonable to consider tend to share a few features:
Allodynia or hyperalgesia out of proportion to any ongoing tissue damage
Pain that has spread beyond a single injured area
Overlap with CRPS, fibromyalgia, small-fiber symptoms, or dysautonomia
Poor tolerance of sedating nerve-pain medications
No need for opioid pain medication
Think of these as educated guesses, not validated predictors.
Safety and what to know before starting
LDN is generally well tolerated. The most common complaints are vivid dreams, trouble sleeping, headache, and mild stomach upset, and they often ease with time. The big issue is opioids. Naltrexone is contraindicated with opioid pain medicines, methadone, and buprenorphine, and it can trigger withdrawal [26,27]. It can also blunt opioid-containing cough and antidiarrheal products and complicate pain control around surgery or emergencies. People with significant liver disease need individual review.
Dosing is individualized, usually starts low, and rises gradually. Published studies use a fairly narrow low-dose range, but there's no proven best dose for any specific condition. For detailed dosing guidance and the underlying clinical evidence, please visit ifmsynergy.com.
Benefit, when it comes, often takes one to three months to show up. A sensible trial sets goals in advance: average and worst pain scores, function (eating, speaking, walking, working), sleep, and a simple overall rating of change at 8 to 12 weeks. If there's no meaningful benefit after an adequate trial, that's a good reason to stop.
The bottom line
LDN has a credible rationale and a growing, but still modest, clinical signal in nerve pain. It looks most promising for painful diabetic and mixed neuropathic pain, is suggestive but very low-certainty for CRPS, is preclinical or observational for trigeminal pain, and is unproven for post-herpetic neuralgia.
So LDN is best thought of as an off-label adjunct, not a replacement for proven care. Classical trigeminal neuralgia still starts with carbamazepine or oxcarbazepine and a proper imaging workup [19,20]. PHN still starts with gabapentinoids, tricyclics, and topical options [21,22]. CRPS still centers on early rehabilitation and multidisciplinary care [18]. If you're living with nerve pain and considering LDN, talk with a clinician who can review your full history, your medications, and your goals.
Important: This article is for educational purposes only and is not medical advice. Low-dose naltrexone is used off-label for these conditions. Do not start, stop, or change any medication without talking with your own healthcare provider.
References
Primary clinical studies
1. Srinivasan A, Dutta P, Bansal D, Chakrabarti A, Bhansali AK, Hota D. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. Journal of Diabetes. 2021;13(10):770-778. doi:10.1111/1753-0407.13202. PMID: 34014028. [link]
2. Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN). Journal of Neuroimmune Pharmacology. 2013;8(3):470-476. doi:10.1007/s11481-013-9451-y. [link]
3. Ananthan S, Heir G, Korczeniewska O. Use of low-dose naltrexone in the management of posttraumatic trigeminal neuropathic pain: A retrospective case series. Quintessence International. 2025;56(8):682-690. doi:10.3290/j.qi.b6335903. PMID: 40590142. [link]
4. McKenzie-Brown AM, Boorman DW, Ibanez KR, Agwu E, Singh V. Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series. Journal of Pain Research. 2023;16:1993-1998. doi:10.2147/JPR.S389957. [link]
5. Dieckmann G, Ozmen MC, Cox SM, Engert RC, Hamrah P. Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain. The Ocular Surface. 2021;20:33-38. doi:10.1016/j.jtos.2020.12.003.
6. Corser-Jensen CE, et al. Retrospective Analysis of Naltrexone for Persistent Neuropathic Pain: Case Series. Pain Medicine Case Reports. 2023;7:377-383.
7. Soin A. Management of Pediatric Complex Regional Pain Syndrome with Low-Dose Naltrexone. Pain Medicine Case Reports. 2021;5:109-113.
Mechanism and preclinical literature
8. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology. 2014;33(4):451-459. doi:10.1007/s10067-014-2517-2.
9. Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Medical Sciences. 2018;6(4):82. doi:10.3390/medsci6040082.
10. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of Toll-like receptor 4. European Journal of Neuroscience. 2008;28(1):20-29. doi:10.1111/j.1460-9568.2008.06321.x.
11. de Oliveira CL, Medeiros LF, de Souza VS, et al. Low-dose naltrexone reverses facial mechanical allodynia in a rat model of trigeminal neuralgia. Neuroscience Letters. 2020;736:135248. doi:10.1016/j.neulet.2020.135248.
12. Naderi Y, Soti M, Soltani M, et al. Co-administration of low-dose naltrexone and carbamazepine remarkably ameliorates allodynia and cognitive deficit in a rat model of trigeminal neuralgia. Scientific Reports. 2025;15:31335. [link]
Systematic and narrative reviews
13. Kim PS, Fishman MA. Low-Dose Naltrexone for Chronic Pain: Update and Systematic Review. Current Pain and Headache Reports. 2020;24:64.
14. Soin A, et al. Low-Dose Naltrexone Use for Patients with Chronic Regional Pain Syndrome: A Systematic Literature Review. Pain Physician. 2021;24:E125-E143. PMID: 34213865. [link]
15. Rupp A, Young E, Chadwick AL. Low-dose naltrexone’s utility for non-cancer centralized pain conditions: A scoping review. Pain Medicine. 2023;24(11):1270-1281.
16. The use of naltrexone in the treatment of chronic pain: A systematic review. 2024. [link]
17. Low-Dose Naltrexone: What is the Evidence? A Narrative Review. 2026. [link]
CRPS and neuralgia standards
18. Harden RN, McCabe CS, Goebel A, et al. Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 5th Edition. Pain Medicine. 2022;23(Suppl 1):S1-S53. doi:10.1093/pm/pnac046. [link]
19. Bendtsen L, Zakrzewska JM, Abbott J, et al. Trigeminal neuralgia: a practical guide. Practical Neurology. 2021;21:392-402. [link]
20. Guidelines for the management of trigeminal neuralgia. Cleveland Clinic Journal of Medicine. 2023;90(6):355-362. [link]
21. Nalamachu S, Morley-Forster P. Diagnosing and Managing Postherpetic Neuralgia. Drugs & Aging. 2012;29(11):863-869.
22. Johnson RW, Rice ASC. Postherpetic neuralgia. New England Journal of Medicine. 2014;371:1526-1533.
Registered studies
23. ClinicalTrials.gov. Low-Dose Naltrexone for the Treatment of Complex Regional Pain Syndrome. Identifier NCT02502162. Stanford; randomized LDN versus placebo; no posted efficacy results at present. [link]
24. ClinicalTrials.gov. Low Dose Naltrexone Therapy for Complex Regional Pain Syndrome. Identifier NCT06306157. Hospital for Special Surgery feasibility study of LDN plus standard care versus placebo plus standard care. [link]
25. ClinicalTrials.gov. Low-Dose Naltrexone for the Treatment of Painful Diabetic Neuropathy. Identifier NCT04678895. Randomized, double-blind, placebo-controlled crossover design. [link]
Safety and regulatory sources
26. DailyMed. Naltrexone hydrochloride tablets: prescribing information, contraindications, opioid-free interval, hepatic precautions, and opioid-overdose risk.[link]
27. Substance Abuse and Mental Health Services Administration. Naltrexone: treatment information and opioid-withdrawal/overdose precautions.[link]
28. FDA Orphan Drug Designations. Naltrexone for post-herpetic neuralgia: orphan designation only; this is not FDA approval for PHN treatment.[link]
Requested organization sources
29. LDN Research Trust. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy—summary of the Srinivasan et al. randomized crossover trial.[link]
30. LDN Research Trust. Chronic Pain conference material, including clinician discussion of CRPS, trigeminal neuralgia, and PHN.[link]
31. Kim YH. Low-Dose Naltrexone in Complex Regional Pain Syndrome: Mechanisms, Clinical Evidence, and Individualized Dosing. IFM Synergy. 2026. [link]
32. Kim YH. Low-Dose Naltrexone: Mechanisms, Individualized Dosing, and Clinical Applications in Integrative Medicine. IFM Synergy. 2026. [link]
33. Kim YH. LDN and Neuropathy: The Potential Role of Low-Dose Naltrexone for Treating Neuropathy. www.directintegrativecare.com. 2025. [link]
34. Kim YH. Low-dose naltrexone therapy: Powerful 2026 Benefits. www.directintegrativecare.com. 2026. [link]
35. Kim YH. Pediatric Dosing of LDN Low Dose Naltrexone. YoonHangKim.com. 2025. [link]
Note on source weight: Educational materials from LDN Research Trust and the clinical websites above are useful but should not be weighed equivalently to controlled trials, guidelines, or regulatory sources. The strongest direct LDN evidence in this topic remains the single randomized painful diabetic neuropathy trial [1]; CRPS evidence is largely case-based, trigeminal neuralgia evidence is mainly preclinical or post-traumatic neuropathy data, and PHN-specific evidence remains insufficient.
Yoon Hang Kim, MD, MPH is the author of MCAS: Epidemic in Plain Sight and LDN Primer, both available on Amazon, and the founder of the LDN Support Group.
Professional: www.yoonhangkim.com | Clinical: www.directintegrativecare.com
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