Using Low-Dose Naltrexone LDN to Treat Fibromyalgia Integrative & Functional Medicine San Antonio
- John Kim
- Dec 16
- 12 min read
A Review of Mechanisms, Evidence, and Clinical Considerations
Edited by Yoon Hang Kim MD, MPH
Dr. Yoon Hang Kim, MD, is a renowned clinical expert in Low-Dose Naltrexone (LDN) and a sought-after presenter at the LDN Research Trust Conference. As an integrative and functional medicine physician, Dr. Kim brings a holistic approach to patient care, combining evidence-based practices with innovative therapies like LDN. He is the author of a book on LDN, which covers its therapeutic potential across various conditions, and has also contributed an insightful article on the subject of using LDN for treating pain.Dr. Kim’s work not only highlights the science behind LDN but also emphasizes its practical application in improving patient outcomes. Dr. Kim also has a YouTube channel focusing on LDN therapy and also serves as an administrator for LDN Support Group.
1. Introduction
Fibromyalgia is a chronic pain syndrome affecting an estimated 2–4% of the global population, with a marked female predominance. My first introduction to the multi-dimensional aspect of fibromyalgia occurred before my discovering LDN. At that time, utilizing acupuncture neurology (a specialty technique within acupuncture) to reset pain yielded about 50% pain control. The other 30% came from resolution of an internal conflict resolved through her faith.Â
The condition is characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive difficulties often referred to as "brain fog." Despite its prevalence, fibromyalgia remains one of the most challenging conditions to treat effectively in conventional medicine.
Current pharmacological approaches—including pregabalin, duloxetine, and milnacipran—offer modest efficacy at best, with meta-analyses suggesting only 30–40% of patients achieve meaningful symptom reduction. Furthermore, these medications frequently produce significant adverse effects including weight gain, cognitive impairment, sedation, and sexual dysfunction, leading to poor adherence and treatment discontinuation.
This therapeutic gap has prompted investigation into alternative approaches, among which Low-Dose Naltrexone (LDN) has emerged as a particularly promising candidate. This article examines the scientific rationale, clinical evidence, and practical considerations for LDN in fibromyalgia management.
2. What is Low-Dose Naltrexone (LDN)?
2.1 Pharmacological Background
Naltrexone is an opioid receptor antagonist originally approved by the FDA in 1984 at doses of 50–100 mg daily for the treatment of opioid and alcohol use disorders. At these standard doses, naltrexone provides sustained blockade of mu-opioid receptors, preventing the euphoric effects of exogenous opioids and reducing alcohol cravings.
Low-Dose Naltrexone refers to the off-label use of naltrexone at doses typically ranging from 0.1 mg to 4.5 mg daily. At these lower doses, naltrexone appears to exhibit fundamentally different pharmacodynamic properties, producing transient rather than sustained opioid receptor blockade and engaging additional receptor systems and cellular mechanisms.
2.2 Proposed Mechanisms of Action
The therapeutic effects of LDN in chronic pain conditions appear to operate through multiple complementary pathways.Â
Anti-inflammatory pathway:
First, LDN modulates glial cell activity by antagonizing Toll-like receptor 4 (TLR4) on microglia and astrocytes. This antagonism reduces the introduction of pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), while simultaneously promoting the release of anti-inflammatory mediators.
Endorphin pathway:
Second, the brief opioid receptor blockade induced by LDN triggers a compensatory upregulation of endogenous opioid production and receptor sensitivity during the "rebound" period after the drug's effects dissipate. This enhanced endorphin system activity may contribute to improved pain modulation and mood regulation.
Immune Modulation pathway:
Third, emerging evidence suggests LDN may influence regulatory T-cell function and modulate broader immune system activity, potentially addressing the immune dysregulation increasingly recognized as a feature of fibromyalgia pathophysiology.
2.3 Off-Label Applications
Beyond fibromyalgia, LDN has been investigated in numerous chronic pain and autoimmune conditions including multiple sclerosis, Crohn's disease, complex regional pain syndrome, and various autoimmune disorders. While the evidence base varies across conditions, the accumulating clinical experience has informed our understanding of LDN's therapeutic potential and more importantly, it speaks to the safety profile LDN.
3. The Science Behind LDN and Fibromyalgia
3.1 Fibromyalgia Pathophysiology: Current Understanding
Contemporary models of fibromyalgia pathophysiology emphasize central sensitization—a state of heightened excitability in spinal and supraspinal pain-processing circuits that amplifies nociceptive signaling and reduces descending inhibitory control. Functional neuroimaging studies consistently demonstrate altered pain processing in fibromyalgia patients, with enhanced activation of pain-related brain regions in response to normally non-painful stimuli.
Increasingly, neuroinflammation has been recognized as a potential driver of central sensitization in fibromyalgia. Positron emission tomography (PET) studies using radioligands that bind to translocator protein (TSPO)—a marker of activated glial cells—have demonstrated elevated microglial activation in multiple brain regions of fibromyalgia patients compared to healthy controls.
Additionally, cerebrospinal fluid analyses have revealed elevated concentrations of pro-inflammatory cytokines and chemokines in fibromyalgia patients, further supporting the neuroinflammatory hypothesis. These inflammatory mediators can directly sensitize nociceptive neurons, disrupt inhibitory neurotransmission, and contribute to the cognitive and mood disturbances characteristic of the condition.
3.2 How LDN Addresses Fibromyalgia Mechanisms
LDN's proposed mechanism of action aligns remarkably well with current understanding of fibromyalgia pathophysiology. By reducing microglial activation and pro-inflammatory cytokine production, LDN may directly address the neuroinflammatory component of central sensitization. The reduction of IL-1β and TNF-α levels could decrease nociceptive neuron sensitization and restore more normal pain processing. I share with my patients that LDN appears to calm neuroinflammation.
Furthermore, LDN's effects on the endogenous opioid system may help restore the dysfunctional descending pain inhibition observed in fibromyalgia. Studies have demonstrated reduced mu-opioid receptor availability in key pain-modulating brain regions of fibromyalgia patients, and the receptor upregulation induced by LDN could potentially compensate for this deficit.
The multi-modal mechanism of LDN—simultaneously targeting neuroinflammation, central sensitization, and endogenous analgesia—may explain its clinical efficacy in a condition characterized by such complex and interconnected pathophysiology.
4. Key Research Studies
4.1 Younger's Pilot Study (2009)
The first clinical investigation of LDN specifically for fibromyalgia was conducted by Dr. Jarred Younger and colleagues at Stanford University. This single-blind, crossover pilot study enrolled ten women with fibromyalgia who received 4.5 mg of naltrexone daily for eight weeks, with daily symptom assessments using handheld computers.
Results demonstrated a 30% reduction in fibromyalgia symptoms compared to placebo, with the most pronounced effects observed for pain, fatigue, and overall sense of well-being. The placebo response is important to document as it is known in other therapies such as acupuncture. Most importantly, the treatment was well-tolerated, with no serious adverse events reported. These promising findings provided the foundation for more rigorous investigation.
4.2 Younger's Randomized Controlled Trial (2013)
Building on the pilot data, Younger and colleagues conducted a randomized, double-blind, placebo-controlled, crossover trial published in Pain Medicine in 2013. The study enrolled 31 women with fibromyalgia who received both LDN 4.5 mg daily and placebo for 12 weeks each, separated by a 4-week washout period.
The primary outcome—daily self-reported pain—showed a statistically significant reduction during LDN treatment compared to placebo. Secondary analyses revealed improvements in general satisfaction with life and mood, though fatigue and sleep parameters did not reach statistical significance. Notably, participants with higher baseline erythrocyte sedimentation rates (ESR), suggesting greater systemic inflammation, demonstrated the greatest response to LDN treatment.
This finding supports the hypothesis that LDN's anti-inflammatory properties may be particularly relevant to its analgesic effects in fibromyalgia. The study also confirmed LDN's favorable safety profile, with vivid dreams being the most commonly reported adverse effect.
4.3 Inflammatory Marker Studies
Parkitny and Younger (2017) published an important mechanistic study examining the effects of LDN on peripheral inflammatory markers in fibromyalgia patients. Their analysis revealed significant reductions in multiple pro-inflammatory cytokines during LDN treatment, providing direct evidence for the proposed anti-inflammatory mechanism.
These findings were particularly significant because they demonstrated that LDN's effects extend beyond symptomatic improvement to measurable changes in inflammatory biomarkers. This mechanistic validation strengthens the scientific rationale for LDN use in fibromyalgia and other conditions characterized by chronic inflammation.
4.4 Additional Supporting Evidence
Beyond the controlled trials, substantial observational and clinical experience has accumulated supporting LDN's efficacy in fibromyalgia. Retrospective analyses and case series from multiple clinical centers have reported response rates ranging from 50–70% in fibromyalgia patients treated with LDN, often in individuals who had failed multiple conventional therapies.
Experimental pain studies have demonstrated that LDN reduces temporal summation of pain (a marker of central sensitization) and mechanical hyperalgesia in laboratory models. These findings provide additional mechanistic support for LDN's effects on central pain processing.
5. Insights from the LDN Research Trust
The LDN Research Trust was founded by a colleague - Linda Elsegood. Along with Dr. Bihari, Linda transformed LDN from an obscure medication to the prominent medication well known, gaining even more popularity, and most importantly organized researchers, clinicians, and patients together through conferences, podcasts, and on-line. The last in-person conference was completed in 2025 with promise of on-line and in-real-life gathering in 2027.
The LDN Research Trust has played a pivotal role in advancing awareness, research, and clinical application of LDN for fibromyalgia and other chronic conditions. Founded in 2004, this nonprofit organization has facilitated international collaboration among researchers, clinicians, and patients interested in LDN therapy.
Through annual conferences bringing together leading researchers and clinicians, the LDN Research Trust has created a forum for sharing clinical experiences, research findings, and best practices. The organization maintains an extensive database of patient testimonials and case studies, providing valuable real-world evidence complementing formal clinical trials.
Patient testimonials collected through the LDN Research Trust consistently report improvements in pain levels, energy, cognitive function, and overall quality of life. Many fibromyalgia patients describe LDN as "life-changing," particularly those who had experienced years of inadequate relief from conventional treatments. While such testimonials cannot substitute for controlled trials, they provide meaningful insights into LDN's real-world effectiveness and patient acceptability.
The LDN Research Trust website (ldnresearchtrust.org) offers comprehensive resources for both patients and healthcare providers, including prescribing guides, compounding pharmacy directories, research summaries, and educational materials. These resources have been instrumental in facilitating informed discussions between patients and their healthcare providers about LDN therapy.
6. Benefits and Safety of LDN
6.1 Advantages Over Conventional Treatments
LDN offers several distinct advantages compared to FDA-approved fibromyalgia medications. Most notably, the side effect profile of LDN is remarkably benign. Unlike pregabalin and duloxetine, LDN is not associated with weight gain, cognitive impairment, or sexual dysfunction—adverse effects that frequently lead to treatment discontinuation with conventional therapies.
Additionally, LDN has no known abuse potential or addiction liability. As an opioid antagonist rather than agonist, it cannot produce euphoria or physical dependence. This safety characteristic is particularly valuable given the current concerns about prescription medication misuse and the challenges many fibromyalgia patients face in obtaining adequate pain treatment.
Cost represents another significant advantage. Compounded LDN typically costs about one dollar per pill without insurance coverage. Today, the costs tend to be still this range even with inflation with price variance in various pharmacies. This affordability enhances accessibility for patients, particularly those with limited insurance coverage or high deductibles.
6.2 Common Side Effects
The most frequently reported adverse effect of LDN is vivid or unusual dreams, occurring in approximately 37% of patients in clinical trials. This effect typically diminishes within one to two weeks of treatment and rarely necessitates discontinuation. Some clinicians recommend taking LDN in the morning rather than evening if vivid dreams prove troublesome.
Other reported side effects include mild headache, nausea, and transient anxiety, each occurring in fewer than 10% of patients. These effects are typically mild, self-limiting, and resolve with continued treatment or minor dose adjustments. Serious adverse events have not been reported in LDN clinical trials.
6.3 Safety Profile and Contraindications
LDN demonstrates an excellent safety profile across numerous clinical studies and decades of use. However, certain contraindications warrant careful consideration. Ultra low dose naltrexone (1 microgram or lower) should be used in patients currently taking opioid medications. Regular LDN dose as the antagonist effect could precipitate acute withdrawal symptoms. Because half-life of naltrexone is between 4 to 6 hours. I believe as short as 4 to 5 half lives 16 - 30 hours should suffice as washout period for opioid using surgical preparation. Longer wash out period of 72 hours would more likely to assure that LDN would not affect opioid medications.Â
Patients with active liver disease should use LDN with caution, as naltrexone is hepatically metabolized. While hepatotoxicity has been reported with standard-dose naltrexone (50–300 mg daily), this has not been observed at the low doses used in LDN therapy. Nonetheless, baseline liver function assessment is prudent in patients with known hepatic pathology.
LDN use during pregnancy and lactation has not been systematically studied, and most clinicians recommend discontinuation during pregnancy unless the benefits clearly outweigh potential risks.
7. Practical Considerations for Clinical Use
7.1 Dosing Protocol
The standard approach to LDN initiation involves gradual dose titration to minimize initial side effects and identify the optimal therapeutic dose for each patient. Most practitioners begin with 0.1 mg to 0.5 mg daily, taken at bedtime, and increase the dose every one to four weeks until reaching the target dose of 4.5 mg daily.
Some patients experience optimal effects at doses below 4.5 mg, while others may benefit from doses up to 6, 9, or 12 mg daily. Individualization based on clinical response and tolerability is critical. Therapeutic effects may not become apparent for four to twelve weeks, necessitating patient education about realistic expectations and the importance of consistent adherence during the trial period.
For patients with particular sensitivity or those with complex conditions such as mast cell activation syndrome, ultra-low-dose initiation strategies may be warranted, starting at doses as low as 0.001 mg or 1 microgram with very gradual titration.
7.2 Accessing LDN
Because LDN is not available as a commercial preparation at the required doses, it must be obtained from a compounding pharmacy. Naltrexone tablets are available in 50 mg strength, but these cannot simply be divided to achieve the low doses required—precise compounding is necessary for accurate dosing.
A valid prescription is required, and healthcare providers should specify the exact dose, formulation (typically immediate-release capsules), and any filler preferences. Some patients report sensitivity to certain compounding fillers, and alternative formulations may be requested if tolerability issues arise.
The LDN Research Trust maintains a directory of compounding pharmacies experienced in preparing LDN, which can be a valuable resource for patients and providers seeking reliable compounding services.
7.3 Working with Healthcare Provider/Support Group
Successful LDN therapy requires collaboration with a healthcare provider knowledgeable about its use. Providers experienced with LDN can offer valuable guidance on dose optimization, management of initial side effects, and integration with other treatment modalities. They can also monitor for efficacy and adjust the treatment plan as needed based on individual response. If unavailable, LDN Support Groups such as LDN Support Group can provide peer support and sharing of personal experiences.
8. Conclusion
In my practice, LDN is a foundation treatment for many conditions - especially neuroinflammation and nerve pain (technically all pain involves nerve for conduction of pain. Low-Dose Naltrexone represents a compelling treatment option for fibromyalgia patients. Its mechanisms of action—targeting neuroinflammation and central sensitization while enhancing endogenous opioid function—means an ideal treatment modality targeting multiple aspects of fibromyalgia.
The clinical evidence, while still evolving, consistently demonstrates meaningful symptom reduction with an exceptionally favorable safety profile. The combination of efficacy, tolerability, non-addictive properties, and low cost positions LDN as an attractive option in the fibromyalgia treatment armamentarium.
Further research, including larger randomized controlled trials and longer-term follow-up studies, will be valuable in more precisely defining LDN's role in fibromyalgia management and identifying which patient subgroups are most likely to benefit. Until such data are available, LDN is a safe and affordable alternative with favorable side effect profile.
9. References
1. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663-672.
2. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529-538.
3. Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines. 2017;5(2):16.
4. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-1555.
5. Loggia ML, Chonde DB, Akeju O, et al. Evidence for brain glial activation in chronic pain patients. Brain. 2015;138(Pt 3):604-615.
6. Albrecht DS, Forber C, Engström M, et al. Brain glial activation in fibromyalgia—a multi-site positron emission tomography investigation. Brain Behav Immun. 2019;75:72-83.
7. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn's disease, and other chronic pain disorders. Pharmacotherapy. 2018;38(3):382-389.
8. LDN Research Trust. Resources and Research. Available at: https://ldnresearchtrust.org. Accessed 2024.
9. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27(37):10000-10006.
10. Toljan K, Vrooman B. Low-dose naltrexone (LDN)—review of therapeutic utilization. Med Sci (Basel). 2018;6(4):82.
Resources:
Yoon Hang Kim MD YouTube Channel
LDN Support Group Website
Support Groups Where Dr. Kim Moderates
Dr. Kim’s Book: 2025 LDN Therapy: LDN plus other tools for healing
Dr. Kim’s paper back book: Low Dose Naltrexone (LDN) Therapy: An Evidence Based Review and Case HistoriesÂ
Various AI Tools are used by Dr. Kim who subscribes to multiple AI platforms including Grok, Claude, Jasper, and AskEasy. Additional AI used include Gemini and OpenEvidence. Dr. Kim’s experience is that all AI platforms are capable of misrepresentation and deception - so, Dr. Kim edits these articles carefully. This article took about 3 hours over the course of two days.
Dr. Kim's Clinic
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.Â
Yoon Hang Kim MD
Integrative & Functional Medicine Physician
Virtual Practice Serving IA, IL, MO, FL, GA, and TX