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When Low-Dose Naltrexone Does Not Work: A Clinical Perspective on Optimizing LDN Therapy

When LDN does not work Yoon Hang Kim MD

By Yoon Hang Kim, MD, MPHDirect Integrative Carewww.directintegrativecare.com

Introduction

Low-dose naltrexone (LDN) has emerged as a promising therapeutic option for numerous chronic conditions, from fibromyalgia and chronic pain to autoimmune disorders and mast cell activation syndrome. As a physician who has been prescribing LDN for over two decades and has presented at multiple LDN Research Trust conferences, I have witnessed its remarkable benefits in many patients. However, I have also observed a clinical reality that warrants honest discussion: approximately one-third of patients do not respond to standard LDN therapy.

This observation aligns with published literature showing response rates typically ranging from 57-65% in various chronic pain populations (Kim et al., 2023; Younger et al., 2013). Understanding why LDN fails—and what to do about it—is crucial for clinicians seeking to optimize outcomes for their patients.

Understanding the LDN Response Spectrum

In my clinical experience, patients fall into three distinct categories when it comes to LDN therapy:

Category 1: LDN as Sufficient Therapy

For some patients, LDN alone produces profound and sustained improvement. These patients typically have:

  • Adequate baseline endorphin reserves

  • Moderate disease severity

  • Conditions primarily driven by neuroinflammation or immune dysregulation

  • Good overall functional capacity

Research supports that LDN can be highly effective as monotherapy in conditions like fibromyalgia, where studies have demonstrated a 28.8% reduction in pain compared to 18% with placebo (Younger et al., 2013). A retrospective analysis from Mayo Clinic found that 65% of patients taking LDN for chronic pain reported perceived benefit (Toljan & Vrooman, 2018).

Category 2: LDN as Necessary but Not Sufficient

In complex cases, LDN plays a vital role but cannot achieve remission on its own. These conditions include:

  • Mold toxicity and chronic inflammatory response syndrome (CIRS)

  • Cancer

  • Mast cell activation syndrome (MCAS)

  • Long COVID

  • Complex regional pain syndrome (CRPS)

  • Chronic Lyme disease

For these patients, LDN serves as one critical component of a multimodal treatment strategy. As noted by researchers studying MCAS, LDN does not target the root cause directly but "can calm the immune system enough to make deeper treatment more successful and better tolerated" (Restorative Medicine Center, 2024).

Category 3: Non-Responders

Some patients simply do not respond to LDN at any dose. This may relate to:

  • Severely depleted endorphin reserves

  • Genetic variations in opioid receptor function

  • Conditions not primarily mediated by the pathways LDN modulates

  • Co-existing factors that override LDN's mechanisms

The Clinical Approach: Assessing Endorphin Reserve

My clinical approach begins with estimating a patient's endorphin reserve by assessing their functional capacity in everyday life. This concept is fundamental to personalizing LDN therapy.

Assessment Questions I Consider:

  1. Duration of illness: How long have they been sick?

  2. Sleep quality: Do they achieve restorative sleep?

  3. Energy levels: What is their baseline energy throughout the day?

  4. Resilience: How quickly do they recover from setbacks?

  5. Functional capacity: Can they work, exercise, or perform daily activities?

Patients with severely depleted endorphin reserves—those who are very ill or have very low functional capacity—require a different approach than the standard 4.5 mg dosing.

Dosing Strategies for Challenging Cases

Starting Low: Microgram Dosing

For patients who are very ill, have low functional capacity, or are children, I advocate for starting at significantly lower doses than the conventional 1.5-4.5 mg range. This approach is sometimes called ultra-low-dose naltrexone (ULDN) or very-low-dose naltrexone (VLDN).

The LDN Research Trust's dosing guidelines recognize three categories (LDN Research Trust, 2024):

  • Ultra-low dose: Microgram dosing (1-2 mcg)

  • Very-low dose: 0.1-0.5 mg daily

  • Low dose: 1-4.5 mg (sometimes up to 10 mg)

My 2018 presentation at the LDN Research Trust Conference detailed the rationale for microgram dosing, explaining that at 1 microgram, naltrexone binds to opioid receptors but is not likely to overwhelm the system, potentially acting as a weak agonist through the phenomenon of hormesis—where a substance acts as an inhibitor at high concentrations but as a stimulator at lower concentrations (Kim, 2018).

The Nanogram Option

For patients who cannot tolerate even microgram doses, there are options to dilute further to nanogram ranges. These preparations are not typically available from pharmacies and require specialized compounding or self-dilution protocols. While clinical evidence at this dose range is limited, some highly sensitive patients have reported benefit.

Titration Protocol for Sensitive Patients

For sensitive patients, I recommend:

  • Start at 0.5-1 mg (or lower if indicated)

  • Increase slowly over extended periods

  • Some patients may need 2-week intervals between dose increases

  • Others may require 4-week intervals

  • The most sensitive patients may need 3-month intervals between adjustments

This contrasts with typical protocols that escalate to 4.5 mg within 2-4 weeks. Patience is essential.

When Standard LDN Fails: Alternative Strategies

Strategy 1: Higher-Dose Naltrexone for Neuropathy

If there is no response to standard LDN dosing, especially in neuropathic pain conditions, I consider:

  1. Adding ketosis support (ketogenic diet or exogenous ketones)

  2. Increasing the dose to 25 mg or even up to 45 mg

This higher-dose approach moves into "moderate-dose" territory and may work through different mechanisms than traditional LDN. A dose-response study found that the effective dose in 95% of fibromyalgia patients (ED95) was 5.40 mg, with some patients benefiting from doses up to 6 mg (Bruun et al., 2021). However, clinical experience suggests some neuropathy patients respond to even higher doses.

The rationale for combining with ketosis relates to the metabolic and anti-inflammatory effects of ketone bodies, which may synergize with naltrexone's mechanisms in neuropathic conditions.

Strategy 2: MCAS Protocol Enhancement

For complex conditions like mast cell activation syndrome (MCAS), I consider adding:

  1. Ketotifen (1-2 mg at bedtime, increasing as tolerated)

  2. Cromolyn sodium (mast cell stabilizer)

  3. Methylene blue combined with ketosis

The Role of Ketotifen and Cromolyn

Ketotifen is an oral mast cell stabilizer that inhibits the release of histamine, tryptase, and various prostaglandins from mast cells. It reduces antigen-induced mast cell degranulation and stabilizes calcium permeability in mast cell membranes (Rosenberg, 2022). Combined with cromolyn sodium, which works by inhibiting immediate and late-phase mast cell release, these medications can significantly improve MCAS symptoms including urticaria, nausea, diarrhea, and neurological manifestations.

A landmark case study published in BMJ Case Reports demonstrated dramatic improvement in a patient with severe POTS and MCAS using a combination of LDN, intravenous immunoglobulin, and treatment of underlying small intestinal bacterial overgrowth (Weinstock et al., 2018).

Methylene Blue and Mitochondrial Support

Methylene blue has gained attention for its ability to enhance mitochondrial function by acting as an alternative electron carrier in the electron transport chain. It can increase ATP production, reduce oxidative stress, and decrease neuroinflammation (Yang et al., 2017). For patients with chronic fatigue, MCAS, or conditions involving mitochondrial dysfunction, methylene blue combined with ketosis may provide synergistic benefits that support overall healing alongside LDN.

The Role of the Integrative Medicine Specialist

There is a clear role for physicians who are well-versed in both LDN therapy and functional medicine to assist patients with complex conditions. Standard primary care providers may not have the experience to:

  • Properly assess endorphin reserve

  • Navigate non-standard dosing protocols

  • Integrate complementary therapies

  • Recognize when LDN is necessary but not sufficient

  • Troubleshoot treatment failures

As the LDN Research Trust notes, "Low Dose Naltrexone has been studied extensively since 1985. There are well over 900-950 articles, scientific papers, research papers, clinical abstracts, and double-blind studies done on Low Dose Naltrexone" (LDN Research Trust, 2024). Yet this wealth of information is not typically taught in medical schools or mainstream continuing education programs, leaving many patients without access to knowledgeable prescribers.

Practical Recommendations Summary

Scenario

Recommended Approach

Standard patient, moderate illness

Start 1.5 mg, titrate to 4.5 mg over 2-4 weeks

Severely ill / low functional capacity

Start 0.5 mg or lower; titrate every 2-4 weeks

Children

Microgram dosing; very slow titration

Extreme sensitivity

Consider nanogram ranges; titrate every 1-3 months

Side effects at low doses

Drop to lower dose; slower titration

Non-response in neuropathy

Consider higher doses (up to 25-45 mg) + ketosis

Complex MCAS

Add ketotifen, cromolyn, consider methylene blue + ketosis

Treatment-resistant cases

Comprehensive functional medicine workup

Conclusion

LDN is a powerful tool in the integrative medicine toolkit, but it is not a universal solution. Approximately one-third of patients will not respond to standard protocols, and recognizing this reality is the first step toward better outcomes. By carefully assessing each patient's endorphin reserve, tailoring dosing strategies, and integrating complementary approaches when needed, we can optimize results and offer hope even to patients with treatment-resistant conditions.

The key is individualization. There is no one-size-fits-all approach to LDN therapy. Whether it means starting at microgram doses for the severely depleted patient or pushing to higher doses for refractory neuropathy, the clinician must be willing to think beyond standard protocols while remaining grounded in the science.

For patients struggling with complex chronic conditions, working with a physician experienced in LDN and functional medicine can make the difference between treatment failure and meaningful improvement.




References

Bruun, K. D., Christensen, R., Amris, K., Vaegter, H. B., & Toft, E. (2021). Low-dose naltrexone for the treatment of fibromyalgia: Protocol for a double-blind, randomized, placebo-controlled trial. Trials, 22(1), 804. https://pmc.ncbi.nlm.nih.gov/articles/PMC8591911/

Kim, Y. H. (2018). Ultra low dose naltrexone, micro dosing [Conference presentation]. LDN Research Trust 2018 Conference. https://ldnresearchtrust.org/dr-john-kim%E2%80%99s-presentation-ultra-low-dose-naltrexone-uldn-and-micro-dosing-ldn-2018-conference

LDN Research Trust. (2024). Dosing information for prescribers. https://ldnresearchtrust.org/sites/default/files/2024-02/Dosing-Guide-2024_0.pdf

LDN Research Trust. (2024). Why are so many doctors resistant to low dose naltrexone? https://ldnresearchtrust.org/why-are-so-many-doctors-resistant-low-dose-naltrexone-ldn

Rosenberg, S. (2022). Ketotifen: How it works and its uses in your practice. Oregon Association of Naturopathic Physicians. https://www.mcmc-research.com/post/low-dose-naltrexone-and-mcas-treatment

Takkouche, B. W., Rahimi, A., & Younger, J. (2018). Low-dose naltrexone (LDN)—Review of therapeutic utilization. Medical Sciences, 6(4), 82. https://pmc.ncbi.nlm.nih.gov/articles/PMC6313374/

Toljan, K., & Vrooman, B. (2023). Efficacy of low-dose naltrexone and predictors of treatment success or discontinuation in fibromyalgia and other chronic pain conditions: A fourteen-year, enterprise-wide retrospective analysis. Biomedicines, 11(4), 1087. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10135963/

Weinstock, L. B., Brook, J. B., Myers, T. L., & Goodman, B. (2018). Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Reports, 2018, bcr2017221405. https://pmc.ncbi.nlm.nih.gov/articles/PMC5778345/

Yang, S. H., Li, W., Sumien, N., Forster, M., Bhatti, I. K., Bhatti, M. T., & McCord, J. M. (2017). Mitochondria as a target for neuroprotection: Role of methylene blue and photobiomodulation. Translational Neurodegeneration, 9(1), 19. https://link.springer.com/article/10.1186/s40035-020-00197-z

Yang, J., Shin, K. M., Do, A., Bierle, D. M., Abu Dabrh, A. M., Yin, Z., Bauer, B. A., & Mohabbat, A. B. (2023). The safety and efficacy of low-dose naltrexone in patients with fibromyalgia: A systematic review. Journal of Pain Research, 16, 1017-1023. https://pmc.ncbi.nlm.nih.gov/articles/PMC10039621/

Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). 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 & Rheumatism, 65(2), 529-538. https://pubmed.ncbi.nlm.nih.gov/23359310/

Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451-459. https://pmc.ncbi.nlm.nih.gov/articles/PMC3962576/

Additional Resources

Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting or modifying any treatment regimen.

About the Author

Yoon Hang Kim, MD, MPH is a board-certified physician specializing in integrative and functional medicine. A graduate of Dr. Andrew Weil's Integrative Medicine Fellowship at the University of Arizona, Dr. Kim has been practicing integrative medicine since 1999. He is recognized internationally as an expert in LDN therapy and has presented at multiple LDN Research Trust conferences. Dr. Kim practices telemedicine through Direct Integrative Care, serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

Yoon Hang Kim MD MPH Integrative & Functional Medicine Expert


 
 
 

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