Edited by Yoon Hang "John" Kim, MD, MPH

Board-Certified Integrative Medicine Physician

Ehlers-Danlos Syndrome (EDS), particularly the hypermobile subtype (hEDS), presents one of the most challenging chronic pain conditions in clinical practice. Patients often experience diffuse, symmetrical musculoskeletal pain that responds poorly to conventional analgesics. As an integrative medicine physician who has worked extensively with low-dose naltrexone (LDN) therapy, I am frequently asked about its potential role in managing EDS-related pain. This article examines what the current evidence tells us about this promising but still emerging treatment option.

Understanding the Evidence Landscape

It is important to acknowledge upfront that we do not yet have randomized controlled trials specifically examining LDN in EDS populations. What we do have is observational data from chronic pain cohorts enriched with hEDS patients, combined with broader evidence from centralized pain conditions and rheumatologic diseases that share pathophysiological features with EDS-related pain (Hatfield et al., 2024; Mathieson et al., 2023).

The most directly relevant study comes from a 2024 observational analysis published in Pain Medicine, which examined LDN dosing in a chronic pain cohort where hEDS patients represented a key subgroup. Of 385 charts reviewed, 260 patients with chronic diffuse, symmetrical pain underwent LDN titration, with 41 meeting strict inclusion criteria for outcome analysis using validated measures including the Brief Pain Inventory (BPI) and PROMIS domains (Hatfield et al., 2024).

What the hEDS-Enriched Data Shows

Several important findings emerged from this work that are directly relevant to clinical practice with EDS patients.

Highly Variable Dose-Response

Maximally effective doses ranged dramatically from 0.1 to 6.0 mg daily. The calculated ED50 (dose producing 50% of maximum effect) was approximately 3.9 mg, with ED95 around 5.4 mg. However, response was highly idiosyncratic—only 11 of 25 dose-analyzable patients met criteria as "responders" (Hatfield et al., 2024). This underscores why a one-size-fits-all approach to LDN dosing fails many patients.

hEDS Patients Show Unique Patterns

While hEDS patients did not differ significantly in their maximally effective doses compared to non-EDS chronic pain patients, they tended to present with more multiorgan dysfunction and showed less improvement in some PROMIS functional domains even when pain intensity improved on BPI measures (Hatfield et al., 2024). This suggests that addressing pain alone may not fully capture the treatment benefit—or limitations—in this complex population.

Hormetic Dose-Response Pattern

The data reveals what appears to be a hormetic response pattern: some hEDS patients achieve optimal benefit at ultra-low doses (1-2 mg or even lower), while others require doses closer to 4-5 mg. This reinforces the critical importance of slow, individualized titration rather than declaring treatment failure after a single fixed-dose trial (Ehlers-Danlos Society, 2024).

Supporting Evidence from Related Conditions

While EDS-specific RCTs are lacking, there is a substantial body of evidence supporting LDN use in conditions that share pathophysiological mechanisms with EDS-related pain.

A comprehensive scoping review of LDN for non-cancer centralized pain conditions—including fibromyalgia and complex regional pain syndrome—found consistent signals for reduced pain and improved well-being with a generally favorable safety profile (Mathieson et al., 2023). Given the significant overlap between nociplastic pain mechanisms in these conditions and EDS, this evidence provides reasonable support for extrapolation.

A 2025 real-world chronic pain cohort study reported subjective symptom relief in approximately 54% of patients, with pain and fatigue being the most commonly improved symptoms. Tolerability was good, with rare discontinuations due to side effects (Butera et al., 2025).

In rheumatologic diseases—including fibromyalgia, Sjögren's syndrome, rheumatoid arthritis, scleroderma, and dermatomyositis—LDN has demonstrated improvements in pain scores, global symptoms, and in some cases allowed reduction in NSAIDs and DMARDs, again with few serious adverse effects (Toljan & Vrooman, 2023).

Mechanistic Rationale for EDS

The theoretical basis for LDN in EDS pain involves two primary mechanisms that are particularly relevant to the condition's pathophysiology.

Analgesic effect via endogenous opioid upregulation: Transient opioid receptor blockade at low doses triggers a rebound upregulation of endogenous opioids (endorphins, enkephalins) and their receptors. This enhanced endogenous opioid tone may help modulate the chronic pain signaling characteristic of EDS (Toljan & Vrooman, 2023).

Anti-inflammatory and neuroimmune modulation: LDN blocks Toll-like receptor 4 (TLR4) on microglia and possibly peripheral immune cells. This dampens cytokine-driven central sensitization, fatigue, and mood symptoms that commonly accompany EDS. This mechanism may be particularly relevant for the subset of EDS patients who also experience mast cell activation-related symptoms (Hatfield et al., 2024; Toljan & Vrooman, 2023).

The EDS-MCAS-POTS Connection

Many hEDS patients present with the well-recognized triad of EDS, mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS). This overlap is clinically significant when considering LDN therapy.

In the 2024 chronic pain study, hEDS patients frequently exhibited mast cell-related pruritus and multiorgan dysfunction. The authors noted prior case series where LDN reduced pruritus associated with mast cell activation, suggesting potential benefit beyond pain relief for this phenotypic cluster (Hatfield et al., 2024).

Clinical experience reports from pain clinics and the LDN Research Trust describe LDN helping subgroups of patients with the EDS-POTS-MCAS triad, particularly with diffuse pain, fatigue, sleep disturbances, and symptom flares. However, these remain observational reports rather than controlled trials (Pain RI, 2024).

Practical Dosing Considerations for EDS Patients

Based on the available evidence and clinical experience, several dosing principles emerge for LDN use in EDS populations.

Start low and go slow: Expert practice reports describe starting as low as 0.1 mg in EDS/MCAS patients and titrating slowly (every 1-2 weeks). A significant fraction of these patients are dose-sensitive and may actually worsen at conventional 4.5 mg starting doses (Pain RI, 2024).

Expect individual variation: The observational data shows maximally effective doses ranging from 0.1 to 6.0 mg daily. Many chronic pain patients cluster around 3-5 mg, but a substantial minority benefit at doses of 2 mg or below (Hatfield et al., 2024).

Avoid premature discontinuation: The hormetic dose-response pattern means that patients who fail to respond at one dose may respond at a different (sometimes lower) dose. A single fixed-dose trial should not be considered definitive.

Monitor broadly: Given that hEDS patients may show improvement in pain intensity without corresponding functional improvement, monitoring should include quality of life measures, sleep, fatigue, and other symptoms beyond pain scores alone.

Safety Profile

Across rheumatology and chronic pain series, LDN demonstrates consistent tolerability with mostly minor side effects. The most commonly reported include vivid dreams, transient sleep disturbance, and mild GI symptoms. Serious adverse events are rare (Toljan & Vrooman, 2023; Butera et al., 2025). This favorable safety profile makes LDN an attractive option for the chronic, long-term management that EDS patients typically require.

How to Position LDN in EDS Management

Given the current evidence, LDN should be positioned as an adjunctive, off-label treatment option for EDS-related chronic pain. The strength of evidence remains observational, without EDS-specific RCTs. However, the combination of the hEDS-enriched chronic pain data, supporting evidence from related centralized pain conditions, plausible mechanisms, favorable safety profile, and clinical experience reports provides reasonable justification for considering LDN in appropriate patients.

The best-supported outcomes include reduction in diffuse nociplastic pain and some improvement in function and quality of life, with additional possible benefits in fatigue, sleep, mood, and mast cell-linked pruritus for a subset of patients (Hatfield et al., 2024; Mathieson et al., 2023).

Patients should understand that while LDN can be helpful for many, response is not universal—roughly half of patients in real-world cohorts experience meaningful benefit. The individualized titration process requires patience and close follow-up, but the low risk profile makes this investment reasonable for many EDS patients struggling with inadequate pain control.

Conclusion

Low-dose naltrexone represents a promising tool in our limited armamentarium for EDS-related chronic pain. While we await definitive RCT evidence, the existing observational data—particularly from hEDS-enriched cohorts—combined with mechanistic plausibility and an excellent safety profile, supports its consideration as part of a comprehensive integrative approach to this challenging condition. The key lies in individualized dosing, patient expectations management, and recognition that LDN is one component of what typically needs to be a multimodal treatment strategy.

References

Butera, K. A., et al. (2025). Real-world effectiveness and tolerability of low-dose naltrexone to treat chronic pain. Journal of Pain Research, 18. https://doi.org/10.2147/JPR.S500969

Ehlers-Danlos Society. (2024). Effective doses of low-dose naltrexone for chronic pain: An observational study. Retrieved from https://www.ehlers-danlos.com/effective-doses-of-low-dose-naltrexone-for-chronic-pain-an-observational-study/

Hatfield, E., Phillips, K., & Swidan, S. (2024). Effective doses of low-dose naltrexone for chronic pain: An observational study. Pain Medicine, 25(4), 267-277. https://doi.org/10.1093/pm/pnae005

Mathieson, S., et al. (2023). Low-dose naltrexone for the treatment of chronic non-cancer pain: A scoping review. Pain Medicine, 24(11), 1270-1281. https://doi.org/10.1093/pm/pnad086

Pain RI. (2024). LDN (low-dose naltrexone) may help with Ehlers-Danlos Syndrome (EDS). Retrieved from https://www.painri.com/post/ldn-low-dose-naltrexone-may-help-with-ehlers-danlos-syndrome-eds

Toljan, K., & Vrooman, B. (2023). Low-dose naltrexone (LDN): Review of therapeutic utilization in rheumatologic diseases. Journal of Clinical Rheumatology, 29(4), 218-226. https://doi.org/10.1097/RHU.0000000000001915

About the Editor

Yoon Hang "John" Kim, MD, MPH is a board-certified integrative medicine physician with over 20 years of clinical experience. He completed his integrative medicine fellowship at the University of Arizona under Dr. Andrew Weil and holds certifications in preventive medicine, medical acupuncture, and integrative/holistic medicine.

Dr. Kim is a recognized expert in Low-Dose Naltrexone (LDN) therapy, having authored three books and more than 20 articles on the subject. He leads the LDN Support Group, a community of over 7,000 members, and has presented at LDN Research Trust conferences on the clinical applications of this therapy for autoimmune conditions, chronic pain, and integrative oncology.

He operates Direct Integrative Care, a membership-based telemedicine practice deliberately capped at 99 patients to ensure personalized, root-cause–focused care. His practice serves patients across Iowa, Illinois, Missouri, Texas, Georgia, and Florida, specializing in complex conditions including fibromyalgia, chronic fatigue, MCAS, and mold toxicity.

Learn more:

US Practice: www.directintegrativecare.com

Education and Consulting: www.yoonhangkim.com

Disclaimer: This article is for educational purposes only and does not constitute medical advice. LDN is an off-label treatment that should only be used under the supervision of a qualified healthcare provider. Individual responses to treatment vary, and decisions about therapy should be made in consultation with your physician based on your specific clinical circumstances.