Low-Dose Naltrexone for Endometriosis Pain: What Do We Actually Know?

Living with endometriosis or adenomyosis often means living with pain that doesn’t behave like “normal” chronic pain, which is most often constant and unremitting. It can flare without warning, persist even after surgery due to comorbid conditions, and come bundled with fatigue, sleep disruption, bowel or bladder discomfort, and nervous-system symptoms that make your whole body feel on high alert. It’s understandable that many patients go looking for options beyond standard hormones, NSAIDs, and repeat procedures—including low dose naltrexone (LDN).

LDN is widely discussed online as a potential anti-inflammatory or “immune-modulating” medication for chronic pain. But what does the research actually say—especially for people with endometriosis and adenomyosis?

Pulling together evidence from multiple recent papers (including scoping reviews, observational pain studies, and small real-world chart reviews/case series in related conditions), the big picture is this: LDN is promising for some types of chronic, centralized (nociplastic) pain and some pelvic pain overlaps, but it has not been proven as an endometriosis/adenomyosis pain-ameliorating treatment per se. If you’re considering it, the most evidence-based approach is to treat it as an experimental, symptom-focused add-on—with careful dose-finding and clear goals.

First: What is low dose naltrexone (LDN)?

Naltrexone at standard doses (often 50 mg) is used as a long term treatment of opioid and alcohol use disorders and is related to Naloxone (Narcan) which is used for emergency reversal of opioid overdose. LDN uses much smaller doses (commonly around 0.5–4.5 mg/day in many protocols, though some reports go higher).

Why would a low dose help pain? Research reviews and mechanistic papers commonly point to two broad ideas:

• Central anti-inflammatory / immunomodulatory effects: LDN is hypothesized to influence neuroinflammation, including pathways involving microglia and receptors such as toll-like receptor 4 (TLR4). This is discussed as a potential reason it could help “centralized” pain conditions where the brain and spinal cord (CNS or central nervous system) is sensitized so much that, in the worse case, even light touch can be perceived as a painful stimulus.
• Effects on pain signaling and possibly immune-cell function: A mechanistic study in another chronic illness population (ME/CFS) reported lab signals in immune cells (NK cells) that the authors interpreted as “restored” ion-channel activity (TRPM3-like currents) among people taking LDN—interesting biology, but not proof of symptom benefit for endometriosis.

For endometriosis/adenomyosis patients, the key point is: these mechanisms are plausible but not confirmed for pelvic disease pain, and they don’t tell us whether or how LDN affects lesions, inflammation in the pelvis, bleeding, fertility, or disease progression.

Does LDN help endometriosis or adenomyosis pain?

The complete current answer: we don’t have direct clinical trials yet.

Across the included research, endometriosis and adenomyosis are not directly studied as target conditions, so we can’t responsibly say LDN “treats endometriosis pain.” In one small case series of people with POTS, endometriosis appeared only as a comorbidity in a single patient—LDN was being tried for dysautonomia symptoms, not pelvic pain.

That said, patients aren’t asking about LDN in a vacuum—they’re asking because their pain often has features of central sensitization (pain amplification by the nervous system), mixed pelvic pain generators (muscle, bladder, vulvar pain), and fatigue/sleep issues. This is where the indirect evidence matters.

Where the indirect evidence is strongest: centralized (nociplastic) pain

A 2023 scoping review looked across dozens of studies of LDN in “centralized pain” conditions (like fibromyalgia, CRPS, diabetic neuropathy, and others). Across that mixed-quality literature, many reports describe improvements in patient-reported pain and sometimes sleep, function, or quality of life, but the authors emphasize that study designs are often small and not consistently rigorous, and dosing/timing vary widely.

Older but influential clinical review work also highlights small placebo-controlled crossover trials in fibromyalgia showing that a meaningful subset of participants improved on LDN—again, not endometriosis data, but it supports the concept that LDN can change pain experience in at least some centralized pain populations.

How this maps to endometriosis/adenomyosis:

Some people with endometriosis develop a “two-layer” pain problem:

1. pain from lesions/inflammation/bleeding, directly and by stimulating the pelvic floor, and
2. pain from a sensitized nervous system that keeps firing even when the original trigger is reduced.

LDN, if it helps at all in endometriosis, may be more likely to help with that second layer (central sensitization features)—but this is still a hypothesis, not a proven indication.

Pelvic pain overlap evidence: vulvodynia (very small, but relevant)

One 2025 case series described three postmenopausal patients with refractory vulvodynia who reported improvement after adding LDN to existing care, with no side effects reported in that tiny sample. Vulvodynia isn’t endometriosis, but many patients live with overlapping pain conditions (pelvic floor myalgia, bladder pain syndrome, vulvar pain, fibromyalgia-like symptoms). This case series supports a real-world clinical reality: some pelvic pain specialists are trialing LDN as an adjunct when standard options haven’t been enough.

Still, it’s crucial to keep the scale in mind: case series can suggest “this might be worth studying,” not “this works.” For a more definitive recommendation with full risk and benefit assessed, clinical trials are required.

What about LDN for fatigue, brain fog, or POTS-like symptoms some patients have?

Some endometriosis patients also report orthostatic intolerance, tachycardia, temperature dysregulation, GI motility issues, or meet criteria for dysautonomia/POTS. Two papers provide limited real-world data here:

• A small 6-patient POTS case series reported that about half subjectively felt some symptom improvement, while others discontinued for lack of benefit or had no documented change—with no side effects recorded in those charts.
• A 29-patient dysautonomia chart review found mixed pain outcomes (roughly a quarter improved, some had no change, some worsened, and many had missing documentation). Importantly, average autonomic symptom scores (COMPASS-31) did not significantly improve at the group level. Mild side effects were reported in a minority (including insomnia, nausea, migraines, brain fog, nightmares).

What this means for endometriosis patients: if you’re considering LDN mainly for fatigue or autonomic symptoms, the best available evidence in dysautonomia populations suggests results are inconsistent, and group-level improvement isn’t clearly demonstrated in real-world datasets. It may help some individuals, but it should not be assumed to be a reliable “POTS fix.”

Dosing: why “one-size-fits-all” may backfire

One of the most practically useful findings for patients is that effective dosing appears highly individual.

A 2024 observational study in people with nociplastic (centralized) musculoskeletal pain reported that “maximally effective doses” varied widely—from 0.1 mg to about 5.6 mg/day—and many people’s best dose was 2 mg/day or less. The authors describe patterns consistent with “hormesis,” meaning a person might feel better at one dose but worse at a higher dose. That is a big deal for patients who try 4.5 mg, feel worse, and conclude LDN “failed”—it may have been the wrong dose for them (though we still can’t rule out placebo/nocebo effects in uncontrolled studies).

Across the broader literature, 4.5 mg daily is commonly mentioned, but the scoping review emphasizes that dosing and response timing are variable and not standardized.

Practical implication: If you and your clinician decide to trial LDN for endometriosis-related chronic pain symptoms (again: off-label, unproven), the evidence leans toward slow upward titration and individualized dosing, rather than jumping straight to a fixed dose and calling it quits quickly.

Timeline: when would you expect to know if it’s helping?

LDN is not typically described as an instant painkiller. Clinical review work in fibromyalgia suggests that separating LDN benefit from placebo early on can be hard, and that some people may need several weeks, with around 2 months sometimes used as a practical window to judge effect in research contexts.

Real-world follow-up intervals in dysautonomia chart reviews were often 3–9 months, but documentation was incomplete and outcomes mixed—so this doesn’t give a clean “you’ll know by X weeks” rule.

A reasonable, patient-centered expectation (to discuss with your clinician): a structured trial long enough to assess change (often weeks to a couple of months), with symptom tracking and a plan for dose adjustments.

Side effects and safety: “generally tolerated” isn’t the same as “risk-free”

Across studies summarized in the scoping review, side effects were often described as mild, with commonly noted issues like vivid dreams, insomnia, headache, nausea, diarrhea. The dysautonomia chart review similarly reported mild effects in a minority (including insomnia/nightmares and brain fog).

Small case series in POTS and vulvodynia reported no side effects, but those sample sizes are too small to provide reassurance about uncommon problems. Again, to get good assurances about side effects and risks, clinical trials are required which look at the safety profile of various doses.

The biggest practical safety issue: opioids

A recurring caution in the clinical review literature is that LDN studies commonly exclude people taking opioid pain medication, and there has historically been uncertainty about co-administration in low-dose ranges. Because naltrexone blocks opioid receptors, combining it with opioids can reduce opioid pain control or precipitate withdrawal depending on circumstances.

If you use any opioid medication (even intermittently), this needs explicit, clinician-led planning.

Who might be most likely to consider (or benefit from) LDN?

Because we don’t have endometriosis trials, it is not possible to give strong “best candidate” rules or even guidance. But the combined evidence suggests LDN is most often considered when:

• Pain looks centralized/nociplastic (widespread pain, sleep disturbance, heightened sensitivity, disproportionate pain amplification)
• There are overlapping pain syndromes (fibromyalgia-like features, vulvar pain, bladder pain syndrome, pelvic floor myalgia)
• Standard therapies haven’t provided enough relief and you’re looking for a symptom-modulating add-on, not a cure

Also, if your main goal is actually treating endo by shrinking or excising lesions, improving fertility, or controlling heavy bleeding, the current evidence base does not support LDN as a primary strategy.

Practical takeaways (how to have an evidence-based conversation)

• “What symptom are we targeting?” (daily pelvic pain, flares, sleep, fatigue, vulvar pain, etc.) and how will we measure it? Consider a simple baseline and follow-up score (pain interference, sleep quality, days missed, flare frequency).
• “What dosing strategy will we use?” The chronic pain observational evidence supports individualized dosing; ask about starting low and titrating slowly rather than assuming 4.5 mg is “the dose.”
• “What’s our stop rule?” Decide in advance what counts as meaningful improvement and by when, and what side effects would prompt stopping.
• “Is it compatible with my current meds—especially opioids?” This is essential.
• “What else should we treat at the same time?” Pelvic pain is often multi-factorial; LDN (if tried) is usually an adjunct, not a replacement for pelvic floor therapy, targeted hormonal management (when appropriate), or treatment of bladder/vulvar contributors.

What we still don’t know and why results vary so much

The evidence base summarized here has a consistent limitation: most data are based on very small series, uncontrolled, and not specific to endometriosis/adenomyosis. That creates several uncertainties:

We don’t know:

• Whether LDN helps endometriosis or adenomyosis pain specifically, compared with placebo
• Whether it helps particular subgroups (deep infiltrating disease, post-surgical persistent pain, adenomyosis-heavy bleeding patterns, etc.)
• Optimal dosing for pelvic pain (including whether higher doses help some people, as a vulvodynia case series and broader dosing discussions suggest)
• Long-term safety and sustained benefit in pelvic pain populations
• Whether symptom improvement (when it happens) reflects reduced neuroinflammation, altered pain processing, placebo effects, regression to the mean, or changes in other simultaneous treatments

The mixed results in dysautonomia chart reviews—and the variability seen across patient-reported outcome measures in small series—also underline an important truth for patients: some people feel noticeably better, some feel nothing, and some feel worse, and current research evidence can’t yet predict which group you’ll fall into.

If you’re considering low dose naltrexone for endometriosis or adenomyosis, the most evidence-aligned approach today is to treat it as an individualized, monitored trial aimed at symptom modulation—while keeping expectations realistic and continuing to address the underlying drivers of pelvic pain with a comprehensive plan.