Hailey–Hailey disease (familial benign pemphigus) is a chronic, relapsing inflammatory skin condition that can cause painful erosions, fissuring, and recurrent flares, particularly in areas exposed to heat, sweating, and friction. Symptoms can be persistent and may have a significant impact on comfort, daily activities, and quality of life.
Management typically focuses on reducing triggers, protecting the skin barrier, and treating secondary infection or inflammation when present. However, some patients experience ongoing or treatment-refractory disease despite standard measures. In this context, low-dose naltrexone (LDN) has been reported as an off-label option in a small number of case reports and case series.
This article reviews the available clinical evidence for LDN in Hailey–Hailey disease, outlines the dosing ranges described in the literature, and summarises practical considerations for use, including limitations of the evidence base and key safety points.
5 key takeaways (LDN in Hailey–Hailey disease)
- Evidence is limited but promising. The published support for LDN in Hailey–Hailey disease is mainly small case reports and case series, not large clinical trials.
- It’s used off-label, usually for refractory disease. LDN is generally considered when standard approaches (trigger control, barrier care, topical therapies, infection management) have not been enough.
- Responses can be quick in reports. Several cases describe improvement within days to a couple of weeks, with more substantial clearing over weeks, although this is not guaranteed.
- Doses vary and there’s no agreed “best” dose. Reports include roughly 1.5–6 mg daily, with some cases describing benefit only at higher doses. This means dosing often needs careful, individual titration.
- Relapse after stopping can happen. Some reports describe flares when LDN is discontinued and improvement again when restarted, suggesting ongoing treatment may be needed for maintenance in some patients.
Can LDN be used in Hailey Hailey Disease, what does the evidence say?
Low-dose naltrexone (LDN) has a plausible but still preliminary role in Hailey–Hailey disease (HHD), mainly as an off-label option for refractory disease. The direct evidence consists of small uncontrolled case series and case reports rather than randomised comparative trials. In the earliest 2017 case series, three patients with severe HHD received 3 mg nightly, with two titrated to 4.5 mg; all improved within 1–2 weeks and had clinical resolution within two months. Disease flared after discontinuation and cleared again within 2–3 days after restarting LDN, which supports a treatment effect but does not exclude placebo effects, regression to the mean, or the influence of concurrent care. [1]
What do the reports say?
Other reports point in the same direction. A separate three-patient series using 1.5–3 mg/day reported at least 80% improvement in disease extent in every patient, 90% clearance in one, improved quality of life, and no recorded adverse effects. [2] A 66-year-old woman with biopsy-confirmed, treatment-refractory HHD achieved complete clearing six weeks after starting 6.25 mg nightly. [3] A 2025 three-patient series started at 3 mg/day and titrated to 6 mg/day over eight weeks; all three had resolution of erosions or ulcerations, less pain and erythema, and no flare during four months of follow-up. [4] These findings are encouraging, but the sample sizes are very small, outcomes are mostly clinical and unblinded, and the patients were selected for difficult-to-treat disease.
What dose should be used?
Dose and durability remain uncertain. Published responses have occurred at approximately 1.5–6.25 mg/day, while a dosing-focused report argues that some patients may require higher doses; it cites 95% skin improvement only at 9 mg/day in one prior patient and successful treatment with 12.5 or 50 mg in other reports. This heterogeneity means there is no validated HHD-specific dose or established dose–response relationship. [5] Relapse after stopping treatment has been reported, and long-term safety data in HHD are lacking; in one case, remission after 5 mg/day was lost when LDN was stopped but returned on restarting, while a topical ketamine/diphenhydramine regimen permitted withdrawal of LDN with remission maintained for four months. [6]
The proposed mechanism of action
The proposed rationale is that transient opioid-receptor blockade may increase endogenous opioid signalling, while Toll-like receptor 4 antagonism may reduce inflammatory signalling; authors have hypothesised downstream effects on calcium mobilisation, keratinocyte differentiation, and wound healing. These mechanisms remain theoretical in HHD, not clinically validated. [1], [7]
Summary
In practice, LDN is best considered an experimental adjunct or alternative for selected patients whose disease remains refractory to standard measures, with explicit discussion of uncertain efficacy, compounded-drug access, possible relapse on withdrawal, and the absence of long-term HHD safety evidence. It should not replace management of friction, sweating, infection, and other recognised flare triggers; one refractory case series noted that repeated friction and sweating could impair treatment response. [8]
Compounding at Courier
When the standard option isn’t the right fit, we can make one to order
Courier is a compounding pharmacy. Where a prescriber decides it’s appropriate for you, we can prepare bespoke, made-to-order preparations — tailored to the individual, under full clinical governance. It’s the same principle that runs through everything we do.
References
[1] L. N. Albers, J. Arbiser, and R. Feldman, “Treatment of hailey-hailey disease with low-dose naltrexone,” JAMA dermatology, 2017, doi: 10.1001/jamadermatol.2017.2446.
[2] O. Ibrahim, S. Hogan, A. Vij, and A. P. Fernandez, “Low-dose naltrexone treatment of familial benign pemphigus (Hailey-Hailey disease),” JAMA Dermatology, 2017, doi: 10.1001/jamadermatol.2017.2445.
[3] M. G. Cantero, M. C. Martín, Á. A. García, D. Ruíz-Sánchez, J. Valtueña, and P. M. López, “Use of low?dose naltrexone in the treatment of severe Hailey–Hailey disease: One case report,” Dermatologic Therapy, 2019, doi: 10.1111/dth.12892.
[4] G. B. Gavali, H. Khatri, and S. Agrawal, “Low-dose naltrexone therapy in recalcitrant hailey-hailey disease,” Indian Journal of Postgraduate Dermatology, 2025, doi: 10.25259/ijpgd\_113\_2024.
[5] C. Grolleau et al., “The importance of dosage for naltrexone treatment in hailey-hailey disease,” JAAD Case Reports, 2022, doi: 10.1016/j.jdcr.2021.11.036.
[6] S. Sonthalia, M. Agrawal, A. Talwar, and M. Goldust, “Low-dose naltrexone-induced remission in hailey–hailey disease maintained in remission with topical combination of ketamine and diphenhydramine,” Indian Dermatology Online Journal, 2019, doi: 10.4103/idoj.IDOJ\_453\_18.
[7] K. Toljan and B. Vrooman, “Low-dose naltrexone (LDN)—review of therapeutic utilization,” Medical Sciences, 2018, doi: 10.3390/medsci6040082.
[8] F. Alamon?Reig, L. Serra-García, X. Bosch-Amate, C. R.-M. Loughlin, and J. Mascaró, “Dupilumab in hailey?hailey disease: A case series,” Journal of the European Academy of Dermatology and Venereology, 2022, doi: 10.1111/jdv.18350.
