Hailey–Hailey disease (HHD) is a rare autosomal dominant skin disorder caused by mutations in the ATP2C1 gene 1. It presents as a painful, recurrent blistering disease that severely impacts quality of life. Conventional therapies often provide inadequate relief, prompting patients to seek alternatives. Use of low-dose naltrexone (LDN) became popularized on social media platforms through patient success stories, with subsequent case reports and small case series further supporting use of the treatment for HHD 2. We conducted a focused literature review to assess the current evidence on the use of LDN in HHD. A comprehensive search of PubMed, Embase, and Scopus was performed on May 20, 2025. Search terms included: (“Hailey–Hailey disease” OR “Hailey Hailey disease” OR “benign familial pemphigus” OR “familial benign pemphigus” OR “Hailey disease”) AND (“naltrexone”), identifying 53 published cases that met inclusion criteria (Supplementary Table available via Mendeley, doi: 10.17632/6xz5sjpyg4.1). The mean age of patients was 54.5 ± 13.6 years, with a female predominance (n = 35, 66.0%). Among these, 37 of 53 patients had an initial LDN dose ≤ 4.5 mg/day. Most patients achieved improved response (n = 46, 86.8%). No response was observed in 7 patients (13.2%). Most patients remained stable during follow-up (n = 30, 57.7%), while 16 patients (30.8%) experienced relapse and 6 patients (11.5%) discontinued treatment (Table 1). Logistic regression analysis showed no significant association between initial dose and response (odds ratio OR = 1.33, p = 0.389) after adjusting for patients' age, gender, and disease severity, while higher maximum doses showed a negative association with clinical clearance (OR = 0.908, p = 0.044). Disease severity was quantified by affected body surface area and the Dermatology Life Quality Index (DLQI), which was only available in 28 patients. Adverse events were rare (n = 8, 15.1%) and showed no significant association with either the initial dose (OR = 1.110, p = 0.639) or the maximum dose received (OR = 1.090, p = 0.291). Among the 53 patients, 2 (3.8%) experienced vivid dreams, 5 (9.4%) reported dizziness, and 1 (1.9%) developed loose stool. Twelve patients (22.6%) received systemic concomitant therapy alongside LDN, while the remaining 41 (77.4%) patients were treated with LDN monotherapy. In the overall cohort, lower doses (maximum dose ≤ 4.5 mg/day) showed a trend toward reduced relapse compared with those on higher doses (OR = 0.133, p = 0.109). Similar trends were observed in the monotherapy subgroup, with higher maximum doses associated with reduced clinical clearance (OR = 0.892, p = 0.058), and lower doses with reduced relapse (OR = 0.116, p = 0.085) (Table 2). These results indicate LDN offers a potentially useful treatment in HHD. However, results demonstrate that dose escalation may not confer therapeutic benefit. While potential publication bias and lack of controls should be considered in evaluating overall efficacy, the lack of response to dose increases suggests maximal therapeutic benefit at low doses. The therapeutic mechanisms of LDN in HHD may be associated with its anti-inflammatory and immunomodulatory properties. LDN intermittently binds to opioid receptors found in the skin layers 1, producing a rebound increase in endogenous opioids (e.g., β-endorphins and opioid growth factor OGF) and increased expression of mu, delta, and OGFr receptors 3, resulting in reduced pain, pruritus, and increased epithelial repair. LDN also antagonizes Toll-like receptor 4 (TLR4), which promotes the production of proinflammatory mediators in keratinocytes and macrophages 4, 5, ultimately reducing epidermal stress responses and HHD flare severity. Although LDN does not directly fix the calcium pump defect in HHD, it may improve cell adhesion by modulating intracellular Ca2+ signaling, reducing calcium influx, and supporting calcium redistribution required for desmosome assembly 1. Further studies should elucidate its dose-dependent biologic effects and therapeutic potential. The authors have nothing to report. This study was considered exempt from the formal approval of the Institutional Review Board. K.T.A. has received research support from Astra Zeneca and Sanofi. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Wang et al. (Tue,) studied this question.