ArticlePDF Available
Journal of Cutaneous Medicine and Surgery
2019, Vol. 23(4) 453 –454
© The Author(s) 2019
Article reuse guidelines:
DOI: 10.1177/1203475419843122
Darier (DD) and Hailey-Hailey (HHD) diseases are both
genodermatoses caused by defective calcium transport and
homeostasis. DD is caused by a mutation of the ATPA2A
gene and HHD by a mutation of the ATP2C1 gene. Clinically,
the former is characterized by itchy, painful macerations
with red-brownish papules in a seborrheic distribution; the
latter manifests with painful blisters that rupture, leaving
erosions in intertriginous areas. Treatment options for both
conditions are limited and include topical steroids, systemic
steroids, retinoids, antibiotics, topical aminoglycosides, as
well as dapsone and immunosuppressive therapies.1-3 One
additional promising and novel therapeutic option for these
diseases is naltrexone.
Naltrexone is a long-lasting opiate receptor antagonist. In
dermatology it is used in recalcitrant chronic pruritis or neu-
rodermatoses such as prurigo nodularis. The exact mecha-
nism of action in these conditions is unknown, but it is
thought to be due to its anti-inflammatory and antianalgesic
effects.4 Naltrexone is a known Toll-like receptor 4 antago-
nist, which leads to decreased amounts of TNF-alpha, IL-6,
and nitric oxide. These effects are involved in calcium
Low-dose naltrexone (LDN) initiated at 3 mg nightly and
then maintained on 4.5 mg nightly showed significant
improvement in 3 patients with refractory HHD. These
patients previously failed topical, intralesional, and intra-
muscular steroids, along with failing oral and topical antibi-
otics. One of the 3 patients periodically discontinued and
then restarted the medication multiple times. Each time he
would develop lesions a few days after stopping and they
would resolve shortly after resuming naltrexone.1
Another set of 3 patients with HHD was treated with LDN:
Two showed a significant improvement with naltrexone alone
or in combination with topical regimens of tacrolimus and
corticosteroids. The third patient had mild improvement.
Interestingly, 1 of the patients who had significant improve-
ment was on 12.5 mg of naltrexone at that time and reported
slower healing of lesions than on the 4.5 mg dose.5
Another refractory patient with HHD had a dramatic
response to LDN at 4.5 mg daily. This patient failed topical
and oral steroids, prophylactic acyclovir and doxycycline,
dapsone, acitretin, and cyclosporine. In the report, 4 other
members of the same family responded well to LDN.1
Given the therapeutic success of naltrexone in HHD case
series, Boehmer et al recently explored the use of LDN in a
series of biopsy-proven DD patients. In this study, patients
were treated with LDN 4.5 mg and magnesium 200 mg once
daily. Authors supplemented the LDN with magnesium,
given that dysfunction of the SERCA2 calcium pump is
known to be magnesium dependent. Patients were followed
monthly for 12 weeks. Of 6 patients included in the study, 4
had a severe disease defined by a Physician Global
Assessment (PGA) score of 4, while 2 had mild-to-moderate
disease. Only those with mild-to-moderate disease demon-
strated clinical improvement. Of the 2 responders, 1 received
a concurrent treatment with oral acitretin, while the other
was not on any additional treatments.2
The use of LDN at 4.5 mg once daily in patients with HHD
has shown promise in early observational studies. In contrast
to the classic doses of 50-100 mg, LDN does not need any
laboratory monitoring and has a favourable safety profile,
with common side effects of vivid dreams and headache.1
Prior to LDN therapy, patients should be carefully screened
for recent use and/or prior dependence of opioids.1 Further
studies to assess the efficacy of naltrexone in low-dose or
higher doses in these 2 diseases are needed.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Medical Letter
843122CMSXXX10.1177/1203475419843122Journal of Cutaneous Medicine and SurgeryJfri et al
1Division of Dermatology, McGill University Health Centre, Montreal
General Hospital, QC, Canada
Corresponding Author:
Elena Netchiporouk, Montreal General Hospital, McGill University Health
Centre, Department of Medicine, Division of Dermatology, 1650 Cedar
Ave, Montreal, QC H3G 1A4, Canada.
Naltrexone for the Treatment of Darier
and Hailey-Hailey Diseases
Abdulhadi Jfri1, Ivan V. Litvinov1,
and Elena Netchiporouk1
Darier disease (DD), Hailey-Hailey disease (HHD), low-dose naltrexone (LDN), naltrexone
454 Journal of Cutaneous Medicine and Surgery 23(4)
The authors received no financial support for the research, author-
ship, and/or publication of this article.
Abdulhadi Jfri
1. Lee B, Elston D. The uses of naltrexone in dermatological con-
ditions [published online ahead of print December 21, 2018]. J
Am Acad Dermatol. doi:10.1016/j.jaad.2018.12.031
2. Boehmer D, Eyerich K, Darsow U, Biedermann T, Zink A.
Variable response to low-dose naltrexone in patients with
Darier disease: a case series [published online ahead of print
February 3, 2019]. J Eur Acad Dermatol Venereol. doi:10.1111/
3. Kellermayer R, Szigeti R, Keeling KM, Bedekovics T, Bedwell
DM. Aminoglycosides as potential pharmacogenetic agents
in the treatment of Hailey-Hailey disease. J Invest Dermatol.
2006;126(1):229-231. doi:10.1038/sj.jid.5700031
4. Younger J, Parkitny L, McLain D. The use of low-dose naltrex-
one (LDN) as a novel anti-inflammatory treatment for chronic
pain. Clin Rheumatol. 2014;33(4):451-459. doi:10.1007/
5. Cao S, Lilly E, Chen ST. Variable response to naltrexone
in patients with Hailey-Hailey disease. JAMA Dermatol.
2018;154(3):362-363. doi:10.1001/jamadermatol.2017.5463
Are you an amateur photographer? Interested in seeing your work in print? JCMS is
now publishing member photography of interesting, non-dermatological artistic photos
of the world around us. Submit your photographs to to be
considered for publication in the journal. Photographs must be of very high quality and
your original work. The photographs will be published at the discretion of the editor
as space allows.
... Low-dose naltrexone and oral magnesium chloride represent emerging treatments. 5,8 It is believed that naltrexone, a μ-opioid receptor antagonist, modulates opioid receptors expressed in keratinocytes, resulting in increased cellular adhesion. 9 Moreover, it exerts anti-inflammatory effects by antagonizing toll-like receptor 4. 10 Improvement in HHD with low-dose naltrexone has been reported in case series with sustained response after a follow-up of 3-12 months, while others showed a variable response. ...
Full-text available
Hailey–Hailey disease is a rare autosomal dominant acantholytic disorder due to mutation in the ATP2C1 gene and presents with flaccid blisters in intertriginous regions. Its chronic and relapsing course may negatively impact patients’ quality of life. Multiple medical and interventional treatments have been described with various efficacy. Low-dose naltrexone and oral magnesium chloride represent emerging treatments. Sustained improvement in Hailey–Hailey disease has been reported with the former in case series, while others have shown variable results. Oral magnesium chloride has been reported in four patients with possible results after 2–4 weeks. Two recent cases suggest that the combination of both treatments may have a synergistic effect. Herein, we present a 63-year-old woman with long-standing and recurrent bilateral inguinal Hailey–Hailey disease who significantly improved with low-dose naltrexone and oral magnesium chloride, representing the third case described with this combination.
... Boehmer et al. used naltrexone to treat 6 patients with Darier disease after it was shown to be effective in patients with Hailey-Hailey disease and based on the similarities in pathophysiology of the 2 diseases. [55][56][57][58] Naltrexone was used off-label at a dose of 5 mg with 200 mg of magnesium supplementation. Patients were followed up every 4 weeks for 12 weeks. ...
Full-text available
Darier disease (DD) is a rare type of inherited keratinizing disorder with no definitive therapeutic approach. The objective of this study is to provide a detailed literature review of all the available treatment modalities of Darier disease, including those that are both surgical and non surgical, to compare their efficacies and to propose a novel therapeutic approach. A complete search of the literature for all articles describing the different treatments of Darier disease, with no restrictions on patients’ ages, gender or nationalities, was performed with the use of PubMed. A total of 68 articles were included in the study: 3 prospective studies, 44 case reports/case series and 21 letters/correspondences/clinical images. The treatments described were topical, oral or physical. Retinoids (isotretinoin, tazarotene and adapalene) and fluorouracil were the two most effective topical treatments. Oral retinoids were the most effective oral therapy and were prescribed in the cases of generalized Darier disease. For localized and resistant skin lesions, physical therapies including surgical excision, dermabrasion and CO2 laser ablation were the first line choices. Limitations of this article include the inability to verify the accuracy of the published data, the relatively small sample size, the absence of randomized controlled clinical trials and possible unidentified confounding factors in various studies. In every therapeutic approach to Darier disease, consideration of patient comorbidities, disease distribution, severity and treatment accessibility is essential. Large and randomized clinical trials are necessary for the comparison of the efficacy and the safety of all the treatments of Darier disease and settling a consensus for management.
... La terapéutica sistémica por vía oral, incluye corticosteroides por periodos cortos (prednisolona 40 mg/día, realizando la suspensión en dosis decrecientes), retinoides (isotretinoína 0.5 mg/kg/día, acitretina 0.25-0.5 mg/kg/día o alitretinoína 30 mg/día), antibióticos por su función antiinflamatoria (tetraciclinas), ciclosporina (2.5 mg/kg/día) y naltrexona (4.5 mg/ día) asociada a magnesio (200 mg/día) 9,12,13 . ...
... As a Toll-like receptor 4 antagonist, naltrexone can lead to a lower production of tumor necrosis factor (TNF)-alpha, interleukin-6 and nitric oxide, which are known to play a role in the calcium homeostasis known to be dysregulated in HHD. 4 In rare cases, surgical excisions have also been described. ...
Full-text available
Hailey-Hailey disease is an autosomal dominant genodermatosis leading to chronic hyperkeratotic and fissured lesions in the intertriginous areas. We present a 53-year-old woman with a case of vulvar and inguinal Hailey-Hailey disease resistant to usual treatments. She was efficiently treated with alitretinoin 10 mg daily combined with injections of onabotulinumtoxinA every 9 months. The combination led to an almost complete resolution of the lesions and symptoms at follow-ups.
Although rare, a number of genodermatoses may have vulval involvement which requires specific management such as in epidermolysis bullosa. Others may be incidental findings causing no symptoms. However, a knowledge of how genetic problems can present in the skin is important as occasionally the cutaneous features are the first clue to the diagnosis.
Full-text available
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
Full-text available
HHD, Hailey–Hailey disease; hSPCA1, human secretory pathway Ca2+/Mn2+ ATPase
Background Darier disease is a rare autosomal‐dominant genodermatosis with a loss of function of a Ca²⁺‐ATPase pump (SERCA2‐pump). Clinically, the disease is characterized by red‐brown keratotic papules mainly in seborrheic areas and has only limited and unsatisfactory treatment options. Previously, low‐dose naltrexone was described as a successful treatment option in Hailey‐Hailey‐disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca²⁺‐ATPase pump (hSPCA1‐pump). Objective To assess the efficacy of low‐dose naltrexone as a treatment option in Darier disease. Methods Six patients with biopsy‐proven Darier disease (4 had severe, 1 had moderate and 1 mild clinical manifestations). The patients received off‐label therapy with naltrexone (5 mg per os [p.o.]) and magnesium (200 mg p.o.). Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. Results The clinical response to naltrexone varied after 12 weeks. The 4 patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the 2 patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. Conclusion Low‐dose naltrexone did not have an effect on severe Darier disease compared to Hailey‐Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses. This article is protected by copyright. All rights reserved.
Background: Naltrexone in standard and reduced doses is efficacious in many inflammatory and acantholytic disorders. Objective: We summarized the current data of naltrexone that are relevant to dermatologic practice. Methods: An English language PubMed literature search was performed using the terms naltrexone, low-dose naltrexone, Hailey-Hailey, psoriasis, lichen planopilaris, alopecia, opioid, opioid receptor, treatment, dermatology, monitoring, side effect, skin, pruritus, cutaneous, acantholytic, and Darier. Results: Opioid receptors are found throughout the skin and affect cell proliferation, migration, and adhesion. μ Opioid receptors have been found in all layers of the epidermis, while δ receptors are concentrated at cell junctions and can reduce desmoglein expression. Typical doses of naltrexone result in continuous binding to receptors. Low doses result in intermittent blockade with increased ligand and receptor expression, potentiating their effect. Limitations: Our review was restricted to the English language literature. Conclusion: Naltrexone affects inflammation, cell adhesion, and keratinocyte proliferation and migration. While low-dose naltrexone has demonstrated efficacy in treating patients with Hailey-Hailey disease, further dose-ranging studies are needed. Data suggest that naltrexone could be helpful in the treatment of pruritus and a variety of inflammatory and acantholytic skin diseases that are refractory to other treatments. At higher doses, liver function tests should be monitored on a periodic basis.
Hailey-Hailey disease (HHD) is a genetic intraepidermal blistering disorder characterized by chronic macerated erosions in intertriginous areas.¹ The recent report of 2 case series²,3 demonstrating the efficacy of low-dose naltrexone in the treatment of HHD represents exciting progress in the management of a disease with limited therapeutic options. Herein we present 3 additional cases of HHD demonstrating varying responses to naltrexone.