Naltrexone therapy for Hailey-Hailey disease: Confirming my addiction to evidence-based medicine

By Warren R. Heymann, MD
Aug. 28, 2017

I was fascinated by a presentation at the recent World Congress of Pediatric Dermatology discussing improvement of epidermolysis bullosa wounds with topical CBD (cannabis) oil. I asked the presenter how he came up with his hypothesis. He acknowledged that the idea was not his — it came from EB families touting its use on the web.

When I read about the use of low-dose naltrexone (LDN) for Hailey-Hailey disease (HHD) I asked myself the same question – how did the authors devise this therapy? Unsurprisingly, LDN has been advocated on social media for a variety of maladies. Following a TV documentary in 2013, there was a tremendous increase in low dose naltrexone (LDN) use in a wide range of unapproved indications in Norway, from an insignificant number to 0.3% of the population. There was a high willingness to use and prescribe LDN off label despite limited evidence. (1)

Before considering the potential role of LDN in HH, I thought it would be prudent to survey its use in other diseases. The following abstract was published by the Norwegian Institute of Public Health (2):
 
In Norway, naltrexone is approved as supportive treatment of alcohol dependence. The recommended dose is 50 mg, equivalent to the marketed tablet. Naltrexone in much lower doses than 50 mg has been used in Norway for the treatment of a variety of diseases, such as multiple sclerosis (MS), Crohn’s disease, fibromyalgia, cancer, inflammatory bowel disease, chronic fatigue syndrome, and amyotrophic lateral sclerosis. Doses of 3 to 5 mg per day have often been termed low dose naltrexone. This use is beyond the approved indication. The purpose of this report is to examine whether there is a documented effect of the use of naltrexone in low doses. We summarized data from a systematic review and several randomized controlled and prospective controlled studies in order to investigate the effect of using naltrexone in low doses on illness, and on functioning in daily life and to examine the risk of side effects. We identified studies for people with: Crohn’s disease (one systematic review, two studies); multiple sclerosis (two studies); fibromyalgia (two studies); cancer (one study). HIV (one study); various pain conditions (three studies); opioid dependence (six studies). All studies were either small, of short duration, or had other methodological limitations. We considered the documentation to have very low quality. That means that we cannot conclude whether the use of naltrexone in low doses is effective or safe.
 
HHD (aka benign familial pemphigus), is a late-onset blistering disorder that involves the flexures, presenting as painful erosions in affected areas. Lesions generally begin between 20 and 40 years of age. In two-thirds of cases, a positive family history is detected. HHD is due to a defect in desmosomal keratinocyte adhesion secondary to an ATP2 C1 gene mutation, resulting in acantholysis. The histopathologic correlates are formation of intraepidermal bullae with partial acantholysis appearing like a “dilapidated brick wall”. Menstruation, pregnancy, skin infections, physical trauma, excessive sweating and exposure to ultraviolet radiation are important triggering factors. Management focuses on eliminating (or treating) any triggering factors, if possible. Topical therapies, notably topical steroids, antifungal agents, and topical antibiotics are used most frequently. A summary of other topical and systemic treatments (virtually everything you can think of!) is provided by Engin et al. (3) For extensive Hailey-Hailey disease that is recalcitrant to conventional therapy, laser ablation, photodynamic therapy, electron beam radiotherapy, botulinum toxin type A, dermabrasion, glycopyrrolate, and afamelanotide have been reported as useful treatments, but comparative trials are lacking. (4)

Albers et al reported a case series of 3 patients with severe HHD who were recalcitrant to at least 4 therapies. LDN, 3 mg nightly, was administered, titrated to 4.5 mg nightly in 2 patients. All 3 patients noted significant healing of erosions and plaques starting from the peripheral aspect within 1 to 2 weeks of treatment, and clinical resolution of lesions within 2 months. Discontinuation of low-dose naltrexone resulted in flaring of symptoms, which cleared within 2 to 3 days on rechallenge with low-dose naltrexone. (5) Ibrahim et al treated 3 patients with biopsy-proven recalcitrant HHD with LDN at a dosage of 1.5 to 3.0 mg per day. The 3 patients included a woman in her 40s and 2 men in their 60s. Each patient exhibited at least an 80% improvement in extent of disease, with one patient demonstrating 90% clearance. All 3 patients had substantial improvement in quality of life, with one patient reporting improvement in his depression. No adverse effects were recorded. (6) The authors of both studies appropriately acknowledge that further research is required to determine the validity of these results and to learn about how naltrexone may be exerting its effect(s). LDN must be compounded (the lowest dose available is 50 mg) — it cannot be overemphasized that its use is strictly off-label.
 
Current theories consider the antagonistic effects of naltrexone on mu and delta receptors which, in turn, may affect Toll-like receptors, leading to a diminution of proinflammatory cytokines, and changes in intracellular calcium metabolism.

Every day patients ask for my opinion about something they found on the internet. Usually I have no idea what they are talking about. I listen carefully, and tell them that I only recommend treatments that have at least met the minimum criteria of being reported on PubMed. I search it immediately, and if there is no mention of it, I politely shrug my shoulders, and say that I have no opinion (and will not have one until I see some data that I can trust). I want evidence, and the higher on the evidence-based medicine pyramid, the better. The use of LDN has at least entered my realm of consciousness. Whether it ultimately becomes part of our standard therapeutic palette remains to be determined by careful, controlled, randomized clinical trials. I’ll keep an open mind though. I’m sure that physicians in 1787 were skeptical when William Withering reported the use of foxglove for dropsy (digitalis for congestive heart failure). (7)

1. Raknes G, Smabrekke L. A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. Pharmacoepidemiol Drug Sat 2017; 26: 136-42.
2. Ringerike T, et al. The use of naltrexone in low doses beyond the approved indication [internet]. NIPH Systematic Reviews: Executive Summaries No 8-2015.
3. Engin B, et al. Hailey-Hailey disease: A fold (intertriginous) dermatosis. Clin Dermatol 2015; 33: 452-5.
4. Farahnik B, et al. Interventional treatments for Hailey-Hailey disease. J Am Acad Dermatol 2017; 76: 551-8.
5. Albers LN, et al. Treatment of Hailey-Hailey Disease with Low-Dose Naltrexone. JAMA Dermatol 2017 Aug 2 [Epub ahead of print]
6. Ibrahim O, et al. Low-dose naltrexone treatment of familial benign pemphigus (Hailey-Hailey Disease. JAMA Dermatol 2017 Aug 2 [Epub ahead of print]
7. Allen DE. William Withering and the foxglove. Med Hist 1987; 31: 375-6.

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