LDN in Atopic Dermatitis Atopic dermatitis (AD) is one of the most common chronic inflammatory skin disorders, affecting up to 20% of children and 10% of adults in the industrialized world.18 While the pathogenesis of AD is not fully understood, it is currently theorized that AD arises due a disruption in the epidermal barrier leading to: 1. increased permeability of the epidermis, 2. pathological inflammation in the skin, and 3. percutaneous sensitization to allergens.3 Thus, many treatment strategies seek to target specific aspects of the skin barrier or cutaneous inflammation.Given the well-established role of both immune dysfunction and pruritus in of AD, the idea of LDN as a potential treatment is intriguing. Chronic pruritic disorders such as atopic dermatitis demonstrate downregulation of the μ-opioid receptor.19 Topically administered naltrexone has been shown to cause upregulation of the μ-opioid receptor and provide better relief of pruritic symptoms relative to placebo.20 A trial of a topical formulation of 1% naltrexone in 40 patients with severe atopic dermatitis revealed a 29% improvement in pruritus after just 2 weeks of use. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50%, while the placebo required 74 minutes. Punch biopsies were performed in 11 of the patients before and after the application of the cream and histopathological examination revealed increased staining of epidermal mu-opioid receptors after 2 weeks of naltrexone application.20 This suggests that a naltrexone-mediated upregulation of opioid receptors in the epidermis may be responsible for the decrease in pruritus. A recent study tested the efficacy of absorption of a LDN cream and found that it may be an effective formulation for the sustained transdermal delivery of LDN.21 This means that a potentially effective preparation for transdermal delivery of LDN could be tested in AD.Oral LDN has not been studied in AD, but oral HDN has been trialed. Several single-arm trials, case series, and case reports have reported variable responses to HDN.22 In a case series of 4 patients, only 1 patient achieved full remission of pruritus on 50 mg naltrexone.23 A follow-up study in 16 patients showed anti-pruritic effect in 50% of patients, further suggesting a mixed response to HDN.24 Trials of a structurally and functionally similar opioid derivative, nalmefene, have shown that lowering the dose to 20 mg and 10 mg leads to resolution of pruritus in 35% and 60% of patients, respectively.25 These studies lead us to the following questions: Could an even lower dose of naltrexone i.e. LDN lead to even better outcomes? And, could LDN clear AD lesions?The role of LDN in halting AD pathogenesis and potential applications to clinical disease has not been studied. It is now know that atopic dermatitis is a predominantly T-cell-driven disease,26 and changes in the T-cell populations and the associated cytokines during the acute and chronic phases of AD can cause variations in disease presentations and treatment responses. In theory, LDN’s blockade of the OGFR axis and/or stimulation of beta-endorphins and enkephalins could serve to blunt T-cell over-proliferation and production of inflammatory cytokines.3 However, such speculation requires further scientific research to elucidate a potential mechanism of action and potential clinical efficacy.One final caveat has been posed in literature: Does low-dose naltrexone decrease the pleasure derived from scratching (thus terminating the itch-scratch cycle) or the pruritus itself?27 Could it be a combination of both? Again, further studies are needed to shed light on this notion.
Despite LDN’s increasing prevalence of off-label use and growing scientific interest, there are still many unanswered questions. Some animal and in vitro studies support the use of LDN, but its clinical efficacy as an analgesic and anti-inflammatory has been tested only in a small number of chronic conditions such as multiple sclerosis, fibromyalgia, Crohn’s disease, and Charcot-Marie-Tooth.5 Within dermatology, the supporting literature for LDN is limited to only a few case series; few replications of the findings have been performed. As a result, the overall quality of the evidence thus far is insufficient to allow any definitive conclusions as to the efficacy of LDN in anti-inflammation or disease modification.