INTRODUCTION
The concept of low-dose naltrexone (LDN) has been successfully studied as an immunomodulatory and anti-inflammatory therapy in a wide range of conditions. These include Crohn’s disease, fibromyalgia, major depressive disorder, cancer, chronic regional pain syndrome, Charcot-Marie-Tooth, and multiple sclerosis.1-5 LDN is an attractive treatment option because its side effects are generally mild (including vivid dreams, nightmares, headaches, and anxiety),6 it has a low abuse potential,4 and it is cost-effective at approximately $35 per month.6Recently, off label LDN has been shown to improve dermatologic conditions such as systemic sclerosis, Hailey-Hailey Disease, lichen planopilaris, and guttate psoriasis.6-9 In this article, we examine the existing evidence for use of LDN in skin disease and discuss its potential application in the treatment of atopic dermatitis (AD).What is Low Dose Naltrexone? Naltrexone was synthesized in 1963 as an orally active competitive opioid receptor antagonist.10 Naltrexone is structurally and functionally similar to the opioid antagonist naloxone, but it has greater oral bioavailability and a longer biologic half-life of 4 hours.11 It is now well known that naltrexone actually exerts its effects on humans via at least two distinct receptor mechanisms. The first effect is a directly antagonistic effect on mu-opioid receptors. The second is via antagonism of the Toll-like receptor 4 (TLR4)-mediated proinflammatory pathway in macrophages and microglia.3,5,12 Notably, sustained mu-opioid receptor blockade by naltrexone has been shown to lead to inflammation and proliferation of immune cells.3Naltrexone was first approved by FDA in 1984 for the treatment of opioid addiction. The typical daily dosage for opioid addiction is 50-100 mg daily, and 50 mg tablets are available commercially.4 This typical daily dosage has been referred to as “high dose naltrexone” (HDN) in literature.3 Low-dose naltrexone (LDN) refers to daily dosages of naltrexone that are approximately 1/10th of the typical opioid addiction treatment dosage. Common LDN doses range from 1-4.5 mg daily.5The mechanism of LDN is thought to be distinct from high-dose naltrexone (HDN). Proposed mechanisms include: 1. Blockade of the opioid growth factor receptor (OGFR) axis, which normally stimulates B and T cell proliferation; and, 2. Stimulation of beta-endorphin and enkephalin release, which has anti-inflammatory effects on T and B cells.6,13 In contrast to high dose naltrexone, which stimulates the immune system, the intermittent activity of LDN is thought to depress immune cell proliferation and activity.3 Remarkably, this implies that naltrexone can both be anti-inflammatory as well as pro-inflammatory depending on its duration of action, squarely placing the drug in the “immunomodulatory” category.3 HDN has a longer duration of action, and thus continuously blocks the OGFR axis leading to increased cellular proliferation and inflammation. LDN, on the other hand, has a shorter duration of action which results in an intermittent blockade of the OFGR axis, leading to a compensatory mechanism that upregulates production of OGF receptors and endogenous opioids. This strengthens the inhibitory effects of the OGFR axis on cellular proliferation and inflammation. The OFGR axis and its unique responses to sustained and intermittent blockade may potentially explain the paradoxical dose-associated effects
