Research

BACKGROUND: Naltrexone in standard and reduced doses is efficacious in many inflammatory and acantholytic disorders.

OBJECTIVE: We summarized current data of naltrexone relevant to dermatological 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. Mu opioid receptors have been found in all layers of the epidermis while delta 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 Hailey-Hailey disease, further dose-ranging studies are needed. Data suggest naltrexone could be helpful in the treatment of pruritus and a variety of inflammatory and acantholytic skin diseases refractory to other treatments. At higher doses, liver function tests should be monitored on a periodic basis.

This mini-review presents information on the intermittent blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis by low-dose naltrexone (LDN), and the role of enkephalin (i.e. OGF) in autoimmune disorders, specifically multiple sclerosis, Crohn's, and fibromyalgia. Clinical reports on subjects taking LDN have documented reduced fatigue, few side-effects, and improved overall health. Preclinical studies on mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, revealed that immunization for EAE reduces serum OGF. Intermittent OGFr blockade with LDN restores serum enkephalin levels that correlate with reduced behavioral and pathological signs of EAE; LDN also increases enkephalin levels in naïve mice. The interplay between LDN, and the onset and treatment of autoimmune diseases, chronic pain, and other addictive behaviors requires further investigation, but highlights a central role for enkephalins and intermittent blockade of the OGF-OGFr pathway in pathogenesis and treatment of these disorders.

IMPORTANCE: Dermatology is encountering increasing rates of autoimmune disease manifesting in primary skin conditions that are difficult to treat without a risk of immunosuppression. Naltrexone is an orally active opioid antagonist that influences a variety of systemic pathways, including the immune system, in low doses of 1.5 to 4.0 mg/d. This phenomenon has piqued the interest of researchers and practitioners in regard to low-dose naltrexone's potential in the treatment of several autoimmune conditions.

OBJECTIVE: To review the existing literature on naltrexone treatment for dermatologic conditions.

EVIDENCE REVIEW: A primary literature search was conducted using PubMed in April 2018 for all articles published from 1971 to April 2018. Search terms consisted of naltrexone or low dose naltrexone or low-dose naltrexone and dermatology or skin or hair or nails. Reviews, animal studies, and nondermatologic and pharmacologic studies were excluded.

FINDINGS: From 1037 articles, 22 were deemed to be appropriate for inclusion in this review for a qualitative synthesis. The 22 articles included randomized clinical trials, case reports, and series. There were 7 articles on low-dose naltexone, 1 on topical naltrexone, and 14 on high-dose naltrexone use in dermatology. In high, low, and topical doses, naltrexone was effective in treating pruritus attributable to atopic dermatitis, prurigo nodularis, cholestatsis, burn injury, systemic sclerosis, Hailey-Hailey disease, and lichen planopilaris. High-dose naltrexone was ineffective in treating flushing and uremic pruritus most likely because of the lack of opioid involvement in the pathophysiologic mechanisms of these conditions.

CONCLUSIONS AND RELEVANCE: The findings suggest that low-dose naltrexone is safe and effective in the treatment of Hailey-Hailey disease and lichen planopilaris and both low- and high-dose naltrexone successfully treat pruritus attributable to various pathologic conditions; however, more adverse effects occurred in those taking high doses. Low-dose naltrexone has the potential for the treatment of chronic inflammatory skin conditions; however, additional evidence is needed for dosing and long-term treatment guidelines.

The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.

Low-dose naltrexone has been shown to treat autoimmune conditions, such as multiple sclerosis, fibromyalgia, and Crohn's disease. We present two cases in which low-dose naltrexone proved an effective therapy for dermatomyositis (DM), an idiopathic inflammatory myopathy. A search of PubMed for “low dose naltrexone” and “dermatomyositis” did not reveal any reported cases of the use of low-dose naltrexone in DM. We suspect that low-dose naltrexone produces an antiinflammatory effect via inhibition of toll-like receptor 4 (TLR4) and augmentation of endogenous opioid production. Low-dose naltrexone as treatment for DM is promising, as the cost of the medication is low, and its adverse effects are minimal.

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.

A 60-year-old white woman presented with a history of moderate, generalized plaque psoriasis covering 10% of her body surface area (BSA). The patient began low-dose naltrexone, 4.5 mg daily. The patient's psoriatic lesions were significantly improved at 3 months, and the affected BSA had decreased from 10% to 1% after 6 months of treatment. The calculated PASI (psoriasis area severity index) score decreased from 7.2 to 0.9 after 6 months of treatment. Symptoms of pruritus also improved with naltrexone. No other adjuvant medications were used during this period. No side effects from the treatment were reported. As of this writing, the patient has continued therapy with low-dose naltrexone without any adverse effects and with continued success. Treatment of psoriasis with low-dose naltrexone may be appealing because of its low side-effect profile, low cost, and its efficacy in patients with chronic inflammatory conditions.

Hailey-Hailey disease, otherwise known as familial benign chronic pemphigus, is a genetic intraepidermal blistering disorder. In nongeneralized HHD, there have been a few published case reports of HHD treated successfully with low-dose naltrexone (LDN). The exact mechanism by which naltrexone works for HHD is unclear.

The phenotypic expression of HHD can be quite variable. Although at times minimal, in rare cases, this disorder cannot only become generalized but result in systemic sequelae due to fluid and protein loss, with lesions providing an ideal media for bacterial colonization and infection. The use of antibiotics to cover significant pathogens or colonization should be used in combination with other primary treatment modalities. It is unclear how much the antibiotics contributed to resolution of our patient's disease initially; however, the patient clearly showed improvement with only use of naltrexone during weeks 5 through 8. Furthermore, the patient has maintained clearance of his disease using LDN at variable doses and has not used any additional antibiotics. There is a clear correlation between the lowering of the dose and flare of his disease. Because the patient has had no significant side effects from the medication, it has been continued per patient preference.

Until this point, treatments have only modified the disease, as they have not clearly targeted the pathophysiologic components. Despite the uncertainty of mechanism of action, LDN in this patient as well as a few other documented case reports of HHD treated with LDN, led to dramatic clinical improvement, with minimal side effects. Overall, this intriguing topic needs future investigation, as there are limited published data. Based on recent literature and experience with LDN, it would appear to be the treatment of choice for HHD when more conventional treatment modalities fail. Moreover, its use provides a powerful addition to the therapeutic armamentarium for generalized HHD.

The ancient autoimmune skin condition psoriasis is still ubiquitous worldwide, produces the same, often-intolerable effects noted in its earliest recorded descriptions, and remains without cure. Management options designed to resolve the itchy, scaly, weeping, erythematous, and often widespread lesions of that disorder are now available, but they vary in efficacy, most are associated with the development of severe adverse effects, and many are prohibitively expensive. In this article, we describe the successful use of a compounded formulation of oral low-dose naltrexone to manage guttate psoriasis in a 75-year-old white male patient. That therapy produced only 1 adverse effect (dry skin near the lesions on the patient's arms and legs) and was relatively inexpensive. The formulation for that preparation and comments from the patient, the pharmacist who suggested its use, the prescriber, and the compounder who prepared it are included. Many clinicians are unaware of the benefits of compounded low-dose naltrexone in treating autoimmune diseases. We hope that this case report will encourage compounding pharmacists to consider and suggest it as an alternative therapy for patients who cannot tolerate or afford manufactured medications to treat psoriasis.

Low dose naltrexone (LDN) has been promising as a complementary medication for patients with a broad range of medical disorders. Although not a proven cure, evidence from clinical trials supports LDN as being a valuable adjunct for disorders in which the immune system plays a centralized role. Additionally, clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors including non-small cell lung cancer (NSCLC) at the cellular level by augmenting the immune system. We present a case of a 50-year-old male with a prolonged survival and a past medical history of prostate and lung cancer.