Research

Over the past decade there has been significant advancement in understanding the multitude of ways naltrexone interacts with human physiology. The two main theories purported in literature are suppression of cytokine production by glial cells and transient blockade of the mu- opioid receptor. This case report highlights a chronic pain patient that sustained a wean from high dose opioid regimen utilizing low dose naltrexone. Her daily pain score, as calculated using the Defense and Veterans Pain Rating Scale, was lower after she was weaned from opioids.

Sjogren’s Syndrome is a chronic autoimmune disorder that causes the inflammation of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. In addition, fatigue and musculoskeletal pain, often described as aching, is very common. Treatment directed toward alleviating the fatigue and pain associated with Sjogren’s is currently very limited. This report describes a case of a 47-year-old female with suspected Sjogren's based on long-standing dry eyes, dry mouth, joint pain, fatigue, elevated measures of inflammation, and a positive rheumatoid factor. She failed standard therapy but improved clinically with low-dose naltrexone therapy.

In recent years, low dose naltrexone (LDN) has been used as an off-label therapy for several chronic diseases. Results from small laboratory and clinical studies indicate some beneficial effects of LDN in autoimmune diseases, but clinical research on LDN in rheumatic disease is limited. Using a pharmacoepidemiological approach, we wanted to test the hypothesis that starting LDN leads to reduced dispensing of medicines used in the treatment of rheumatic disease. We performed a controlled before-after study based on the Norwegian Prescription Database (NorPD) to compare prescriptions to patients one year before and one year after starting LDN in 2013. The identified patients (n = 360) were stratified into three groups based on LDN exposure. Outcomes were differences in dispensing of medicines used in rheumatic disease. In persistent LDN users, there was a 13% relative reduction in cumulative defined daily doses (DDD) of all medicines examined corresponding to -73.3 DDD per patient (95% CI -120,2 to -26.4, p =0.003), and 23% reduction of analgesics (-21.6 DDD (95% CI -35.5 to -7.6, p<0.009)). There was no significant DDD change in patients with lower LDN exposure. Persistent LDN users had significantly reduced DDDs of NSAID and opioids, and a lower proportion of users of DMARDs (-6.7 percentage points, 95% CI -12.3 to-1.0, p = 0.028), TNF-α antagonists and opioids. There was a decrease in the number of NSAID users among patients with the least LDN exposure. Important limitations are that prescription data are proxies for clinical effects and that a control group unexposed to LDN is lacking. The results support the hypothesis that persistent use of LDN reduces the need for medication used in the treatment of rheumatic and seropositive arthritis. Randomised clinical trials on LDN in rheumatic disease are warranted.

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.

Naltrexone is an opioid receptor antagonist with FDA approval for treating opioid addiction since 1984. While typical dose for treating opioid addiction with naltrexone is between 50 mg to 150 mg, the use of low dose naltrexone (LDN) with doses ranging from 1.5 mg to 4.5 mg per day has been growing in popularity. The most common use of LDN has been treating autoimmune disorders; consequently, there have been clinical trials investigating the effectiveness of LDN for clinical conditions such as multiple sclerosis, systemic sclerosis, and Crohn’s disease. More recently, exploring the role low dose naltrexone and ultra-low dose naltrexone (microgram dosing of naltrexone) for chronic pain have been described in the literature. It has been proposed that LDN halts inflammatory cascades via glial cell inactivation. In addition, the role of microgram dosing of naltrexone has shown promise as a means to increase analgesia and decrease tolerance to opioid medications. This review evaluates the existing evidence for using LDN for treating pain and its microgram dosing in the potentiation of opioid medication while reducing side effects.

This clinical case demonstrates the benefits of patient treatment with low-dose naltrexone(LDN) used in erythrodermic psoriasis. A patient with a confirmed history of psoriasis by histopathology was treated with 4.5 mg of LDN during six months follow-up after an erythrodermic psoriasis flare-up. The patient showed significant improvement in her flare-upand psoriasis remission after only three months of 4.5 mg of LDN on a daily basis. Low-dose-naltrexone (LDN) has proven to be a great ally in treating erythrodermic psoriasis flare-ups as an alternative treatment with less collateral side effects.

BACKGROUND: Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 to 250 mg. The aim of this review was to extensively evaluate the safety of oral naltrexone by examining the risk of serious adverse events and adverse events in randomised controlled trials of naltrexone compared to placebo.

METHODS: A systematic search of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, other databases and clinical trials registries was undertaken up to May 2018. Parallel placebo-controlled randomised controlled trials longer than 4 weeks published after 1 January 2001 of oral naltrexone at any dose were selected. Any condition or age group was included, excluding only studies in opioid or ex-opioid users owing to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-analyses harms checklist throughout. Numerical data were independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane risk-of-bias tool. Meta-analyses were performed in R using random effects models throughout.

RESULTS: Eighty-nine randomised controlled trials with 11,194 participants were found, studying alcohol use disorders (n = 38), various psychiatric disorders (n = 13), impulse control disorders (n = 9), other addictions including smoking (n = 18), obesity or eating disorders (n = 6), Crohn's disease (n = 2), fibromyalgia (n = 1) and cancers (n = 2). Twenty-six studies (4,960 participants) recorded serious adverse events occurring by arm of study. There was no evidence of increased risk of serious adverse events for naltrexone compared to placebo (risk ratio 0.84, 95% confidence interval 0.66-1.06). Sensitivity analyses pooling risk differences supported this conclusion (risk difference -0.01, 95% confidence interval -0.02-0.00) and subgroup analyses showed that results were consistent across different doses and disease groups. Secondary analysis revealed only six marginally significant adverse events for naltrexone compared to placebo, which were of mild severity.

CONCLUSIONS: Naltrexone does not appear to increase the risk of serious adverse events over placebo. These findings confirm the safety of oral naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications.

The use of low-dose naltrexone for the treatment of chronic pain is novel because it is a nonopioid alternative. Oral naltrexone in a dosage range from 1 mg to 4.5 mg is referred to as low-dose naltrexone. Low-dose naltrexone use is "off label" and has been used successfully to manage chronic pain, autoimmune disorders, and dermatologic conditions. Low-dose naltrexone could be a viable treatment option for chronic pain because other agents for chronic pain, such as nonsteroidal agents, have adverse effects of gastrointestinal bleeding, renal injury, and increase a patient's risk of myocardial infarction or stroke. Additionally, low-dose naltrexone has minimal adverse effects, no drug-drug interactions, and is relatively inexpensive compared with other options for chronic pain.

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.