Research

PURPOSE: Neuropathic corneal pain (NCP) is a recently described ocular pain modality resulting from nerve damage and presenting with symptoms of pain or persistent unpleasant sensations, such as dryness, burning, or light sensitivity. When symptoms do not resolve with topical anesthetics, this point to a non-ocular source of pain. Low-dose naltrexone (LDN) acts as a neuromodulator with a neuroprotective effect via inhibition of microglial activation in the central nervous system and upregulation of endogenous opioid production. We aimed to assess the efficacy and tolerability of LDN for NCP.

METHODS: In a retrospective cohort study,patients diagnosed with ocular pain and the keyword “naltrexone” were identified. All patients were required to have been diagnosed with NCP and using LDN for at least 3 months. Diagnosis was based on medical history, discordance in clinical signs and symptoms, and corneal in vivo confocal microscopic findings. Patients were required to exhibit persistent ocular discomfort/pain after instillation of 0.5% proparacaine hydrochloride. Patients were excluded if they had any ocular pathology that might cause pain.

RESULTS: Thirty out of 71 identified patients were included in the final data-set based on inclusion/exclusion criteria. Mean age was 45.60±19.30 years with a white (80.00%) female (73.33%) predominance. Time between visits (duration of LDN use) was 14.87±11.25 months (range 1-36 months) and duration of NCP prior to treatment was 17.53±17.29 months (range 3-79 months). The average percent improvement was -49.22%. Sixteen patients (53.33%) had equal to or more than 50% improvement, 4 patients (13.33%) had 30-49% improvement, 5 patients (16.67%) had 1-29% improvement, and 5 patients (16.67%) did not improve. Mean Quality of life (QoL) score by the ocular pain assessment survey was 5.84±2.57 (range 1.14-9.00) at the first visit (p<0.0001). Mean QoL score improved to 3.77±2.91 (range 0-8.86) at the last visit (p=0.023). Pre-treatment comorbidities were dry eye disease (66.67%), neuropsychiatric diseases (30.61%) and auto-immune diseases (10.20%). All patients were on previous systemic medications (most common being Nortriptyline 26.7% and SSRI 16.7%).

CONCLUSIONS: LDN was effective and well tolerated as an adjunct therapy for NCP.

Hailey-Hailey disease (HHD) is an uncommon autosomal dominant disorder resulting from a mutation in the ATP2C1 gene resulting in dysfunction of the Golgi apparatus calcium-associated ATPase, thus interfering with intercellular calcium signaling.

HHD presents clinically as flaccid blisters and erosions in intertriginous areas, especially the axillae and groin. The major histologic finding is acantholysis throughout the spinous layer of the epidermis, commonly referred to as a “dilapidated brick wall” appearance. The initial lesions and associated symptoms usually develop during the second or third decade of life. Complications of HHD include infections (bacterial, fungal, and viral), and malignant transformation (cutaneous squamous cell carcinoma). A 56-year-old female presented to clinic with a worsening rash located on her upper arms, inguinal region, and lower back. Physical exam revealed erythematous, macerated, crusted plaques located on the upper arm, inguinal region, and lower back. The erosions had a “worm-eaten” pattern. Shave biopsy was performed on lesions revealing widespread acantholysis of the epidermis and minimal dyskeratosis. Over the course of several months, the patient was treated with multiple therapies including high potency topical corticosteroids, oral therapy with doxycycline, and two intramuscular injections of 40 mg/ml triamcinolone acetonide. Due to the progressively worsening and recalcitrant nature of the disease, the patient was started on 3 mg/day of oral naltrexone. After 3 months of treatment on 3 mg daily of naltrexone, the patient had almost complete resolution of active lesions on her upper arms, inguinal region, and lower back. The remaining skin changes represent post-inflammatory hyperpigmentation.

BACKGROUND: Lichen planopilaris (LPP) is one of the important causes of cicatricial alopecia. We aimed to evaluate the efficacy and safety of low-dose naltrexone (LDN) in the setting of a clinical trial in patients with LPP.

METHODS: We included patients with LPP between 2018 and 2020. Patients were allocated to two groups. The first group received topical clobetasol plus oral low dose naltrexone (3mg) while the second received topical clobetasol plus placebo. The assessment was made for the disease severity by lichen planopilaris activity index (LPPAI) instrument and the safety of the drug in 2-month intervals up to 6 months. To compare both groups, we used the ANOVA test for repeated measures.

RESULTS: Thirty-four patients were analyzed in intention-to-treat fashion. There was a decrescendo pattern on LPPAI scores that was statistically significant within the LDN (P = 0.001) but almost significant within the placebo group (P = 0.060) and non-significant between the groups (P = 0.813). The side effects attributable to the low dose naltrexone was not statistically different between studied groups.

CONCLUSION: Low dose naltrexone (3mg) failed to improve the severity of the LPP more than what is achievable with topical clobetasol.

Safe, inexpensive, and convenient psoriasis therapy is desirable. Two recent case reports suggested that low-dose naltrexone is effective. Cases from our practice are presented in order to further the evidence of efficacy and safety of low-dose naltrexone in the treatment of psoriasis. Patients included 13 females, 2 males; mean age 57 years; mean psoriasis duration 16 years. Of the patients, 8 had psoriatic arthritis. In the past, 5 had completely failed and 10 had partially responded to =1 topical therapies. Patients used a self-assessed Likert scale on the effect of low-dose naltrexone on their psoriasis: 1 - worse; 2 - unchanged; 3 - slightly improved; 4 - somewhat improved; 5 - marked improvement. The response to 4.5 mg of oral naltrexone was as follows: 8/15 marked improvement; 2/15 somewhat improved; and 5/15 unchanged. Three adverse events included insomnia, diarrhea, and self-limited headache. Marked improvement was seen by 53% of the 15 patients. Low-dose naltrexone regulates lymphocyte responses, reduces cytokine production, and likely reduces mast cell activity. Low-dose naltrexone is safe, inexpensive, and appears be effective in this open-label study.

Pharmacist Dr. Loyd V. Allen, Jr. reviews methods of preparation, uses, packaging, labeling, stability, and quality control of 1.5mg and 4.5mg capsules of low dose naltrexone. An interesting and unexpected effect of naltrexone is its action in pain relief for different disorders. A notable aspect of naltrexone use in pain patients is that the dose is only about one-tenth of the normal dose. Since naltrexone HCl is available in 50-mg tablets, low-dose naltrexone must be compounded for patients.

We read with great interest the study by Jasans-Barceló et al. where they report the response of low-dose naltrexone in 8 patients of HHD. One interesting observation we made in the article was the response of one patient to the standard higher dose (50 mg) of naltrexone. Two previous studies that used the 50mg dose in HHD patients (3 patients total) had failed to show any positive response.

The incidence of colorectal cancer (CRC) is increasing annually worldwide. However, traditional chemotherapy has obvious side effects. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Therefore, the aim of this study was to explore the mechanisms underlying the inhibitory effect of LDN on CRC progression in vivo and in vitro. We found that expression of macrophage markers (F4/80, CD68) was increased in nude mice treated with LDN compared with the control group (p < 0.05). Additionally, levels of M1 macrophage phenotypic markers (CD80) and cytokines (tumor necrosis factor-α, TNF-α) were higher than in the control group (p < 0.05). LDN was able to upregulate expression of the opioid growth factor receptor (OGFr) and apoptosis-related factors Bax, caspase-9, caspase-3, and PARP and downregulate expression of Bcl-2, Survivin, and Ki67 to promote tumor cell apoptosis. Therefore, we speculate that LDN reduces tumor size by increasing levels of M1-like macrophages and activating the Bax/Bcl-2/caspase-3/PARP signaling pathway to induce apoptosis. We suggest that LDN has potential for the treatment of CRC.

Multiple sclerosis (MS) is accompanied by decreases in serum endogenous enkephalin/endorphins and alterations in inflammatory cytokines. This retrospective analysis of serum levels was conducted in 53 patients with established relapsing-remitting MS treated with the disease-modifying therapies (DMT) glatiramer acetate, dimethyl fumarate or with the biotherapeutic low dose naltrexone (LDN) to elevate enkephalins, an off-label alternative. Opioid growth factor (OGF), an inhibitory endogenous opioid involved in modulating cellular replication, was measured and correlated to serum β-endorphin, IL-17A and TNFα. Results revealed that MS leads to a significant reduction in OGF levels in subjects on DMTs, but patients on LDN had OGF levels comparable to non-MS controls. Individuals on DMTs had significantly elevated TNFα levels, while IL-17A levels were significantly elevated only in patients taking dimethyl fumarate. A direct correlation was established between OGF and IL17A indicating a potential interaction between the OGF-OGFr axis and pro-inflammatory T-helper cells providing insight into the disease etiology

Low-dose naltrexone (LDN) has become a hot topic in many fields of medicine, including dermatology. It has gained popularity as an alternative, off-label treatment that works by targeting inflammation. Patients may ask you about LDN as a treatment option for a variety of inflammatory skin conditions, specifically in comparison to more traditional systemic treatments. It is important for dermatologists to know what LDN is, how it works, how to prescribe it, and what side effects should be monitored.