Research

Recent anecdotal evidence suggests that oral low-dose naltrexone (LDN) is effective for Hailey–Hailey disease (HHD) but suffers the limitation of immediate relapse following cessation of the medication. With lack of safety data on long-term administration of LDN, we explored the utility of a topical diphenhydramine/ketamine (DK) cream in maintaining the remission achieved with LDN. A 42-year-old male with treatment-refractory HHD remitted with 5 mg naltrexone/day but relapsed on stopping the drug. Symptoms abated after restarting LDN. The impact of regular twice-a-day application of a specially formulated DK cream containing diphenhydramine (2% w/w) and ketamine (1% w/w) over the affected areas on maintenance of remission was explored till the next relapse. Our approach enabled dose reduction of naltrexone to 3 mg/day without loss of treatment benefit. After 3-month overlap of naltrexone and DK cream, withdrawal of naltrexone maintained remission with only the topical regime with no adverse effects till 4 months of follow-up. The use of topical agents with anti-inflammatory, antipruritic, antinociceptive, and naltrexone-mimicking properties merits exploration as an option to provide short but significant period of naltrexone-free maintenance of remission to patients with HHD.

Hailey-Hailey disease (HHD), or benign familial pemphigus, is an autosomal dominant genodermatosis that usually presents between the second and fourth decades of life as painful blisters and erosions in the intertriginous areas. It is characterized by a remitting, relapsing course, and recurrent episodes of superinfection. HHD is caused by mutations in the ATP2C1 gene.

Although HHD is not life threatening, it has a significant negative impact on patient quality of life. Many treatments exist, but none is highly effective. We report a case of a patient with recalcitrant HHD dramatically improving with the combination of low dose naltrexone and magnesium chloride supplementation.

Naltrexone is a competitive antagonist of μ, k and γ opioid receptors, used for treatment of alcoholism and opioid addiction. Low-dose naltrexone (LDN) is defined as daily doses ranging from 1mg to 5mg. This is purported to have a paradoxical effect that leads to an increase in endogenous opioids, including beta-endorphins, which have anti-inflammatory properties. These mechanisms may also justify their possible role in the treatment of inflammatory conditions. The aim of this article is to discuss the use of LDN as an adjuvant therapeutic option in symptomatic alopecias presenting with trichodynia. Trichodynia is defined as scalp discomfort of variable intensity presenting as diffuse or localized dysesthesia and may be described by patients as pain, pruritus, or burning. These are common symptoms in patients with hair loss that negatively impacts quality of life. Scalp discomfort may be refractory to conventional therapies and does not yet have a specific therapeutic guideline. For these cases, LDN would be a possible alternative to be added to the therapeutic arsenal owing to its anti-inflammatory properties, analgesic potential, low cost, and few adverse effects described. Further studies are needed to standardize dosing, better understand its mechanism of action, and evaluate its potential therapeutic indications.

Endogenous opioids are neuro-peptides with multifunctional properties. Historically, opioids are used to mediate pain; however, excess opiate consumption can lead to addiction. One endogenous opioid, methionine enkephalin (MENK), was reported to modulate cell growth, MENK was identified as an opioid growth factor (OGF) that interacts with the OGF receptor (OGFr) and regulates cell proliferation. Further, opioid antagonists, including naltrexone and naloxone are widely used to reverse drug and alcohol overdoses. Naltrexone (NTX) acts on all opioid receptors, blocking the interaction between OGF and OGFr, and thus influencing cell growth. During the last decades, insights have been made concerning the interaction between OGF and OGFr, confirming that both opioids and opioid antagonists have an important role in balancing host homeostasis, host immunity and mediating cancer therapy. This review provides insight into the interactions between OGF and OGFr in the treatment of cancers.

Darier (DD) and Hailey-Hailey (HHD) diseases are both genodermatoses caused by defective calcium transport and homeostasis. DD is caused by a mutation of the ATPA2A gene and HHD by a mutation of the ATP2C1 gene. Clinically, the former is characterized by itchy, painful macerations with red-brownish papules in a seborrheic distribution; the latter manifests with painful blisters that rupture, leaving erosions in intertriginous areas. Treatment options for both conditions are limited and include topical steroids, systemic steroids, retinoids, antibiotics, topical aminoglycosides, as well as dapsone and immunosuppressive therapies. One additional promising and novel therapeutic option for these diseases is naltrexone.

The use of LDN at 4.5 mg once daily in patients with HHD has shown promise in early observational studies. In contrast to the classic doses of 50-100 mg, LDN does not need any laboratory monitoring and has a favourable safety profile, with common side effects of vivid dreams and headache. Prior to LDN therapy, patients should be carefully screened for recent use and/or prior dependence of opioids. Further studies to assess the efficacy of naltrexone in low-dose or higher doses in these 2 diseases are needed.

Gottron papules, a heliotrope rash, scalp and extremity erythema, pruritus, and fatigue are the characteristic signs and symptoms of amyopathic dermatomyositis (ADM). Amyopathic dermatomyositis is considered a distinct entity from dermatomyositis (DM) because the characteristic muscle weakness and muscle enzyme elevations of DM are absent in ADM. With respects to treatment, ADM treatments have traditionally included topical corticosteroids and/or systemic immunosuppressants and immunomodulators. Herein we present a patient with refractory ADM that was responsive to low-dose naltrexone therapy

University of Barcelona physicians studied the effect of low dose naltrexone (LDN) on 14 patients with Hailey-Hailey disease (HDD), also known as benign chronic pemphigus. The authors suggest that future studies be done to determine if certain genetic profiles are associated with favorable responses to LDN.

INTRODUCTION: Hailey-Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions and macerated intertriginous skin.

CASE REPORT: We present a 66-year-old woman with a personal 35-year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25mg nightly. Six weeks later, complete clearing was observed.

DISCUSSION: At typical doses, naltrexone blocks μ and δ opiod receptors, thereby blocking the union of β -endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low-dose naltrexone may also exert an anti-inflammatory action through its antagonist effect on toll-like receptor 4 found on macrophages.

CONCLUSION: We consider that low-dose naltrexone is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.

A 36- year old male with a past history significant for bipolar disorder, depression, and PTSD presented to UW Pain Clinic for management of ongoing pain related to an electrical burn injury (4.5%) to the left hand and flank sustained in August 2016. He underwent a skin graft for the burn six months later and has experienced difficulties with his pain since. During the consult, the patient described his pain as a burning, tingling sensation over the left flank and hand. He also experiences sharp muscle cramps in that area which are made significantly worse in cold temperatures. His described pain upon initial presentation was an 8-9/10. Prior to the consult, the patient was prescribed several medications for muscle spasms and neuropathic pain including baclofen, Lyrica®, Topamax®, Cymbalta®, and topical pain creams without significant benefit. Patient then underwent a trial of IV lidocaine infusion however this treatment likewise did not provide any significant pain relief. Considering the lack of success with the previous attempted treatment regimens, patient was prescribed Low Dose Naltrexone (LDN). Within 8 weeks, the patient reported meaningful pain relief compared to the previous unsuccessful treatments with continued progress reported during subsequent visits. In this case, LDN provided effective relief for neuropathic burn related pain where previous conventional modalities failed. Potential explanations include direct pharmacological effects of LDN and/or its synergistic effects with the patient's other medications that continued to be prescribed. This case provides the opportunity to further explore the use and benefits of LDN for neuropathic pain in patients, particularly those with burn related injuries who do not favorably respond to conventional medication therapies.

The first scientific reference of fibromyalgia as a medical disorder occurred in 1981. Since then, pain management experts have continuously debated diagnosis criteria, potential pathologies, and viable treatment options due to the complex nature of the disease. For both patient and clinician, the efficacy of current pharmacologic treatments can be frustrating. The clinical benefit of medications is often modest at best. In fact, the 2016 European League Against Rheumatism (EULAR) guideline for managing fibromyalgia could only endorse a 'weak for' recommendation for medication management based on currently available evidence. Additionally, patients may have allergies, contraindications, or previous adverse drug effects precluding the use of available pharmacotherapy. For this reason, and in the context of the opioid crisis, it is important to continue research on practical pharmacotherapy options for fibromyalgia. The purpose of this project is to evaluate the clinical effectiveness of low-dose naltrexone for the treatment of fibromyalgia. This study is a retrospective analysis comparing adapted Brief Pain Inventory scores both pre-, and post- a low-dose naltrexone medication trial (primary outcome). Additional data to be collected includes age, sex, previous/current fibromyalgia pharmacotherapy, participation in non-pharmacologic therapy (i.e. physical therapy, exercise, pain psychology), and adverse drug reactions attributed to low-dose naltrexone. Inclusion criteria is broad and includes all adults diagnosed with fibromyalgia and prescribed low-dose naltrexone from January 2018-January 2019 in the Ascension Wisconsin Center for Pain Management clinics. Results and conclusion are pending IRB approval. (Macfarlane et al, Ann Rheum Dis, 2016).