Research

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).

One can compound LDN using commercially available tablets and orange juice. Doing so helps improve the texture and taste over using water. The ratio of medicine to juice is described. It is recommended to keep the mixture in the refrigerator and shake it prior to dispensing. Other juice flavors can be used based on patient preference. Following this procedure, patients can expect to get 3 months of medicine for about $15. Making LDN inexpensively should allow for the expansion of the use of LDN.

AIMS: Opioid receptor blockers such as naloxone and naltrexone have been suggested to have a bone mass-increasing effect. However, the mechanisms at play have not been clarified. We examined the effects of naltrexone on osteoblasts and determined the expression of opioid growth factor receptor (OGFR) in osteoblasts. Naltrexone blocks the OGFR and other canonical opioid receptors. Thus, we designed experiments to clarify the effects of naltrexone on bone tissue by examining the physiological role of OGFR signaling in osteoblasts and the changes in bone structure after naltrexone systemic administration in mice.

MAIN METHODS: We used mouse osteoblast-like cell line MC3T3-E1 for in vitro experiments. We cultured MC3T3-E1 cells in the presence of the OGFR agonist met-enkephalin (met-enk). Then, we measured cell proliferation activity and analyzed the expression levels of cell proliferation-related genes. For our in vivo experiments, we administered naltrexone intraperitoneally to mice daily for 28 days and administered the animals in the control group equivalent volumes of saline. After sacrificing the mice, we performed micro-computed tomography and bone morphology analyses.

KEY FINDINGS: Met-enk suppressed cell proliferation in MC3T3-E1 cells. Moreover, low dose naltrexone administration significantly increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when comparing the values for the same variables in the control group.

SIGNIFICANCE: Our results suggest that naltrexone increases bone mass due to osteoblast number increments caused by the OGFR signaling block. Opioid receptor blockers have potential as therapeutic agents for osteoporosis as well as opioid antagonists.

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use.

Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Naltrexone is a competitive opioid receptor antagonist approved as supportive treatment in alcohol dependence and opioid addiction. In a dose 50-100 mg daily, naltrexone is used off-label in dermatology for the treatment of trichotillomania and different types of pruritus. At a dose as low as 1-5 mg of drug per day, naltrexone demonstrates immunomodulatory action i.e. modulates Toll-like receptors signaling, decreases release of proinflammatory cytokines (tumor necrosis factor, interleukin-6, interleukin-12), inhibits T lymphocyte proliferation, down-regulates the expression of chemokine receptors and adhesion molecules. The efficacy of standard and low doses of naltrexone in a variety of dermatological disorders has been reported. These include diseases such as familial benign chronic pemphigus (Hailey-Hailey disease), dermatomyositis, systemic sclerosis, psoriasis and lichen planopilaris. Optimistic preliminary findings, low cost of therapy and good tolerance make naltrexone a promising alternative therapy or adjunct drug in dermatology.