Research

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.

BACKGROUND: 30% of Gulf War veterans developed Gulf War Illness (GWI) with chronic fatigue, pain, and neuropsychological disabilities.

PURPOSE: To assess the efficacy of low-dose naltrexone to treat GWI. Methods: A double-blinded, placebo-controlled crossover trial of naltrexone 4.5 mg/day was conducted. The Clinical global impression scale (CGIS), visual analogue scales (VAS), SF-36 Health Survey, and the Connors Continuous Performance Test assessed treatment response. ClinicalTrials.gov registry Identifier is NCT02206490.

RESULTS: Thirty-seven participants completed the protocol. 100% had upper airway inflammation on examination. 88% were overweight or obese. The CGIS detected improvement in 38% of patients (n = 14) (responders), with 6 of these patients reporting much improvement. Non-responders were rated as showing no change from baseline (n = 18; 49%), or were rated minimally worse (n = 5; 13%). On the SF-36 Health Survey, responders showed significantly less disability than non-responders with respect to emotional limitations (p = 0.01) as well as greater improvement on VAS scales for confusion (p < 0.01), vertigo (p = 0.03) and depression (p = 0.05). All enrolled participants had detectable levels of naltrexone in their serum at the end of the treatment period, with values ranging from 1.5to 18 ng/ml. Anecdotally, some subjects and their spouses felt that naltrexone should be continued after the study ended.

CONCLUSION: This pilot trial suggests low-dose naltrexone may be effective for some with GWI. Further study and consideration of other doses is needed.

Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers.

Fibromyalgia is a syndrome associated with chronic, widespread musculoskeletal pain, fatigue, depression, and cognitive dysfunction. With few U.S. Food and Drug Administration-approved treatment options, there is evidence that low-dose naltrexone, an opioid antagonist approved for opioid and alcohol dependence at high doses, may have efficacy in the treatment of fibromyalgia and chronic pain.

At the doses required for fibromyalgia treatment, naltrexone needs to be compounded, and no data currently exists regarding the long-term stability of low-dose naltrexone capsules. This limits pharmacies to a maximum beyond-use date of 180 days. Our study examined the stability of compounded capsules of low-dose naltrexone in Avicel over 360 days. Naltrexone was extracted from compounded capsules and assessed using reversed-phase high-performance liquid chromatography validated to differentiate between the degraded and undegraded naltrexone. United States Pharmacopeia guidelines state that compounded medications must remain within 10% of the labeled potency at all times during the assigned expiration date for a preparation. Our results show that low-dose naltrexone is stable for 360 days when stored at room temperature and away from light remaining within 90% to 110% of the labeled potency throughout the study period. Based on our study results, the beyond-use date for compounded low-dose naltrexone formulations stored at room temperature and protected from light can be extended to 1 year. The longer beyond-use dating allows patients greater flexibility in using these capsules during the flare-ups associated with fibromyalgia without needing a refill immediately at the onset of symptoms. In addition, it may help compounding pharmacies reduce waste associated with small-batch preparation of these capsules.

BACKGROUND: Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function.

METHODS: Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples.

RESULTS: Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected.

CONCLUSIONS: Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.

Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block toll-like receptor 4, resulting in an analgesic and anti-inflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy.

BACKGROUND AND AIMS: Low dose naltrexone (LDN) is a controversial off-label treatment used by many Crohn’s disease (CD) and ulcerative colitis (UC) patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We wanted to examine whether initiation of LDN therapy by patients with inflammatory bowel disease (IBD) was followed by changes in dispensing of relevant medication.

METHODS: We performed a quasi-experimental before and after study following a sudden increase of LDN use in the Norwegian population in 2013. IBD patients were identified among all patients that had at least one LDN prescription recorded in the Norwegian Prescription Database (NorPD) in 2013. Drug dispensing two years before and after the first LDN prescription was compared.

RESULTS: We identified 582 IBD patients. Among the 256 patients that became persistent LDN users, there were reductions in number of users of all examined drugs (-12%), intestinal anti-inflammatory agents (-17%), other immunosuppressants (-29%), intestinal corticosteroids (-32%), and aminosalicylates (-17%). In subgroups with identified CD and UC patients, there were significant reductions in number of users of intestinal corticosteroids (CD: -44%, UC: -53%) and systemic corticosteroids (UC: -24%). No significant differences in cumulative defined daily doses were observed.

CONCLUSIONS: Our findings imply that the initiation of LDN in IBD is followed by reduced dispensing of several drugs essential in the treatment of CD and UC.

Hailey-Hailey disease (HHD) is a genetic intraepidermal blistering disorder characterized by chronic macerated erosions in intertriginous areas. The recent report of 2 case series demonstrating the efficacy of low-dose naltrexone in the treatment of HHD represents exciting progress in the management of a disease with limited therapeutic options. Herein we present 3 additional cases of HHD demonstrating varying responses to naltrexone.