Research

Hailey-Hailey disease (HHD), or familial benign pemphigus, is a rare autosomal dominant acantholytic dermatosis characterized by blistering, and erythematous, erosive and macerated plaques located primarily in intertriginous areas. Secondary bacterial and viral infections are common. There is no "gold standard" treatment, although many therapeutic modalities have been proposed.

Stiff-Person Syndrome (SPS) is a rare neurologic disorder characterized by severe and progressively worsening muscle stiffness and rigidity. SPS can be very painful due to unpredictable muscle spasms which can be triggered by various stimuli, such as noise, touch, or emotional experiences. There is thought to be an autoimmune component to the disorder. We present the case of a 59-year-old woman diagnosed with SPS who appears to have experienced a dramatic reduction in her symptoms after being treated with Low-Dose Naltrexone (LDN). Prior to this treatment regimen, she had tried many treatments with only limited derived benefit. She was started on LDN and after 6 weeks, reported reductions in pain, anxiety, depression, agoraphobia, and muscle tightness. Upon multiple follow-ups, leading up to 12 months, she continually displayed reduced symptoms and improved quality of life. We conclude that LDN may have some utility in treating and managing the symptoms of SPS. We hypothesize that this may be possible due to LDN operating via anti-inflammatory pathways as well as acting as an opioid antagonist. We assert that further research as it relates to LDN and SPS in addition to other chronic pain conditions is warranted.

Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn's disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances. This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.

AIMS: Cancer is a major worldwide health problem. Cancer cells express opioid growth factor (OGF) which controls their growth. Naltrexone in low dose (LDN) blocks opioid receptors intermittently and controls the replication of cancer cells. The aim of this study was to investigate the effect of LDN and its chemotherapeutic additive effect on the growth of solid Ehrlich carcinoma in mice with focus on the OGFr and immune responses.

MAIN METHODS: Sixty female Swiss albino mice were assigned into 5 groups (n: 12 mice each): (i): normal control, (ii): Solid Ehrlich carcinoma (SEC), (iii): SEC treated with LDN, (iv): SEC treated with 5-fluorouracil (5-FU), (v): SEC treated with LDN + 5-FU. All drugs were started when the tumor became palpable on 9th day. At the end of the study animals were sacrificed, blood and tissue samples were collected. Tumor weight and volume were measured. Splenocytes and myeloid derived suppressor cells (MDSC) were counted. Tumor expression of opioid growth factor receptors (OGFr), serum level of IFN-γ, tumor histopathology (H&E) and immunohistochemistry staining of p21, p53, Bcl2 were assessed.

KEY FINDINGS: All drug-treated groups showed reduction in tumor weight and volume, significant increase of splenocyte with tendency to reduce MDSC cell counts. LDN led to significant increase in OGFr both in solo and in combination with 5FU. Serum IFN-γ is significantly increased by LDN but decreased by 5-FU. Also, LDN and 5FU increased immunehistochemical staining of p21 while decreased immunostaining of Bcl2. In animals treated with a combination of LDN and 5FU a maximal downregulation of the antiapoptotic mediator BCL2 was observed.

SIGNIFICANCE: The current study suggested that LDN may play a role in inhibiting cancer cell growth and highlights the possibility of promising combination with cancer chemotherapeutics, which guarantee further clinical studies for approval.

BACKGROUND: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.

METHODS: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.

RESULTS: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.

CONCLUSIONS: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.

"Treatment with low-dose naltrexone resulted in improvements in pain and quality of life scores without serious side effects among patients with neuropathic corneal pain," according to a presenter at the American Academy of Ophthalmology annual meeting (Oct 11-15, 2019; San Francisco).

“Neuropathic corneal pain is a disease that causes nerve damage and results in pain or discomfort,” Gabriela Dieckmann, MD, from the department of ophthalmology at Tufts Medical Center, said. “Low-dose naltrexone has been used as an off-label treatment for many neuropathic pain diseases, such as fibromyalgia and multiple sclerosis.”

Dieckmann and colleagues conducted a study to determine the efficacy and tolerability of low-dose naltrexone among patients with neuropathic corneal pain (n = 30). All participants were treated with low-dose naltrexone for at least 4 weeks and answered a questionnaire that evaluated ocular pain and quality of life. Patients with any pathology that may cause pain or discomfort were excluded from the study.

The researchers analyzed demographics, changes in pain scores, mean duration of treatment and side effects.

The most common comorbidities prior to treatment were dry eye disease and neuropsychiatric disease. All participants were taking previous systemic medications, mainly nortriptyline and followed by SSRIs.

Treatment with low-dose naltrexone over 14.03 ± 9.8 months reduced mean pain scores by 36.4% (from 4.8 ± 2.18 to 3.08 ± 2). Nearly half of participants (45.8%) showed improvements in pain by at least 50%. Additionally, 12.5% of patients had a positive percentage change in pain scores between 30% and 49.9% and 37.5% of patients improved by less than 30%. Quality of life scores also improved.

Only one patient demonstrated symptoms of a headache related to treatment, but did not discontinue therapy.

“Low-dose naltrexone can be effective as an adjunct treatment for neuropathic corneal pain,” Dieckmann said. “We need to have placebo-controlled studies. We are trying to find the best treatment, the best solution for our patients and with low dose naltrexone we saw an improvement in our patients.”

Poster

In this controlled before-after study based on data from the Norwegian Prescription Database, we examine whether starting off-label use of Low Dose Naltrexone (LDN) is followed by changes in the consumption of psychotropic medicines including antiepileptics. Patients that collected LDN for the first time in 2013 (N = 11247) were included and stratified into three groups based on LDN exposure. We compared differences in means of cumulative number of defined daily doses (DDD) as well as changes in the number of users one year before and one year after starting LDN. There was a dose-response association between increasing LDN exposure and reductions in the number of users of antiepileptics, antipsychotics and antidepressants. There were significant difference-in-differences in DDDs between the groups with the lowest and highest LDN exposure of antipsychotics (1.4 DDD, 95% CI 0.4 to 2.3, p = 0.007), and in number of users of antiepileptics (3.1% points, 95% CI 1.6% to 4.6%, p < 0.001), antipsychotics (2.1% points, 95% CI 1.2% to 3%, p < 0.001), and antidepressants (2.8% points, 95% CI 1.1% to 4.4%, p = 0.001). The findings show an association between the initiation of persistent LDN use and reduced consumption of several psychotropic medicines and antiepileptics. Beneficial effects of LDN in the treatment of psychiatric diseases cannot be ruled out.

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.

INTRODUCTION: Safe and effective alternatives are needed to long-term opioids for the treatment of chronic pain.(1) Low dose naltrexone (LDN) has unique analgesic properties with few side effects. LDN temporarily blocks intrinsic opioid receptors with rebound increase in beta endorphin and methionine enkephalin (Met-Enkephalin) receptors. LDN is also an immune modulator, working at the level of the glial cell as a toll like receptor 4 (TLR4) antagonist.(2) The most commonly reported dose related side effects attributed to LDN include difficulty sleeping and vivid dreams.(2) We reviewed patients who had been prescribed LDN from April 1, 2008 to April 1, 2018. We examined the characteristics of patients who benefitted from LDN and those who did not.

METHODS: After IRB approval, we reviewed the charts of all of our patients for whom we had documentation of a low-dose naltrexone prescription. LDN is not commercially available; prescriptions are filled at compounding pharmacies and rarely covered by insurance. We looked at insurance coverage of each of the patients. We reviewed primary and secondary pain diagnoses, noted responses, frequency and dose of LDN in addition to side effects.

RESULTS: Sixty patients were prescribed LDN. Out of these 60 patients, 26 patients never took LDN or did not return to clinic and 34 patients took LDN. Of the 34 who took LDN, 18 reported no benefit and 16 reported at least ‘some benefit’. We termed those who reported at least ‘some benefit’ as ‘responders’, those who took LDN and did not report any benefit as ‘nonresponders’ and those who did not take LDN or never returned to clinic as ‘noncompliant’. The responders were more likely to have neuropathic pain, complex regional pain syndrome (CRPS) or multiple sclerosis as either a primary or secondary diagnosis. They took LDN for a longer time period and at a higher dose than the nonresponders. (Fig1.; Fig 2) Most of the responders took LDN dose of 3 to 4.5mg/day vs. nonresponders who took 3mg or less daily. (Fig 2) The nonresponders were more likely to have spondylosis or CRPS as a primary or secondary diagnosis. Few nonresponders took LDN for more than 3 months.

DISCUSSION: Responders were more likely to have taken LDN for over 6 months; it may be that LDN takes months for full effect. Among those who took LDN, most had commercial insurance. The retrospective nature of data collection made specific responses to LDN difficult to obtain. There were reports of improvement, often without percentage pain relief or specific reduction in pain scores.

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.