Research

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.

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