Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.

Metrics & More Article Recommendations Dear Editor, I have read with interest the viewpoint entitled Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host−Virus Interaction, and Proposed Neurotropic Mechanisms by Baig et al. 1 This letter is supposed to supplement the aforementioned article with expanded scope on pathophysiological mechanisms which could prove salient in elucidating pathogenesis, seeking treatment, or considering clinical implications.

Alzheimer’s disease (AD) is a neurodegenerative disorder with a growing epidemiological importance characterized by significant disease burden. Sleep-related pathological symptomatology often accompanies AD. The etiology and pathogenesis of disrupted circadian rhythm and AD share common factors, which also opens the perspective of viewing them as a mutually dependent process. This article focuses on the bi-directional relationship between these processes, discussing the pathophysiological links and clinical aspects. Common mechanisms linking both processes include neuroinflammation, neurodegeneration, and circadian rhythm desynchronization. Timely recognition of sleep-specific symptoms as components of AD could lead to an earlier and correct diagnosis with an opportunity of offering treatments at an earlier stage. Likewise, proper sleep hygiene and related treatments ought to be one of the priorities in the management of the patient population affected by AD. This narrative review brings a comprehensive approach to clearly demonstrate the underlying complexities linking AD and circadian rhythm disruption. Most clinical data are based on interventions including melatonin, but larger-scale research is still scarce. Following a pathophysiological reasoning backed by evidence gained from AD models, novel anti-inflammatory treatments and those targeting metabolic alterations in AD might prove useful for normalizing a disrupted circadian rhythm. By restoring it, benefits would be conferred for immunological, metabolic, and behavioral function in an affected individual. On the other hand, a balanced circadian rhythm should provide greater resilience to AD pathogenesis.

Background Multiple sclerosis (MS) with onset in the setting of acute SARS-CoV-2 virus infection has been reported, and reactivation of MS following non-mRNA COVID-19 vaccination has been noted, but there have only been three reports of newly diagnosed MS following exposure to mRNA COVID-19 vaccine. The association cannot be determined to be causal, as latent central nervous system demyelinating disease may unmask itself in the setting of an infection or a systemic inflammatory response. We report a series of 5 cases of newly diagnosed MS following recent exposure to mRNA COVID-19 vaccines. Latency from vaccination to initial presentation varied. Neurological manifestations and clinical course appeared to be typical for MS including response to high dose steroids in 4 cases and additional need for plasmapheresis in one case. Conclusion Acute neurological deficits in the setting of recent mRNA COVID-19 vaccine administration may represent new onset multiple sclerosis.

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