Pharmacology/Drug Development

Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days ), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity.

Mesenchymal stem cells (MSCs) derived exosomes (Exos) are one of the most promising candidate for the treatment of this condition. However, the underlying molecular mechanism remains uncertain. Here we investigated the therapeutic effect of exosomal miR-181c-5p (ExomiR-181c-5p) on a rat model of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI). In this study NP model was established using the CCI method. NP levels were assessed using PWT and PWL. Microarray analysis and RT-PCR were used to determine the relative expression of miR-181c-5p. MSC-derived exosomes were extracted using the total exosome isolation reagent characterized by WB and NTA. MiR-181c-5p was loading into Exos using electroporation. The inflammation response in microglia cells and CCI rats were assessed by ELISA assay respectively. Our study demonstrates that miR-181c-5p expression was obviously decreased in a time-dependent manner in CCI rats. MiR-181c-5p was effectively electroporated and highly detected in MSC-derived Exos. ExomiR-181c-5p internalized by microglia cells and inhibit the secretion of inflammation factors. ExomiR-181c-5p intrathecal administration alleviated neuropathic pain and neuroinflammation response in CCI rats. Taken together, ExomiR-181c-5p alleviated CCI-induced NP by inhibiting neuropathic inflammation. ExomiR-181c-5p may be a valid alternative for the treatment of neuropathic pain and has vast potential for future development.

Currently, ketamine is used in treating multiple pain, mental health, and substance abuse disorders due to rapid-acting analgesic and antidepressant effects. Its limited short-term durability has motivated research into the potential synergistic actions between ketamine and psychotherapy to sustain benefits. This systematic review on ketamine-assisted psychotherapy (KAP) summarizes existing evidence regarding present-day practices. Through rigorous review, seventeen articles that included 603 participants were identified. From available KAP publications, it is apparent that combined treatments can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances. Despite much variance in how KAP is applied (route of ketamine administration, ketamine dosage/frequency, psychotherapy modality, overall treatment length), these findings suggest psychotherapy, provided before, during, and following ketamine sessions, can maximize and prolong benefits. Additional large-scale randomized control trials are warranted to understand better the mutually influential relationships between psychotherapy and ketamine in optimizing responsiveness and sustaining long-term benefits in patients with chronic pain. Such investigations will assist in developing standardized practices and maintenance programs.

Both chronic pain and sleep disorders are associated with a reduction in the quality of life. They can be both a cause and a consequence of each other, and should therefore be simultaneously treated. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related changes in sleep parameters in a preclinical chronic pain mice model, by partial sciatic nerve ligation. We evaluated the quantity, duration, and depth of sleep by analyzing the electroencephalogram and voluntary activity by counting the number of wheel rotations to determine various symptoms of sleep disorders, including reduced total sleep time, fragmentation, low quality, and impaired activity in the daytime. Suvorexant and mirtazapine normalized the reduction in sleep time and fragmented sleep, further regaining the sleep depth at sleep onset in the chronic pain state in nerve-ligated mice. Mirtazapine also increased the percentage of rapid eye movement sleep in mice. Suvorexant decreased voluntary activity, which was prolonged after administration; however, mirtazapine did not decrease it. Although the effects of suvorexant and mirtazapine on sleep and activity are different, both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

Since its adoption as a treatment for neuropathic pain in the 1960s, radiofrequency ablation (RFA) has continued to gain popularity for the management of various pain etiologies. Although RFA is considered to be a safe procedure, post-neurotomy neuritis (PNN), a neuropathic-type pain, is one of the most common side effects. Due to the increasing recognition of PNN, some providers have attempted to mitigate the risk of PNN by injecting local corticosteroids at the site of RFA following the procedure. Recent studies have generally concluded that corticosteroids do not protect against the development of PNN, however, they have been limited by their retrospective study designs and the low incidence of PNN.

Buprenorphine (BUP) can be a safe and effective alternative to traditional opioids for many patients with chronic pain. For patients on higher doses of opioids, rotation to BUP is complicated by the requirement of an opioid-free interval or withdrawal during the transition. Microdosing inductions, in which BUP is gradually titrated, while full agonist opioids are continued, are a viable alternative to traditional inductions. The objective of this article is to review the current literature on BUP microdosing induction, with a focus on patients using opioids for pain. A literature review of the PubMed database was performed in the United States on articles published from inception to May 2021. A total of 34 publications were included. The most commonly utilized microdosing strategy involved administering divided doses of sublingual (SL) products marketed for opioid use disorder treatment, with 25 (73.5%) articles reporting use of partial SL tablets or films (ranging from 1/8 to 1/2 of a 2 mg product) at some point during the induction. Transdermal patches, low-dose SL BUP available in Europe, intravenous BUP, and buccal BUP have also been used. Beyond the products used, the speed of the microinduction, setting, final BUP dosing, and management of concomitant full agonists vary widely in the literature. Microdosing regimens should be individualized based on local guidelines and patient-specific factors. Further studies comparing the safety and efficacy of different protocols are warranted.