Pharmacology/Drug Development

Chronic pain disproportionately affects older adults, severely impacting quality of life and independent living, with musculoskeletal pain most prevalent. Chronic musculoskeletal pain is associated with specific structural alterations in the brain and interindividual variability in brain structure is likely an important contributor to susceptibility for the development of chronic pain. However, understanding of age-related structural changes in the brain and their associations with chronic musculoskeletal pain is currently limited. Oxytocin (OT), a neuropeptide present in the periphery and central nervous system, has been implicated in pain attenuation. Variation of the endogenous OT system (e.g., OT receptor genotype, blood, saliva, and cerebrospinal fluid OT levels) is associated with morphology in brain regions involved in pain processing and modulation. Intranasal OT administration has been shown to attenuate pain. Yet, studies investigating the efficacy of OT for management of chronic musculoskeletal pain are lacking, including among older individuals who are particularly susceptible to the development of chronic musculoskeletal pain. The goal of this focused narrative review was to synthesize previously parallel lines of work on the relationships between chronic pain, brain morphology, and OT in the context of aging. Based on the existing evidence, we propose that research on the use of intranasal OT administration as an intervention for chronic pain in older adults is needed and constitutes a promising future direction for this field. The paper concludes with suggestions for future research in the emerging field, guided by our proposed

Cebranopadol is a novel first-in-class analgesic with highly potent agonistic activity at nociceptin/orphanin FQ peptide (NOP) and opioid receptors. It is highly potent and efficacious across a broad range of preclinical pain models. Its side effect profile is better compared to typical opioids. Mechanistic studies have shown that cebranopadol's activity at NOP receptors contributes to its anti-hyperalgesic effects while ameliorating some of its opioid-type side effects, including respiratory depression and abuse potential. Phase II of clinical development has been completed, demonstrating efficacy and good tolerability in acute and chronic pain conditions.This article focusses on reviewing data on the preclinical in vitro and in vivo pharmacology, safety, and tolerability, as well as clinical trials with cebranopadol.

Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient's quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.

Ion channels, due to their prominent localization in primary sensory neurons and other key structures in pain processing, are regarded as a major class of drug targets for modulating pain sensation and controlling chronic pain. Here, we review the implications of some ion channels in pain transduction and the preclinical and clinical investigations on drugs that target such channels in pain studies. The discussion will be limited to voltage-gated calcium channels, transient receptor potential channels, acid-sensing ion channels, and PIEZO channels. Descriptions of other important channels in pain signaling, including voltage-sensitive sodium channels, are reported elsewhere in this volume.