Interactions of Analgesics with Cisplatin: Modulation of Anticancer Efficacy and Potential Organ Toxicity

Cisplatin (CDDP), one of the most eminent cancer chemotherapeutic agents, has been successfully used to treat more than half of all known cancers worldwide. Despite its effectiveness, CDDP might cause severe toxic adverse effects on multiple body organs during cancer chemotherapy, including the kidneys, heart, liver, gastrointestinal tract, and auditory system, as well as peripheral nerves causing severely painful neuropathy. The latter, among other pains patients feel during chemotherapy, is an indication for the use of analgesics during treatment with CDDP. Different types of analgesics, such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), and narcotic analgesics, could be used according to the severity of pain. Administered analgesics might modulate CDDP’s efficacy as an anticancer drug. NSAIDS, on one hand, might have cytotoxic effects on their own and few of them can potentiate CDDP’s anticancer effects via inhibiting the CDDP-induced cyclooxygenase (COX) enzyme, or through COX-independent mechanisms. On the other hand, some narcotic analgesics might ameliorate CDDP’s anti-neoplastic effects, causing chemotherapy to fail. Concerning safety, some analgesics share the same adverse effects on normal tissues as CDDP, augmenting its potentially hazardous effects on organ impairment. This article offers an overview of the reported literature on the interactions between analgesics and CDDP, paying special attention to possible mechanisms that modulate CDDP’s cytotoxic efficacy and potential adverse reactions.

Asprosin, a Novel Therapeutic Candidate for Painful Neuropathy: An Experimental Study in Mice

Neuropathic pain is primarily caused by nervous system lesions or dysfunction. Evidence strongly suggests that obesity, diabetes and cancer are common in chronic pain conditions, and pain complaints are common in these individuals. Recent studies indicate presence of a strong link between adipokines and neuropathic pain. However, the effects of asprosin, a novel adipokine, on neuropathic pain have not been studied in animal modelsMouse models were employed to investigate the antinociceptive effectiveness of asprosin in the treatment of three types of neuropathic pain, with metabolic (streptozocin/STZ), toxic (oxaliplatin/OXA), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, respectively. Changes in nociceptive behaviors were assessed relative to controls using thermal (the hot plate and cold plate tests, at 50 °C and 4 °C respectively) and mechanical pain (Von Frey test) tests at baseline and 30, 60, 120 and 180 minutes after asprosin administration. Serum level of asprosin was quantified by ELISA. In all three neuropathic pain models (STZ, OXA and CCI), asprosin administration significantly reduced both mechanical and thermal hypersensitivity, indicating that it exhibits a clear-cut antihypersensitivity effect in the analyzed neuropathic pain models. Asprosin levels were significantly lower in three types of neuropathic pain compare to controls (p < 0.05). The results yielded by the present study suggest that asprosin exhibits an analgesic effect in the neuropathic pain models and may have clinical utility in alleviating chronic pain associated with disease and injury originating from peripheral structures.

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

Dispensing patterns of drugs used for neuropathic pain and adherence to NeuPSIG guideline: an observational study

Background Neuropathic pain is a common chronic ailment that can be challenging to treat because of the heterogeneity of its etiologies, symptoms, and underlying mechanisms. Drugs to treat neuropathic pain are highly prescribed; however, limited data exist on the rates and patterns of dispensing in Lebanon. This study was conducted to assess the patterns of dispensing neuropathic pain drugs and adherence to NeuPSIG guideline in the Lebanese adult population. An observational study was conducted at 30 community pharmacies over 10 months. Adults presenting to the community pharmacy with a prescription of at least one pain medication and diagnosed with a neuropathic pain disorder were interviewed using a questionnaire that included demographic characteristics of patients, comorbidities, neuropathic pain disorder type, physicians’ specialty, and the class and number of prescribed medications. Results A total of 360 patients diagnosed with painful neuropathy were enrolled in our study. The mean patients’ age was 50.2 years. Guideline-recommended first-line agents (serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and gabapentinoids) were prescribed to 278 patients (77.2%), with pregabalin being the most used drug (60.5%), nonsteroidal anti‐inflammatory drugs (46.8%), opioids (15.8%), and topical agents (5.5%). Combination treatment for neuropathic pain was prescribed to 78.3% of patients. Conclusions In Lebanon, neuropathic pain management comply with the international NeuPSIG guideline. Pregabalin is the most commonly used drug, and combination treatments are usually needed to alleviate neuropathic pain.

2D vs 3D morphological analysis of dorsal root ganglia in health and painful neuropathy

Dorsal root ganglia (DRGs) are clusters of sensory neurons that transmit the sensory information from the periphery to the central nervous system, and satellite glial cells (SGCs), their supporting trophic cells. Sensory neurons are pseudounipolar neurons with a heterogeneous neurochemistry reflecting their functional features. DRGs, not protected by the blood brain barrier, are vulnerable to stress and damage of different origin (i.e., toxic, mechanical, metabolic, genetic) that can involve sensory neurons, SGCs or, considering their intimate intercommunication, both cell populations. DRG damage, primary or secondary to nerve damage, produces a sensory peripheral neuropathy, characterized by neurophysiological abnormalities, numbness, paraesthesia and dysesthesia, tingling and burning sensations and neuropathic pain. DRG stress can be morphologically detected by light and electron microscope analysis with alterations in cell size (swelling/atrophy) and in different sub-cellular compartments (i.e., mitochondria, endoplasmic reticulum, and nucleus) of neurons and/or SGCs. In addition, neurochemical changes can be used to portray abnormalities of neurons and SGC. Conventional immunostaining, i.e., immunohistochemical detection of specific molecules in tissue slices can be employed to detect, localize and quantify particular markers of damage in neurons (i.e., nuclear expression ATF3) or SGCs (i.e., increased expression of GFAP), markers of apoptosis (i.e., caspases), markers of mitochondrial suffering and oxidative stress (i.e., 8-OHdG), markers of tissue inflammation (i.e., CD68 for macrophage infiltration), etc. However classical (2D) methods of immunostaining disrupt the overall organization of the DRG, thus resulting in the loss of some crucial information. Whole-mount (3D) methods have been recently developed to investigate DRG morphology and neurochemistry without tissue slicing, giving the opportunity to study the intimate relationship between SGCs and sensory neurons in health and disease. Here, we aim to compare classical (2D) vs whole-mount (3D) approaches to highlight “pros” and “cons” of the two methodologies when analysing neuropathy-induced alterations in DRGs.

Diabetic neuropathy: the “anesthetized” complication

Diabetic peripheral neuropathy (DPN) is one of the most common complications of type 1 and type 2 diabetes. This microangiopathic complication is present in 50% of patients with more than 20 years of disease and approximately 18-30% of those who develop it produce painful neuropathy; it is present in 4%-18% of cases. The difficulty in the diagnosis of DPN is currently linked to the absence of a clinical-laboratory marker, such as microalbuminuria for nephropathy, and the need therefore for clinical evaluation by means of: history and objective examination analysed with a score; instrumental confirmation of the presence of fibre damage by studying the small and large nerve fibres. The clinical problem remains to diagnose as soon as possible: the absence of the complication; the presence of DPN in the dichotomous presentation of pain and anaesthesia, in most diabetic patients starting with those who have a longer duration of the disease. This would allow highlighting: patients at high ulcerative risk; those with the presence of important sensory-pain disorders to whom pain therapy should be best addressed. The review will attempt to describe the most recent advances on DPN and therefore also of its diagnosis and its treatment, which starts with lifestyle modification, optimal metabolic control, achieved not too aggressively, intervention on other risk factors, and antioxidant therapy. A more precise and distinct sensory profile of patients with DPN and painful DPN may help to identify those who will respond to one treatment rather than another. Detailed sensory profiles will then lead to tailored treatment for subgroups of patients with painful DPN. KEY WORDS: neuropathy; diabetes; MNSI; MNDS; pain medications.

Peripheral Neuropathy: A Practical Guide for Internists

Diagnosing peripheral neuropathy is essential for the majority of clinical specialties, as it often reveals systemic underlying diseases that are rarely purely neurological. The patient’s history and thorough clinical examination represent the foundation of an early diagnosis. For internal medicine practitioners, it is important to consider common causes at first and search for diabetes, alcoholism or vitamin B12 deficiency, whilst following a diagnosis algorithm that encompasses cues to less popular aetiologies such as systemic vasculitis or paraproteinemia. Prior to requesting nerve conduction studies or further investigations, a few characteristics of peripheral neuropathy should be sought: onset, symmetry, distribution and function impairment (either sensory or motor). Given its interdisciplinary nature, peripheral neuropathies are managed via tight collaboration between the specialist and the internist. Although symptomatic treatment for painful neuropathy is available, treating the underlying disease is fundamental.

Bridging the gap in neuropathic pain treatment: The potential role of astaxanthin

Neuropathic pain is a challenging condition to treat. It is heterogeneous in nature and could be resistant to treatment with commonly prescribed analgesics. Current management strategies fail to achieve adequate or satisfactory pain relief in a high proportion of patients. The previous review mentioned that only less than 50% of patients can achieve good pain control with standard treatment. The available treatment only focuses in the symptom control, and does not interfere with the progressing damage of the nerve. Astaxanthin is a very potent anti-oxidant. In this review, we discuss about the potential use of astaxanthin for the add-on treatment of painful neuropathy.

The Antagonism of the Prokineticin System Counteracts Bortezomib Induced Side Effects: Focus on Mood Alterations

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.