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1.
Opioids and Sepsis: Elucidating the Role of the Microbiome and microRNA-146.
Abu, Y, Vitari, N, Yan, Y, Roy, S
International journal of molecular sciences. 2022;(3)
Abstract
Sepsis has recently been defined as life-threatening organ dysfunction caused by the dysregulated host response to an ongoing or suspected infection. To date, sepsis continues to be a leading cause of morbidity and mortality amongst hospitalized patients. Many risk factors contribute to development of sepsis, including pain-relieving drugs like opioids, which are frequently prescribed post-operatively. In light of the opioid crisis, understanding the interactions between opioid use and the development of sepsis has become extremely relevant, as opioid use is associated with increased risk of infection. Given that the intestinal tract is a major site of origin of sepsis-causing microbes, there has been an increasing focus on how alterations in the gut microbiome may predispose towards sepsis and mediate immune dysregulation. MicroRNAs, in particular, have emerged as key modulators of the inflammatory response during sepsis by tempering the immune response, thereby mediating the interaction between host and microbiome. In this review, we elucidate contributing roles of microRNA 146 in modulating sepsis pathogenesis and end with a discussion of therapeutic targeting of the gut microbiome in controlling immune dysregulation in sepsis.
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Opioids Preconditioning Upon Renal Function and Ischemia-Reperfusion Injury: A Narrative Review.
Palomino, J, Echavarria, R, Franco-Acevedo, A, Moreno-Carranza, B, Melo, Z
Medicina (Kaunas, Lithuania). 2019;(9)
Abstract
Kidneys have an important role in regulating water volume, blood pressure, secretion of hormones and acid-base and electrolyte balance. Kidney dysfunction derived from acute injury can, under certain conditions, progress to chronic kidney disease. In the late stages of kidney disease, treatment is limited to replacement therapy: Dialysis and transplantation. After renal transplant, grafts suffer from activation of immune cells and generation of oxidant molecules. Anesthetic preconditioning has emerged as a promising strategy to ameliorate ischemia reperfusion injury. This review compiles some significant aspects of renal physiology and discusses current understanding of the effects of anesthetic preconditioning upon renal function and ischemia reperfusion injury, focusing on opioids and its properties ameliorating renal injury. According to the available evidence, opioid preconditioning appears to reduce inflammation and reactive oxygen species generation after ischemia reperfusion. Therefore, opioid preconditioning represents a promising strategy to reduce renal ischemia reperfusion injury and, its application on current clinical practice could be beneficial in events such as acute renal injury and kidney transplantation.
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3.
Experimental medication treatment approaches for depression.
Ionescu, DF, Papakostas, GI
Translational psychiatry. 2017;(3):e1068
Abstract
Depression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression-including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors-about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression. After a brief review of the efficacy of approved antidepressant therapies, we will discuss experimental medication treatments for depression. Specifically, we examine novel medications that are thought to primarily modulate the glutamatergic, cholinergic and opioid systems to achieve antidepressant efficacy. We also give examples of anti-inflammatories, neurokinin-1 modulators, vasopressin antagonists and neurogenesis enhancers that may have a therapeutic role in treatment-resistant depression. The current pipeline of antidepressant treatments is shifting towards medications with novel mechanisms, which may lead to important, life-changing discoveries for patients with severe disease.
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4.
Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction-Recommendations of the Nordic Working Group.
Drewes, AM, Munkholm, P, Simrén, M, Breivik, H, Kongsgaard, UE, Hatlebakk, JG, Agreus, L, Friedrichsen, M, Christrup, LL
Scandinavian journal of pain. 2016;:111-122
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Abstract
BACKGROUND AND AIMS Opioid-induced bowel dysfunction (OIBD) is an increasing problem due to the common use of opioids for pain worldwide. It manifests with different symptoms, such as dry mouth, gastro-oesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation and incomplete evacuation. Opioid-induced constipation (OIC) is one of its many symptoms and probably the most prevalent. The current review describes the pathophysiology, clinical implications and treatment of OIBD. METHODS The Nordic Working Group was formed to provide input for Scandinavian specialists in multiple, relevant areas. Seven main topics with associated statements were defined. The working plan provided a structured format for systematic reviews and included instructions on how to evaluate the level of evidence according to the GRADE guidelines. The quality of evidence supporting the different statements was rated as high, moderate or low. At a second meeting, the group discussed and voted on each section with recommendations (weak and strong) for the statements. RESULTS The literature review supported the fact that opioid receptors are expressed throughout the gastrointestinal tract. When blocked by exogenous opioids, there are changes in motility, secretion and absorption of fluids, and sphincter function that are reflected in clinical symptoms. The group supported a recent consensus statement for OIC, which takes into account the change in bowel habits for at least one week rather than focusing on the frequency of bowel movements. Many patients with pain receive opioid therapy and concomitant constipation is associated with increased morbidity and utilization of healthcare resources. Opioid treatment for acute postoperative pain will prolong the postoperative ileus and should also be considered in this context. There are no available tools to assess OIBD, but many rating scales have been developed to assess constipation, and a few specifically address OIC. A clinical treatment strategy for OIBD/OIC was proposed and presented in a flowchart. First-line treatment of OIC is conventional laxatives, lifestyle changes, tapering the opioid dosage and alternative analgesics. Whilst opioid rotation may also improve symptoms, these remain unalleviated in a substantial proportion of patients. Should conventional treatment fail, mechanism-based treatment with opioid antagonists should be considered, and they show advantages over laxatives. It should not be overlooked that many reasons for constipation other than OIBD exist, which should be taken into consideration in the individual patient. CONCLUSION AND IMPLICATIONS It is the belief of this Nordic Working Group that increased awareness of adverse effects and OIBD, particularly OIC, will lead to better pain treatment in patients on opioid therapy. Subsequently, optimised therapy will improve quality of life and, from a socio-economic perspective, may also reduce costs associated with hospitalisation, sick leave and early retirement in these patients.
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Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications.
Hughes, PA, Costello, SP, Bryant, RV, Andrews, JM
American journal of physiology. Gastrointestinal and liver physiology. 2016;(3):G501-13
Abstract
Opioids are one of the most prescribed drug classes for treating acute pain. However, chronic use is often associated with tolerance as well as debilitating side effects, including nausea and dependence, which are mediated by the central nervous system, as well as constipation emerging from effects on the enteric nervous system. These gastrointestinal (GI) side effects limit the usefulness of opioids in treating pain in many patients. Understanding the mechanism(s) of action of opioids on the nervous system that shows clinical benefit as well as those that have unwanted effects is critical for the improvement of opioid drugs. The opioidergic system comprises three classical receptors (μ, δ, κ) and a nonclassical receptor (nociceptin), and each of these receptors is expressed to varying extents by the enteric and intestinal extrinsic sensory afferent nerves. The purpose of this review is to discuss the role that the opioidergic system has on enteric and extrinsic afferent nerves in the lower GI tract in health and diseases of the lower GI tract, particularly inflammatory bowel disease and irritable bowel syndrome, and the implications of opioid treatment on clinical outcomes. Consideration is also given to emerging developments in our understanding of the immune system as a novel source of endogenous opioids and the mechanisms underlying opioid tolerance, including the potential influence of opioid receptor splice variants and heteromeric complexes.
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6.
Opioids for agitation in dementia.
Brown, R, Howard, R, Candy, B, Sampson, EL
The Cochrane database of systematic reviews. 2015;(5):CD009705
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Abstract
BACKGROUND Agitation is a common experience for people living with dementia, particularly as day-to-day function and cognition start to decline more. At the present time there are limited pharmacological options for relieving agitation and little is known about the safety and efficacy of opioid drugs in this setting. OBJECTIVES To determine the clinical efficacy and safety of opioids for agitation in people with dementia. SEARCH METHODS We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 13 June 2014 using the terms: narcotic OR opioid OR opium OR morphine OR buprenorphine OR codeine OR dextromoramide OR diphenoxylate OR dipipanone OR dextropropoxyphene OR propoxyphene OR diamorphine OR dihydrocodeine OR alfentanil OR fentanyl OR remifentanil OR meptazinol OR methadone OR nalbuphine OR oxycodone OR papaveretum OR pentazocine OR meperidine OR pethidine OR phenazocine OR hydrocodone OR hydromorphone OR levorphanol OR oxymorphone OR butorphanol OR dezocine OR sufentanil OR ketobemidone.ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases such as MEDLINE, EMBASE and PscyINFO, as well as numerous trial registries and grey literature sources. SELECTION CRITERIA Randomised, controlled trials of opioids compared to placebo for agitation in people with dementia. DATA COLLECTION AND ANALYSIS Two authors independently assessed the studies identified by the search against the inclusion criteria. MAIN RESULTS There are currently no completed randomised, placebo controlled trials of opioids for agitation in dementia. There are two potentially relevant trials still in progress. AUTHORS' CONCLUSIONS We found insufficient evidence to establish the clinical efficacy and safety of opioids for agitation in people with dementia. There remains a lack of data to determine if or when opioids either relieve or exacerbate agitation. More evidence is needed to guide the effective, appropriate and safe use of opioids in dementia.
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Medical influences, surgical outcomes: role of common medications on the risk of perforation from untreated diverticular disease.
Gravante, G, Yahia, S
World journal of gastroenterology. 2013;(36):5947-52
Abstract
Numerous drugs, largely used in the wards or at home, have a significant influence on patients with untreated diverticular disease. The consequences can be disastrous, may require an emergency operation, postoperative intensive care, and overall influence the patient's length of stay and the final outcomes. Bearing these considerations in mind the routine or chronic administration of pain-killers, steroids and non-steroidal anti-inflammatory should be balanced in patients with known diverticular disease as it normally happens with other conditions potentially affected by these drugs (i.e., peptic ulcer disease or chronic obstructive pulmonary disease). This is even more important in the old and frail patient where an eventual surgical treatment may not always be possible.
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Ontogeny of the pain.
Rokyta, R, Fricová, J
Physiological research. 2012;(Suppl 1):S109-22
Abstract
The article gives an overview of developmental aspects of the ontogeny of pain both in experimental models and in children. The whole article is devoted to the ontogenesis in pain perception and the possible influence on it. The role of endogenous opioids on the development of pain and other important substances such as serotonin, nerve growth factor (NGF) and nicotine are mentioned. There are also important differences of the ontogenesis of thermal and mechanical nociceptive stimulation. The physiological and pathophysiological findings are the backgrounds for principles of treatment, taking into account the special status of analgesics during ontogeny. In particular there are mentioned the special effects of endogenous opioids and especially morphine. It describes the role of vitamin D and erythropoietin during the development of pain perception. This article also mentioned the critical developmental periods in relation to the perception of pain. The attention is paid to stress and immunological changes during the ontogeny of pain. Another important role is played by microglia. The work is concluded by some statements about the use of physiological and pathophysiological findings during the treatment of pain in pediatric practice. Codein analgesia is also described because codein starts to be very modern drug with the dependence.
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A comprehensive review of opioid-induced hyperalgesia.
Lee, M, Silverman, SM, Hansen, H, Patel, VB, Manchikanti, L
Pain physician. 2011;(2):145-61
Abstract
Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.
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Opioids and renal function.
Mercadante, S, Arcuri, E
The journal of pain. 2004;(1):2-19
Abstract
UNLABELLED Opioids, both endogenous and exogenous, have a strong influence on the renal function through different mechanisms, producing changes in the renal excretion of water and sodium. Several studies have demonstrated that opioids influence renal function, according to the agonist profile used. Mu, kappa, and delta agonists produce different renal effects, although the mechanisms remain unclear. Experimental data have given the input for a possible therapeutic role of kappa agonists for some specific conditions, for example, in treating water retention or hyponatremia occurring in patients who have hepatic cirrhosis with ascites. On the other hand, changes in renal function might strongly condition the use of opioids in the clinical setting, and the knowledge of the relationship between opioids and renal function is mandatory for a tailored approach to accommodate the individual responses in terms of pain intensity, tolerance, and adverse effects experienced by these groups of patients. The influence of renal function when using different opioids in the clinical setting is reviewed, as well as problems related to transplantation, renal damage induced by opioid addiction, and problems related to the use of opioid antagonists in such conditions. PERSPECTIVE Endogenous opioids exert physiologic effects on renal function, and the use of opioids may have an influence on renal activity. Renal impairment has a serious impact on the clearance of most opioids used in the clinical setting. Biochemical and clinical monitoring is mandatory to prevent serious complications.