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1
Liren, A.-L., and G. Feuerstein. "The Opioid System in Circulatory Control." Physiology 7, no. 1 (1992): 26–30. http://dx.doi.org/10.1152/physiologyonline.1992.7.1.26.
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Opioid peptides and multiple opioid receptors are found in brain cardiovascular nuclei, autonomic ganglia, the heart, and blood vessels, and opioids induce potent cardiovascular changes. The role of endogenous opioids in normal cardiovascular homeostasis is unclear;however, current data suggest opioid involvement in stress.
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Moyano, Jairo, and Luisa Aguirre. "Opioids in the immune system: from experimental studies to clinical practice." Revista da Associação Médica Brasileira 65, no. 2 (2019): 262–69. http://dx.doi.org/10.1590/1806-9282.65.2.262.
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SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms “immunosuppression,” “immune system,” “surgical procedures,” “analgesics,” “opioids” and “perioperative care.” Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.
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Smith, Howard. "Peripherally-Acting Opioids." Pain Physician 2s;11, no. 3;2s (2008): S121—S132. http://dx.doi.org/10.36076/ppj.2008/11/s121.
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Opioids are broad-spectrum analgesics with potent pain-relieving qualities but also with potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/ formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administered in efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in the brain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during the past decade. It has been known since 1990 that following injection into the rodent hindpaw, d-Ala2 , N-Me-Phe4 , Gly5 -ol-enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administered are too low to have an effect in the central nervous system (CNS). This notion has been supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS, produced antinociception following intradermal administration into the hindpaw, but not when the same dose was administered systemically (subcutaneously at a distant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesic systems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g. respiratory depression, somnolence, addiction). Peripherally-acting opioids, which capitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia with minimal side effects. Key words: Pain, opioids, immune cells, peripherally-acting opioids (PAO), leukocytes, inflammatory pain, peripheral analgesia
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Bleiberg, Benjamin Aaron, Kyle Andrew Westbrook, Chul Ahn, and Saad A. Khan. "Analysis of opioid and adjunctive pain medication prescriptions in lung cancer patients." Journal of Clinical Oncology 39, no. 15_suppl (2021): e24073-e24073. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e24073.
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e24073 Background: Between 1999-2018, the CDC reported 232,000 deaths from prescription opioids. Lung cancer patients receive many opioid and adjunctive pain medication prescriptions. The frequency, duration, and impact of these prescriptions is unknown. Methods: We used the electronic medical record to catalogue opioid and adjunctive pain medication prescriptions given to adult cancer patients at our academic and county-affiliated health systems from 2009-2016. We identified the association of opioid and adjunctive pain medication use with patient characteristics including cancer stage and radiation therapy. Results: 1510 lung cancer patients were identified, of which 1061 had opioid prescriptions (70%). Of patients with prescriptions: hydrocodone was prescribed to 90%, morphine 35%, hydromorphone 17%, fentanyl 16%, and oxycodone 13%. 330/1061 patients had adjunctive medication prescriptions, of which, gabapentin was prescribed to 90%, pregabalin 14% and carbamazepine 2%. 296/330 patients prescribed adjunctive medications also had an opioid prescription with the following frequency: hydrocodone 90%, hydromorphone 33%, fentanyl 27%, morphine 41%, and oxycodone 23% 7/1061 patients with opioids had naloxone prescribed. Opioid usage by cancer stage is shown in the table. 211/1510 patients (13%) had prescriptions for ≥3 different opioids; 97/330 (33%) patients with adjunctive prescriptions, had prescriptions for ≥3 different opioids. Of patients treated with radiation for >4 weeks, 66% received opioids, with the proportion receiving opioids increasing with each fraction of radiation up to a rate of 90% with 5 or more fractions. 87% of patients prescribed opioids alone had an active opioid prescription 3 months after their last date of radiation as did 91% of those prescribed adjunctive medications in addition to opioids. In the total dataset: 55% of patients were from the university system and 45% were from the county system and other settings. Of the lung cancer patients with opioid prescriptions: 69% were from the university system and 31% were from other settings. Conclusions: Opioids are commonly prescribed in patients with any stage of lung cancer, particularly those with stage >1 with hydrocodone being the most prescribed. In the period under study, adjunctive medications such as gabapentin were prescribed much less than and rarely without opioids. Some lung cancer patients received ≥3 distinct opioids, with higher rates seen in those with adjunctive medicine prescriptions. Further studies to evaluate system wide opioid prescribing trends and discrepancies related to demographic factors are needed.[Table: see text]
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Dy, MD, MSc, Sydney Morss, Andrew D. Shore, PhD, Rodney W. Hicks, PhD, ARNP, and Laura L. Morlock, PhD. "Medication errors with opioids: Results from a national reporting system." Journal of Opioid Management 3, no. 4 (2007): 189. http://dx.doi.org/10.5055/jom.2007.0004.
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Background: Errors may be more common and more likely to be harmful with opioids than with other medications, but little research has been conducted on these errors.Methods: The authors retrospectively analyzed MEDMARX®, an anonymous national medication error reporting database, and quantitatively described harmful opioid errors on inpatient units that did not involve devices such as patient-controlled analgesia. The authors compared patterns among opioids and qualitatively analyzed error descriptions to help explain the quantitative results.Results: The authors included 644 harmful errors from 222 facilities. Eighty-three percent caused only temporary harm; 60 percent were administration errors and 21 percent prescribing errors; and 23 percent caused underdosing and 52 percent overdosing. Morphine and hydromorphone had a significantly higher proportion of improper dose errors than other opioids (40 percent and 41 percent compared with 22 percent with meperidine). Hydromorphone errors were significantly more likely to be overdoses (78 percent vs 47 percent with other opioids). Omission errors were significantly more common with fentanyl patches (36 percent compared with 12 percent for other opioids). Wrong route errors were significantly more common with meperidine (given intravenously when prescribed as intramuscular, 34 percent vs 3 percent for morphine). Oxycodone errors were significantly more likely to be wrong drug errors (24 percent vs 11 percent for other opioids), often because of confusion between immediate- and sustained-release formulations.Conclusions: Reported opioid errors are usually associated with administration and prescribing and frequently cause uncontrolled pain as well as overdoses. These patterns of errors should be considered when using opioids and incorporated into pain guidelines, education, and quality improvement programs.
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Herz, Albert. "Opioid reward mechanisms: a key role in drug abuse?" Canadian Journal of Physiology and Pharmacology 76, no. 3 (1998): 252–58. http://dx.doi.org/10.1139/y98-017.
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There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for µ and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective µ and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.Key words: reward mechanisms, endogenouos opioid systems, psychostimulants, alcohol.
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Mafrica, MD, Federica, and Vincenzo Fodale, MD. "Opioids and Down’s syndrome." Journal of Opioid Management 2, no. 2 (2006): 93. http://dx.doi.org/10.5055/jom.2006.0015.
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Opioids are used in clinical practice for sedation, anesthesia, and analgesia. Their effects depend on their pharmacokinetic and pharmacodynamic characteristics. The liver is the major site for the biotransformation of most opioids. The major metabolic pathway is oxidation. Metabolism influences distribution, clearance, onset, and offset of opioid drugs. Action also depends on the coupling of opioids with the class of receptors involved and on localization of specific receptors. Three major types of opioid receptors, designated as μ, ẟ, and ϰ, present in the central nervous system, are coupled to G proteins and inhibit adenylyl cyclase. Down’s syndrome is a congenital condition characterized by mental retardation and particular physical features. Neurotransmission alterations are important. Alteration in the concentration of opioids in the cortex of these patients has been demonstrated. Neurobiological abnormalities and, in some, abnormalities in the neurotransmission systems, anxiety, and, in particular, nociception all suggest that structural and functional alterations of opioid receptors may be present. A clear knowledge of these multiple abnormalities is essential for skillful management of the perioperative period and for a good outcome for patients with Down’s syndrome.
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Corder, Gregory, Daniel C. Castro, Michael R. Bruchas, and Grégory Scherrer. "Endogenous and Exogenous Opioids in Pain." Annual Review of Neuroscience 41, no. 1 (2018): 453–73. http://dx.doi.org/10.1146/annurev-neuro-080317-061522.
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Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein–coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
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Gavidia, R., A. L. Meng, A. Emenike, et al. "0723 Associations Between Opioids, Non-Opioids and Central Sleep Apnea: A Case-Control Study." Sleep 43, Supplement_1 (2020): A275. http://dx.doi.org/10.1093/sleep/zsaa056.719.
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Abstract Introduction Opioids are known to contribute to central sleep apnea (CSA), as they depress responsiveness to carbon dioxide and hypoxia. However, the role of non-opioid medications (antihistamines, myorelaxants, neuroleptics, antidepressants, and hypnotics) in CSA remains unclear. Given the hypothesized impact of non-opioids on the central nervous system, we examined associations between opioid and non-opioid medications and CSA. Methods Among all adults who underwent polysomnography testing at the University of Michigan’s Sleep Center between 2013-2018 (n=10,479), we identified 105 cases of CSA. Of these patients, we randomly selected 300 controls. Demographic and health characteristics, use of medications were obtained from medical charts. We classified study participants into three categories based on medication use: non-opioids only, opioids alone or in combination with non-opioids, and none. CSA was defined as a binary outcome using polysomnographic criteria as per the International Classification of Sleep Disorders-Third Edition. We used logistic regression to examine associations between medication use and CSA. Results Among participants, male:female ratio was 1:1 with a mean age of 49 (±14.3 SD) years. Opioid use alone was rare (4%), but more common in combination with non-opioids (17%), while the exclusive use of non-opioids was found among 38%. In adjusted analyses for age and sex, those who used non-opioid alone were less likely to have a CSA diagnosis (OR=0.88, (95% CI 0.5-1.6); however, the use of opioids (alone or in combination with non-opioids) was associated with a 4-fold higher odds of CSA. Conclusion These data suggest that non-opioids have a protective influence on CSA. Conversely, opioids, alone, or in combination with non-opioids, were associated with increased CSA risk, that may be attributed to opioids alone, or to opioids and non-opioids interactions. However, as opioids were mostly co-prescribed with non-opioids, the sole effect of opioids from the synergistic effect with non-opioids are difficult to disentangle. Support Dr. Gavidia was supported by a T32 Post-Doctoral Fellowship in Neuroscience NIH/NINDS T32 NS 007222
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Gupta, PhD, Kalpna, and Marc L. Weber, MD. "Renal effects of opioid exposure: Considerations for therapeutic use." Journal of Opioid Management 2, no. 4 (2006): 236. http://dx.doi.org/10.5055/jom.2006.0036.
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In recent years, the discovery of peripheral opioid receptors has challenged the dogma of opioids interacting exclusively with the central nervous system. In this article, we describe the current understanding of the roles of opioids and opioid receptors in renal physiology and pathophysiology. The renal response to opioid exposure varies depending upon the specific opioid agonist, dose, and duration of exposure. The known acute effects of opioids on the kidney impact salt and water balance. The chronic effects of opioid exposure on kidney function are largely unknown, but collapsing glomerulopathy has been associated with chronic heroin abuse. Opioid exposure can lead to both physiological and architectural renal changes, and this may have important clinical implications. Since opioids are often used for pain management in patients with existing kidney disease, their role in kidney function warrants attention.
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Hughes, Patrick A., Samuel P. Costello, Robert V. Bryant, and Jane M. Andrews. "Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 3 (2016): G501—G513. http://dx.doi.org/10.1152/ajpgi.00442.2015.
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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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Colasanti, A., EA Rabiner, A. Lingford-Hughes, and DJ Nutt. "Opioids and anxiety." Journal of Psychopharmacology 25, no. 11 (2010): 1415–33. http://dx.doi.org/10.1177/0269881110367726.
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The opioid system plays a crucial role in the neural modulation of anxiety. The involvement of opioid ligands and receptors in physiological and dysfunctional forms of anxiety is supported by findings from a wide range of preclinical and clinical studies, including clinical trials, experimental research, and neuroimaging, genetic, and epidemiological data. In this review we provide a summary of studies from a variety of research disciplines to elucidate the role of the opioid system in the neurobiology of anxiety. First, we report data from preclinical studies using animal models to examine the modulatory role of central opioid system on defensive responses conducive to fear and anxiety. Second, we summarize the human literature providing evidence that clinical and experimental human studies are consistent with preclinical models. The implication of these data is that activation of the opioid system leads to anxiolytic responses both in healthy subjects and in patients suffering from anxiety disorders. The role of opioids in suppressing anxiety may serve as an adaptive mechanism, collocated in the general framework of opioid neurotransmission blunting acute negative and distressing affective responses.
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Gibula-Tarlowska, Ewa, and Jolanta H. Kotlinska. "Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance." Biomolecules 10, no. 10 (2020): 1376. http://dx.doi.org/10.3390/biom10101376.
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Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
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Sehgal, Nalini. "Peripherally Acting Opioids and Clinical Implications for Pain Control." Pain Physician 3;14, no. 3;5 (2011): 249–58. http://dx.doi.org/10.36076/ppj.2011/14/249.
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Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have antiinflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at developing novel treatments for pain with improved side effect profiles. Key words: Opioids, opioid receptors, opioid agonists, peripheral nervous system, peripheral opioid receptors
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Ozdemir, Ercan. "The Role of the Cannabinoid System in Opioid Analgesia and Tolerance." Mini-Reviews in Medicinal Chemistry 20, no. 10 (2020): 875–85. http://dx.doi.org/10.2174/1389557520666200313120835.
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Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of Mitogen-Activated Protein Kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian Target of Rapamycin (mTOR). One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest the reduction of the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception. Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G Protein Coupled Receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations to post-receptor interactions through shared signal transduction pathways. This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.
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Rocchi, Giulio, Bruno Sterlini, Samuele Tardito, et al. "Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders." Neuroscientist 26, no. 4 (2020): 343–58. http://dx.doi.org/10.1177/1073858420902360.
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The opioidergic system and intrinsic brain activity, as organized in large-scale networks such as the salience network (SN), sensorimotor network (SMN), and default-mode network (DMN), play core roles in healthy behavior and psychiatric disorders. This work aimed to investigate how opioidergic signaling affects intrinsic brain activity in healthy individuals by reviewing relevant neuroanatomical, molecular, functional, and pharmacological magnetic resonance imaging studies in order to clarify their physiological links and changes in psychiatric disorders. The SN shows dense opioidergic innervations of subcortical structures and high expression levels of opioid receptors in subcortical-cortical areas, with enhanced or reduced activity with low or very high doses of opioids, respectively. The SMN shows high levels of opioid receptors in subcortical areas and functional disconnection caused by opioids. The DMN shows low levels of opioid receptors in cortical areas and inhibited or enhanced activity with low or high doses of opioids, respectively. Finally, we proposed a working model. Opioidergic signaling enhances SN and suppresses SMN (and DMN) activity, resulting in affective excitation with psychomotor inhibition; stronger increases in opioidergic signaling attenuate the SN and SMN while disinhibiting the DMN, dissociating affective and psychomotor functions from the internal states; the opposite occurs with a deficit of opioidergic signaling.
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Dmytriiev, Dmytro, A. Andriiets, E. Andriiets, V. Bankivsky, and S. Yatsenko. "Management of pain treatment in the early postoperative period. Practice of using ketorolac. A clinical case." Pain medicine 5, no. 3 (2020): 18–26. http://dx.doi.org/10.31636/pmjua.v5i3.3.
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The current strategy of rational perioperative analgesia involves reducing the use of opioid analgesics and preventing associated side effects. Today it is known that the use of opioid analgesics can further lead to the development of hyperalgesia. Opioid-induced hyperalgesia is an adaptive response of the body in response to exogenous administration of opioids, the mechanisms of development of which are associated with the activation of the central glutamatergic system and the release of spinal dinorphins. In contrast, gabapentin, NSAIDs, and ketamine have opioid-preserving properties, reducing the number of opioid-associated side effects. Hyperalgesia is a condition that underlies the formation of chronic pain and develops regardless of the degree of postoperative wound repair.
 For the treatment of pain in the postoperative period, the main group of treatment agents are opioid analgesics, which are prescribed to 60% of patients. However, with severe pain, there is a need for opioids in doses that exceed the standard recommended. It is known that the tactics of increasing the dose of opioid analgesics leads to an increase in the frequency of adverse reactions: severe sedation, respiratory depression, nausea, vomiting, intestinal paresis, dysfunction of the biliary and urinary systems, hallucinations. In order to reduce side effects, the doctor reduces the dose of opioids, which is accompanied by inadequate analgesia.
 Given the above, clinicians prescribe additional drugs of other drug groups that can enhance the analgesic effect of opioids. An important aspect is the ability to reduce the dose of opioids.
 Our data and data of other authors. Until recently, NSAIDs were rarely used in intensive care units, mainly in mild to moderate pain.
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Meier, Isabell M., Marie Eikemo, and Siri Leknes. "The Role of Mu-Opioids for Reward and Threat Processing in Humans: Bridging the Gap from Preclinical to Clinical Opioid Drug Studies." Current Addiction Reports 8, no. 2 (2021): 306–18. http://dx.doi.org/10.1007/s40429-021-00366-8.
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Abstract Purpose of Review Opioid receptors are widely expressed in the human brain. A number of features commonly associated with drug use disorder, such as difficulties in emotional learning, emotion regulation and anhedonia, have been linked to endogenous opioid signalling. Whereas chronic substance use and misuse are thought to alter the function of the mu-opioid system, the specific mechanisms are not well understood. We argue that understanding exogenous and endogenous opioid effects in the healthy human brain is an essential foundation for bridging preclinical and clinical findings related to opioid misuse. Here, we will examine psychopharmacological evidence to outline the role of the mu-opioid receptor (MOR) system in the processing of threat and reward, and discuss how disruption of these processes by chronic opioid use might alter emotional learning and reward responsiveness. Recent Findings In healthy people, studies using opioid antagonist drugs indicate that the brain’s endogenous opioids downregulate fear reactivity and upregulate learning from safety. At the same time, endogenous opioids increase the liking of and motivation to engage with high reward value cues. Studies of acute opioid agonist effects indicate that with non-sedative doses, drugs such as morphine and buprenorphine can mimic endogenous opioid effects on liking and wanting. Disruption of endogenous opioid signalling due to prolonged opioid exposure is associated with some degree of anhedonia to non-drug rewards; however, new results leave open the possibility that this is not directly opioid-mediated. Summary The available human psychopharmacological evidence indicates that the healthy mu-opioid system contributes to the regulation of reward and threat processing. Overall, endogenous opioids can subtly increase liking and wanting responses to a wide variety of rewards, from sweet tastes to feelings of being connected to close others. For threat-related processing, human evidence suggests that endogenous opioids inhibit fear conditioning and reduce the sensitivity to aversive stimuli, although inconsistencies remain. The size of effects reported in healthy humans are however modest, clearly indicating that MORs play out their role in close concert with other neurotransmitter systems. Relevant candidate systems for future research include dopamine, serotonin and endocannabinoid signalling. Nevertheless, it is possible that endogenous opioid fine-tuning of reward and threat processing, when unbalanced by e.g. opioid misuse, could over time develop into symptoms associated with opioid use disorder, such as anhedonia and depression/anxiety.
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Dixit, Anjali A., Catherine L. Chen, Christina Inglis-Arkell, and Solmaz P. Manuel. "Assessment of Unused Opioids Following Ambulatory Surgery." American Surgeon 86, no. 6 (2020): 652–58. http://dx.doi.org/10.1177/0003134820923309.
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Background Surgery is a risk factor for opioid initiation and subsequent abuse. Discharge opioid prescription patterns after surgery are often varied and not evidence based, which may lead to unnecessary prescription of opioids. We aimed to assess opioid prescribing and unused opioid prescriptions in ambulatory surgery patients at our academic hospital. Methods We conducted a retrospective observational study based on phone survey and electronic medical records. Adult patients who underwent ambulatory surgery at our large, multisite, tertiary-care hospital system were asked whether they were using the opioids that were prescribed at discharge. Our main outcomes were opioid prescription (defined as being prescribed an opioid on discharge) and unused opioid prescription (defined as being prescribed an opioid but not taking any opioids on postoperative day 1). We evaluated predictors of opioid prescription and unused opioid prescription through univariable and multivariable analyses. We also stratified outcomes by surgical service. Results Of 4248 adult patients who underwent ambulatory surgical procedures, 3279 (77.2%) responded to the survey. Of all responders, 2146 (65.4%) were prescribed postoperative opioids, and 1240 (57.8%) reported not taking them on postoperative day 1. The highest rates of unused opioid prescriptions were for patients whose primary service were orthopedic surgery (65%) and plastic surgery (62%). Discussion Opioid prescribing and unused opioid prescriptions are prevalent in our hospital’s ambulatory surgical population. Patients undergoing selected ambulatory surgical procedures may not require as much opioid as is currently being prescribed.
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Elliott, MD, Jennifer A., Erica Horton, DO, and Eugene E. Fibuch, MD. "The endocrine effects of long-term oral opioid therapy: A case report and review of the literature." Journal of Opioid Management 7, no. 2 (2018): 145–54. http://dx.doi.org/10.5055/jom.2011.0057.
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The negative effects of long-term opioid administration on the body’s endocrine system have been known for decades.1,2 These effects have been observed and studied with the use of intrathecal opioids and in heroin addicts.3-9 However, they have also been noted to occur with the use of oral opioids, especially in those patients who require chronic opioids for the management of nonmalignant and cancer-associated pain.2,10-13 Epidemiologic data in recent years suggest that up to five million men with chronic nonmalignant pain suffer from opioid-induced androgen deficiency (OPIAD) in the United States.14 Therefore, it is important to understand the physiologic impact of chronic opioid administration in patients. In view of the increasing use of opioids for chronic pain, we must anticipate the potential occurrence of hypogonadism during chronic opioid therapy and monitor patients accordingly. If symptoms of endocrine dysfunction are recognized during chronic opioid therapy, appropriate evaluation, treatment, and follow-up should be instituted. This article describes a case report of a patient who suffered from a clinically significant testosterone deficiency and osteoporosis related to the use of long-term oral opioids for chronic nonmalignant pain. It also includes a review of the existing literature regarding OPIAD and provides recommendations regarding the evaluation and management of OPIAD.
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Falières, Xavier. "Do we really need opioids in anesthesia?" Anaesthesia, Pain & Intensive Care 24, no. 2 (2020): 239–48. http://dx.doi.org/10.35975/apic.v24i2.1264.
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Since the 1990s, high-income countries have seen an exponential increase in opioid use, misuse, and overdose. This “opioid crisis”, or “opioid epidemic”, began in the USA, spread to Europe, and is now extending to Asia. Today, opioids are still rarely available in many low and middle-income countries. In Pakistan, for instance, the only available opioids are morphine, fentanyl, nalbuphine, and tramadol, and these too are available only in tertiary hospitals. Is there a relationship between opioid exposure during anesthesia and opioid-induced hyperalgesia, hospital readmission, opioid addiction, cancer recurrence, immune system impairment, higher risk of postoperative delirium, and cognitive dysfunction? Signs in the recent literature confirm some of these hypotheses, and reducing opioid use in anesthesia is becoming a necessity. The concept of “opioid-free anesthesia” has emerged over the years in the literature. Is opioid-free anesthesia the solution? Is it a real paradigm shift? Nevertheless, it is important to keep in mind that stress-induced postoperative pain negatively influences outcome. The use of opioids in the postoperative phase could be necessary, but they have to be titrated and reduced to the minimum needed. Opioid-free postoperative analgesia is a new debate in the literature.
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Rivas, Samantha R., Alex C. Tessner, and Eli E. Goldwyn. "Calculating prescription rates and addiction probabilities for the four most commonly prescribed opioids and evaluating their impact on addiction using compartment modelling." Mathematical Medicine and Biology: A Journal of the IMA 38, no. 2 (2021): 202–17. http://dx.doi.org/10.1093/imammb/dqab001.
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Abstract In 2016, more than 11 million Americans abused prescription opioids. The National Institute on Drug Abuse considers the opioid crisis a national addiction epidemic, as an increasing number of people are affected each year. Using the framework developed in mathematical modelling of infectious diseases, we create and analyse a compartmental opioid-abuse model consisting of a system of ordinary differential equations. Since $40\%$ of opioid overdoses are caused by prescription opioids, our model includes prescription compartments for the four most commonly prescribed opioids, as well as for the susceptible, addicted and recovered populations. While existing research has focused on drug abuse models in general and opioid models with one prescription compartment, no previous work has been done comparing the roles that the most commonly prescribed opioids have had on the crisis. By combining data from the Substance Abuse and Mental Health Services Administration (which tracked the proportion of people who used or misused one of the four individual opioids) with data from the Centers of Disease Control and Prevention (which counted the total number of prescriptions), we estimate prescription rates and probabilities of addiction for the four most commonly prescribed opioids. Additionally, we perform a sensitivity analysis and reallocate prescriptions to determine which opioid has the largest impact on the epidemic. Our results indicate that oxycodone prescriptions are both the most likely to lead to addiction and have the largest impact on the size of the epidemic, while hydrocodone prescriptions had the smallest impact.
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Sacerdote, Paola, and Silvia Franchi. "Opioids and immune system." Pharmacological Reports 63, no. 1 (2011): 213. http://dx.doi.org/10.1016/s1734-1140(11)70427-3.
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Woods, J. H. "OPIOIDS AND SYSTEM THEORY." Behavioural Pharmacology 9, Supplement (1998): S96. http://dx.doi.org/10.1097/00008877-199808001-00229.
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Woods, J. H. "OPIOIDS AND SYSTEM THEORY." Behavioural Pharmacology 9, no. 1 (1998): S96. http://dx.doi.org/10.1097/00008877-199812001-00229.
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Woods, J. H. "OPIOIDS AND SYSTEM THEORY." Behavioural Pharmacology 9, no. 1 (1998): S96. http://dx.doi.org/10.1097/00008877-199808000-00229.
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Ruchi, Rupam, Shahab Bozorgmehri, Tezcan Ozrazgat-Baslanti, et al. "Opioid Safety and Concomitant Benzodiazepine Use in End-Stage Renal Disease Patients." Pain Research and Management 2019 (October 20, 2019): 1–10. http://dx.doi.org/10.1155/2019/3865924.
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Background. Opioid use is common in end-stage renal disease (ESRD) patients. However, safety of individual opioids and concomitant benzodiazepine use has not been studied. Objective. To study the epidemiology of opioid and concomitant benzodiazepine use in ESRD population. To study the clinical safety profile of individual opioids in patients on hemodialysis. Design. Retrospective analysis of the U.S. Renal Data System. A comprehensive review of the current literature was performed to update currently used opioid safety classification. Participants. ESRD patients ≥18 years on hemodialysis who were enrolled in Medicare A and B and Part D between 2006 and 2012, excluding those with malignancy. Main Measures. Hospital admission with diagnosis of prescription opioid overdose within 30, 60, and 90 days of prescription; death due to opioid overdose. Results. Annually, the percentage of patients prescribed any opioid was 52.2%. Overall trend has been increasing except for a small dip in 2011, despite which the admissions due to opioid overdose have been rising. 30% of those who got a prescription for opioids also got a benzodiazepine prescription. 56.5% of these patients received both prescriptions within a week of each other. Benzodiazepine use increased the odds of being on opioids by 3.27 (CI 3.21–3.32) and increased the odds of hospitalization by 50%. Opioids considered safe such as fentanyl and methadone were associated with 3 and 6 folds higher odds of hospitalization within 30 days of prescription. Hydrocodone had the lowest odds ratio (1.9, CI 1.8–2.0). Conclusions. Concurrent benzodiazepine use is common and associated with higher risk of hospitalization due to opioid overdose. Possible opioid-associated hospital admission rate is 4-5 times bigger in ESRD population than general population. Current safety classification of opioids in these patients is misleading, and even drugs considered safe based on pharmacokinetic data are associated with moderate to very high risk of hospitalization. We propose a risk-stratified classification of opioids and suggest starting to use them in all ESRD patients.
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Wang, Lian, Ruslan L. Tiniakov, and Donovan B. Yeates. "Peripheral opioidergic regulation of the tracheobronchial mucociliary transport system." Journal of Applied Physiology 94, no. 6 (2003): 2375–83. http://dx.doi.org/10.1152/japplphysiol.00741.2002.
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We hypothesized that, in the airway mucosa, opioids are inhibitory neural modulators that cause an increase in net water absorption in the airway mucosa (as in the gut). Changes in bidirectional water fluxes across ovine tracheal mucosa in response to basolateral application of the opioid peptides β-endorphin, dynorphin A-(1–8), and [d-Ala2,d-Leu5]-enkephalin (DADLE) were measured. β-Endorphin and dynorphin A-(1–8) decreased luminal-to-basolateral water fluxes, and dynorphin A-(1–8) and DADLE increased basolateral-to-luminal water flux. These responses were electroneutral. In seven beagle dogs, administration of aerosolized β-endorphin (1 mg) to the tracheobronchial airways decreased the clearance of radiotagged particles from the bronchi in 1 h from 34.7 to 22.0% ( P < 0.001). Naloxone abrogated the β-endorphin-induced changes in vitro and in vivo. Contrary to our hypothesis, the opioid-induced changes in water fluxes would all lead to a predictable increase in airway surface fluid. The β-endorphin-induced increases in airway fluid together with reduced bronchial mucociliary clearance may produce procongestive responses when opioids are administered as antitussives.
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Atluri, Sairam. "Assessment of the Trends in Medical Use and Misuse of Opioid Analgesics from 2004 to 2011." Pain Physician 2;17, no. 2;3 (2014): E119—E128. http://dx.doi.org/10.36076/ppj.2014/17/e119.
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Background: The epidemic of medical use and abuse of opioid analgesics is linked to the economic burden of opioid-related abuse and fatalities in the United States. Multiple studies have estimated the extent to which prescription opioid analgesics contribute to the national drug abuse problem; studies also assessing the trends in medical use and abuse of opioid analgesics have confirmed the relationship between increasing medical use of opioids and increasing fatalities. The available data is limited until 2002.. Study Design: Retrospective analysis of data from 2004 to 2011 from 2 databases: Automation of Reports and Consolidated Orders System (ARCOS) for opioid use data and Drug Abuse Warning Network (DAWN) for drug misuse data. Objective: To determine the proportion of drug abuse related to opioid analgesics and the various trends in the medical use and abuse of 8 opioid analgesics commonly used to treat pain: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. Methods: The data obtained from DAWN is a nationally representative sample of hospital emergency department admissions resulting from drug abuse. Main outcome measure was the identification of trends in the medical use and misuse of opioid analgesics from 2004 to 2011. Results: From 2004 to 2011, there was an increase in the medical use of all opioids except for a 20% decrease in codeine. The abuse of all opioids including codeine increased during this period. Increases in medical use ranged from 2,318% for buprenorphine to 35% for fentanyl, including 140% for hydromorphone, 117% for oxycodone, 73% for hydrocodone, 64% for morphine, and 37% for methadone. The misuse increased 384% for buprenorphine with available data from 2006 to 2011, whereas from 2004 to 2011, it increased 438% for hydromorphone, 263% for oxycodone, 146% for morphine, 107% for hydrocodone, 104% for fentanyl, 82% for methadone, and 39% for codeine. Comparison of opioid use showed an overall increase of 1,448% from 1996 to 2011, with increases if 690% from 1996 to 2004 and 100% from 2004 to 2011. In contrast, misuse increased more dramatically: 4,680% from 1996 to 2011, with increases of 1,372% from 1996 through 2004 and 245% from 2004 to 2011. The number of patients seeking rehabilitation for substance abuse also increased 187% for opioids, whereas it increased 87% for heroin, 40% for marijuana, and decreased 7% for cocaine. Limitations: Limitations of this assessment include the lack of data from 2003, lack of data available on meperidine, and that the aggregate data systems used in the study did not identify specific formulations or commercial products. Conclusion: The present trend of continued increase in the medical use of opioid analgesics appears to contribute to increases in misuse, resulting in multiple health consequences. Key words: Medical use of opioids, inappropriate use of opioids, abuse of opioids, opioid-related fatalities, Automation of Reports and Consolidated Orders System (ARCOS), Drug Abuse Warning Network (DAWN), International Narcotics Control Board (INCB)
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Frisoni, Paolo, Erica Bacchio, Sabrine Bilel, et al. "Novel Synthetic Opioids: The Pathologist’s Point of View." Brain Sciences 8, no. 9 (2018): 170. http://dx.doi.org/10.3390/brainsci8090170.
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Background: New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and other NPS classes, which were not controlled from 1961 to 1971 by the United Nations drug control conventions. Among these, synthetic opioids represent a major threat to public health. Methods: A literature search was carried out using public databases (such as PubMed, Google Scholar, and Scopus) to survey fentanyl-, fentanyl analogs-, and other synthetic opioid-related deaths. Keywords including “fentanyl”, “fentanyl analogs”, “death”, “overdose”, “intoxication”, “synthetic opioids”, “Novel Psychoactive Substances”, “MT-45”, “AH-7921”, and “U-47700” were used for the inquiry. Results: From our literature examination, we inferred the frequent implication of fentanyls and synthetic opioids in side effects, which primarily affected the central nervous system and the cardiovascular and pulmonary systems. The data showed a great variety of substances and lethal concentrations. Multidrug-related deaths appeared very common, in most reported cases. Conclusions: The investigation of the contribution of novel synthetic opioid intoxication to death should be based on a multidisciplinary approach aimed at framing each case and directing the investigation towards targeted toxicological analyses.
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Fitting, Sylvia, MaryPeace McRae, and Kurt F. Hauser. "Opioid and neuroHIV Comorbidity – Current and Future Perspectives." Journal of Neuroimmune Pharmacology 15, no. 4 (2020): 584–627. http://dx.doi.org/10.1007/s11481-020-09941-8.
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AbstractWith the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV.
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Guda, Rahul S., Katherine E. Odegaard, Chengxi Tan, Victoria L. Schaal, Sowmya V. Yelamanchili, and Gurudutt Pendyala. "Integrated Systems Analysis of Mixed Neuroglial Cultures Proteome Post Oxycodone Exposure." International Journal of Molecular Sciences 22, no. 12 (2021): 6421. http://dx.doi.org/10.3390/ijms22126421.
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Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations. To fill this knowledge gap, we employed an integrated system approach to identify proteomic signatures and pathways impacted on mixed neuroglial cultures treated with oxy for 24 h. Differentially expressed proteins were mapped onto global canonical pathways using ingenuity pathway analysis (IPA), identifying enriched pathways associated with ephrin signaling, semaphorin signaling, synaptic long-term depression, endocannabinoid signaling, and opioid signaling. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function.
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Edwards, Helen, and Michael Bennett. "Access to Opioids for Patients with Advanced Disease." Current Pharmaceutical Design 25, no. 30 (2019): 3203–8. http://dx.doi.org/10.2174/1381612825666190716095337.
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Pain at the end of life is common in both malignant and non-malignant disease. It is feared by patients, their families and careers, and professionals. Effective pain control can be achieved for the majority of patients at the end of life using a multimodal approach. Pharmacological management relies predominantly on strong opioids. In spite of this, evidence suggests that under treatment of pain is common resulting in unnecessary suffering. Multiple barriers to use of opioids have been identified. Patient barriers include reluctance to report pain and to take analgesics. Professional barriers include inadequate pain assessment and lack of specialist knowledge and confidence in opioid therapy. Fear of side effects including respiratory depression affects patients and professionals alike. The impact of the “opioid epidemic”, with increasing prescribed and illicit opioid use around the world, has also led to increasingly stringent regulation and concern about under prescribing in palliative care. System barriers to use of opioids at the end of life result from limited opioid availability in some countries and also inconsistent and limited access to palliative care. Multiple interventions have been developed to address these barriers, targeted at patients, professionals and systems. There is increasing evidence to suggest that complex interventions combining a number of different approaches are most effective in optimising pain outcomes for patients at the end of life.
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Lutfy, Kabirullah. "Opioid Crisis—An Emphasis on Fentanyl Analogs." Brain Sciences 10, no. 8 (2020): 485. http://dx.doi.org/10.3390/brainsci10080485.
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Opioids are the mainstay for the management of moderate to severe pain. However, their acute use is associated with several side effects, ranging from nausea, itching, sedation, hypotension to respiratory depression, and death. Also, chronic use of these drugs can lead to the development of tolerance, dependence, and eventually addiction. The most serious side effect, lethality due to opioid-induced overdose, has reached the level of national emergency, i.e., the opioid crisis, which is now the forefront of medicine. In a detailed review (Novel Synthetic Opioids: The Pathologist’s Point of View), Frisoni and colleagues have discussed the side effects of novel licit and illicit fentanyl derivatives, as well as the related compounds which are more potent and faster acting than morphine and other conventional opioids (Frisoni, et al., 2018). These drugs affect the central nervous system (CNS) and can promote the development of addiction due to the quick rush they induce because of their faster entry into the brain. These drugs also arrest the cardiovascular and pulmonary systems, increasing the chance of respiratory arrest, leading to opioid-induced overdose morbidity and mortality. The respiratory arrest induced by opioids can be potentiated by other CNS depressants, such as alcohol or benzodiazepines, and therefore may occur more frequently in polydrug users. Therefore, the use of these newer fentanyl derivatives as well as other fast acting opioids should be avoided or limited to specific cases and must be kept out of the reach of children and adolescents who are more vulnerable to become addicted or overdose themselves.
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Lishmanov, Yu B., L. N. Maslov, N. Yu Naryzhnaya, et al. "ENDOGENOUS OPIOID SYSTEM AS A MEDIATOR OF ACUTE AND LONG-TERM ADAPTATION TO STRESS. PROSPECTS FOR CLINICAL USE OF OPIOID PEPTIDES." Annals of the Russian academy of medical sciences 67, no. 6 (2012): 73–82. http://dx.doi.org/10.15690/vramn.v67i6.287.
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It has been well established that opioid peptides (OPs) affect various hormonal systems. Opioids exhibit stress-limiting and gastro-protective effects in stressed animals, acting via μ- and δ-opioid receptors (OR). Peripheral μ-OR stimulation by endogenous and exogenous opioids increases cardiac tolerance to pathological consequences of stress. Enhancement of prostacyclin synthesis, decrease of thromboxane production as well as suppression of lipid peroxidation can be directly responsible for cardioprotective effects of OPs in stressed animals. Adaptive responses are accompanied by increased OP levels in blood and tissues. Reduction of ventricular arrhythmias induced by repeated short-term immobilization stress is mediated via μ-OR stimulation by endogenous opioids, while δ-OR account for an antiarrhythmic effect of adaptation to chronic intermittent hypobaric hypoxia. The mechanism of infarct size-limiting effect of continuous normobaric hypoxia involves both μ- and δ-OR stimulation. Peptide OR agonists can be considered in future clinical practice for treatment of withdrawal syndrome, stress-related cardiac disease or myocardial injury caused by ischemia-reperfusion insult.
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Yang, Junzhi, Bianca Reilly, Thomas Davis, and Patrick Ronaldson. "Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity." Pharmaceutics 10, no. 4 (2018): 192. http://dx.doi.org/10.3390/pharmaceutics10040192.
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Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB. We will also examine how expression and trafficking of ABC transporters can be modified by pain and/or opioid pharmacotherapy, a novel mechanism that can promote opioid-associated adverse drug events and development of addiction and tolerance.
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Randhawa, Puneet Kaur, and Amteshwar Singh Jaggi. "Opioids in Remote Ischemic Preconditioning-Induced Cardioprotection." Journal of Cardiovascular Pharmacology and Therapeutics 22, no. 2 (2016): 112–21. http://dx.doi.org/10.1177/1074248416660621.
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Remote ischemic preconditioning (RIPC) is an intriguing process whereby transient regional ischemia and reperfusion episodes to remote tissues including skeletal, renal, mesenteric provide protection to the heart against sustained ischemia–reperfusion-induced injury. Clinically, this technique has been used in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery. The endogenous opioid system is extensively expressed in the brain to modulate pain sensation. Besides the role of opioids in relieving pain, numerous researchers have found their critical involvement in evoking cardioprotective effects. Endogenous opioids including endorphins, enkephalins, and dynorphins are released during RIPC and are critically involved in mediating RIPC-induced cardioprotective effects. It has been suggested that during RIPC, the endogenous opioids may be released into the systemic circulation and may travel via bloodstream that act on the myocardial opioid receptors to induce cardioprotection. The present review describes the potential role of opioids in mediating RIPC-induced cardioprotection.
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Hartling, Lisa, Samina Ali, Donna M. Dryden, et al. "How Safe Are Common Analgesics for the Treatment of Acute Pain for Children? A Systematic Review." Pain Research and Management 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/5346819.
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Background. Fear of adverse events and occurrence of side effects are commonly cited by families and physicians as obstructive to appropriate use of pain medication in children. We examined evidence comparing the safety profiles of three groups of oral medications, acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, to manage acute nonsurgical pain in children (<18 years) treated in ambulatory settings.Methods. A comprehensive search was performed to July 2015, including review of national data registries. Two reviewers screened articles for inclusion, assessed methodological quality, and extracted data. Risks (incidence rates) were pooled using a random effects model.Results. Forty-four studies were included; 23 reported on adverse events. Based on limited current evidence, acetaminophen, ibuprofen, and opioids have similar nausea and vomiting profiles. Opioids have the greatest risk of central nervous system adverse events. Dual therapy with a nonopioid/opioid combination resulted in a lower risk of adverse events than opioids alone.Conclusions. Ibuprofen and acetaminophen have similar reported adverse effects and notably less adverse events than opioids. Dual therapy with a nonopioid/opioid combination confers a protective effect for adverse events over opioids alone. This research highlights challenges in assessing medication safety, including lack of more detailed information in registry data, and inconsistent reporting in trials.
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Matzeu, Alessandra, and Rémi Martin-Fardon. "Targeting the Orexin System for Prescription Opioid Use Disorder." Brain Sciences 10, no. 4 (2020): 226. http://dx.doi.org/10.3390/brainsci10040226.
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Prescription opioids are potent analgesics that are used for clinical pain management. However, the nonmedical use of these medications has emerged as a major concern because of dramatic increases in abuse and overdose. Therefore, effective strategies to prevent prescription opioid use disorder are urgently needed. The orexin system has been implicated in the regulation of motivation, arousal, and stress, making this system a promising target for the treatment of substance use disorder. This review discusses recent preclinical studies that suggest that orexin receptor blockade could be beneficial for the treatment of prescription opioid use disorder.
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Smith, MD, Howard S., and Patrick D. Meek, PharmD, MSPH. "Pain responsiveness to opioids: Central versus peripheral neuropathic pain." Journal of Opioid Management 7, no. 5 (2011): 391–400. http://dx.doi.org/10.5055/jom.2011.0080.
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Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathic pain is composed of peripheral neuropathic pain (with a primary lesion or dysfunction in the peripheral nervous system) and central neuropathic pain (CNP; with a primary lesion or dysfunction in the central nervous system). CNP may be further subdivided into supraspinal central neuropathic pain and spinal central neuropathic pain. Opioids have a role in the pharmacologic management of neuropathic pain; however, there is a scarcity of literature on the treatment of CNP with opioids. One of the few statements in the literature regarding the analgesic efficacy of opioids for CNP suggests that despite limited data, the opioid responsiveness for neuropathic pain of central and peripheral etiologies is similar. After reviewing the extremely limited data, it is proposed that although there may be a subpopulation of patients with CNP who have a reasonable analgesic response to opioids, overall, when sensory pain rating is used as the yardstick, CNP appears to respond less well to opioids than peripheral neuropathic pain. Thus, opioids should be considered a second- or third-line agent in any algorithm of the pharmacologic treatment of CNP. Also within CNP, it appears that supraspinal central neuropathic pain may respond less well to a trial of opioids than spinal central neuropathic pain. Moreover, under close monitoring for side effects (eg, constipation), it is suggested that clinicians may want to consider titrating to higher doses of potent opioids before the trial is judged to be unsuccessful for refractory supraspinal central neuropathic pain.
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Wang, Dandan, Hannah M. Stoveken, Stefano Zucca, et al. "Genetic behavioral screen identifies an orphan anti-opioid system." Science 365, no. 6459 (2019): 1267–73. http://dx.doi.org/10.1126/science.aau2078.
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Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.
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Fearon, Nkechi, Gregory Thomas Chesnut, Nicole Benfante, et al. "Decreasing postoperative opioid prescriptions in ambulatory extended recovery patients." Journal of Clinical Oncology 37, no. 15_suppl (2019): 6621. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6621.
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6621 Background: Over-prescription of opioids after surgery contributes to the opioid abuse epidemic. Optimum post-operative opioid dosing is not defined. We evaluated prescribing patterns among different surgical services and created a standardized practice to reduce dispensation of unnecessary opioids. Methods: Opioid-naïve patients over 18 who underwent urologic, gynecologic, or breast surgery between March 2018 and January 2019 were eligible. A 4-month pre-intervention evaluation of number of opioid pills prescribed, number of pills taken, additional refills, and pain-control was obtained by contacting patients 7-10 days post-operatively. Findings were used to standardize prescriptions. Following implementation, patients undergoing surgery for the following 4-months were contacted to assess the impact of standardized opioid prescriptions. Data was compared with the institution’s electronic prescription system. Results: Pre-intervention, 368 eligible urology and gynecology patients (75.6%) responded and were prescribed between 6 and 40 opioid pills. Urology patients received median 28 (20, 30) tablets and 33% reported taking none. Gynecology patients received a median 20 (19, 28) tablets and 41% took none. Of 238 mastectomy patients, 176 (74%) reported taking median 3 and 4.9 of 20 prescribed opioid pills and 39% or 61% took no opioid pills (without vs with reconstruction). Prescriptions were standardized to 8, 7, and 10 tablets for urology, gynecology, and breast services. Post-intervention surveys revealed opioid tablets taken to be unchanged with minimal increase in refill requests. Conclusions: Prior to standardization, a large variation in opioids prescribed was observed. Standardizing opioid prescriptions resulted in fewer opioids dispensed without impacting pain control or refill requests.
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Woodford, Keith Bernard. "Casomorphins and Gliadorphins Have Diverse Systemic Effects Spanning Gut, Brain and Internal Organs." International Journal of Environmental Research and Public Health 18, no. 15 (2021): 7911. http://dx.doi.org/10.3390/ijerph18157911.
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Food-derived opioid peptides include digestive products derived from cereal and dairy diets. If these opioid peptides breach the intestinal barrier, typically linked to permeability and constrained biosynthesis of dipeptidyl peptidase-4 (DPP4), they can attach to opioid receptors. The widespread presence of opioid receptors spanning gut, brain, and internal organs is fundamental to the diverse and systemic effects of food-derived opioids, with effects being evidential across many health conditions. However, manifestation delays following low-intensity long-term exposure create major challenges for clinical trials. Accordingly, it has been easiest to demonstrate causal relationships in digestion-based research where some impacts occur rapidly. Within this environment, the role of the microbiome is evidential but challenging to further elucidate, with microbiome effects ranging across gut-condition indicators and modulators, and potentially as systemic causal factors. Elucidation requires a systemic framework that acknowledges that public-health effects of food-derived opioids are complex with varying genetic susceptibility and confounding factors, together with system-wide interactions and feedbacks. The specific role of the microbiome within this puzzle remains a medical frontier. The easiest albeit challenging nutritional strategy to modify risk is reduced intake of foods containing embedded opioids. In future, constituent modification within specific foods to reduce embedded opioids may become feasible.
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Howard, Susanna Davis, Anish Agarwal, Kit Delgado, et al. "Opioid disposal rates after spine surgery." Surgical Neurology International 12 (September 20, 2021): 472. http://dx.doi.org/10.25259/sni_856_2021.
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Background: Diversion of prescription opioids pills is a significant contributor to opioid misuse and the opioid epidemic. The goal of this study was to determine the frequency and quantity of excess opioid pills among patients undergoing spine surgery. Further, we wanted to determine the frequency of appropriate opioid disposal. Methods: This was a prospective cohort study of patients undergoing elective spine surgery within a multi-hospital, academic, urban university health system enrolled in a text-messaging program used to track postoperative opioid disposal. Patients who self-reported discontinuation of opioid use but with leftover pills were contacted via telephone and surveyed on opioid disposal. Results: Of the 291 patients who enrolled in the text-messaging program, 192 (66%) patients reported discontinuing opioids within 3 months of surgery. Although 76 (40%) reported excess opioid pills after cessation of use, only 47 (62%) participated in the telephone survey regarding opioid disposal. The median number of leftover pills among these 47 patients was 5 (5, 15) and 64% had not disposed of their prescription. Conclusion: Among the 47 telephone survey participants, a persistent gap remained in postoperative opioid excess and improper disposal. Future efforts must focus on initiatives to improve opioid disposal rates to reduce the quantity of opioids at risk for diversion and to reduce excess prescribing.
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A. Elliott, Jennifer, Susan E. Opper, Sonali Agarwal, and Eugene E. Fibuch. "Non-Analgesic Effects of Opioids: Opioids and the Endocrine System." Current Pharmaceutical Design 18, no. 37 (2012): 6070–78. http://dx.doi.org/10.2174/138161212803582414.
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Muzaale, Abimereki D., Matthew Daubresse, Sunjae Bae, et al. "Benzodiazepines, Codispensed Opioids, and Mortality among Patients Initiating Long-Term In-Center Hemodialysis." Clinical Journal of the American Society of Nephrology 15, no. 6 (2020): 794–804. http://dx.doi.org/10.2215/cjn.13341019.
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Background and objectivesMortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis.Design, setting, participants, & measurementsThe cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing.ResultsWithin 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; Pinteraction<0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (Pinteraction=0.72).ConclusionsCodispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.
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Rejas-Gutierrez, Javier, Antoni Sicras-Mainar, and Josep Darbà. "Future projections of opioid use and cost in patients with chronic osteoarthritis pain in Spain." Therapeutic Advances in Musculoskeletal Disease 13 (January 2021): 1759720X2110105. http://dx.doi.org/10.1177/1759720x211010599.
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Background: Opioids are widely used in moderate-to-severe chronic pain which is non-responsive to standard analgesics. Prescriptions have increased in Europe in the last decade, although remain lower than in USA. This work projected the future utilization and costs of opioids in chronic osteoarthritis (OA) pain in the Spanish National Health System (NHS). Methods: An epidemiological model was populated with the opioid dispensing trends from 2010 to 2019 using Spanish Medicinal Agency rates of opioid utilization in subjects over 18 years of age and the real-world OPIOIDS study to estimate chronic-OA-pain patients receiving opioids. A best-fitted trend analysis model was applied estimating the likely number of DHD (defined daily dose/1000 inhabitants per day) to calculate projected opioid utilization and costs for the period 2020–2029. Results: In 2010, an estimated 5.67 DHD were dispensed for the equivalent of 217,076 chronic OA pain patients per day [1.99 DHD, 76,084 refractory to non-steroidal anti-inflammatory drugs (NSAIDs)]. From these trends and OA prevalence, the projected number of DHDs is expected to increase more than threefold to 17.98 DHDs by the year 2029 for the equivalent of 727,356 chronic OA pain patients per day (8.18 DHD, 330,720 refractory to NSAIDs); 41.8% on strong opioids. The estimated cost was €116.9m (€45.0m in NSAID-refractory OA) in 2010 rising by 222% to €376.1m (€199.7m refractory to NSAIDs) by 2029. Conclusion: Chronic-OA-pain-related opioid dispensing and costs to the NHS are set to increase more than threefold from 2010 to 2029 in Spain. Using opioids for OA pain is concerning given disease chronicity and other related costs not computed in these projections. Plain language summary • Opioids are widely used in chronic pain which is non-responsive to standard analgesics. Prescriptions have increased in Europe, although remain lower than in USA. Osteoarthritis (OA) is a degenerative joint disease usually accompanied by pain. Despite not recommended, opioids use in OA have been expanded because this health condition is increasing with ageing and, also, because physicians both primary and specialist boosted their use. • This study aimed to quantify the current burden of opioids used for chronic moderate-to-severe OA pain by estimating the number of defined daily doses per 1000 inhabitants per day (DHD) and associated costs, and to forecast the likely burden on the National Health System (NHS) in Spain for the years 2020–2029. • In 2010, an estimated 5.67 DHDs were dispensed for the equivalent of 217,076 chronic OA pain patients per day. From these trends, the projected number of DHDs is expected to increase more than threefold to 17.98 DHDs by the year 2029 for the equivalent of 727,356 chronic OA pain patients per day; 41.8% on strong opioids. The estimated cost was €116.9m in 2010 rising by 222% to €376.1m by 2029. • Chronic OA-pain-related opioid dispensing and costs to the NHS are set to increase substantially (threefold to more than fourfold) from 2010 to 2029 in Spain. Thus, using opioids for OA pain is concerning given disease chronicity, aging population and other related costs not computed in these projections. Our findings can inform payors and clinicians about ongoing discussions on appropriate analgesic management for longer-term OA pain, including resource requirements at a national level. Clinicians who prescribe opioids for OA pain should consider the potential implications of side effects such as sedation, cognitive deterioration, incremental need of caregivers, particularly in older people, and carefully consider the risk–benefit balance.
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Webster, N. R. "Opioids and the immune system." British Journal of Anaesthesia 81, no. 6 (1998): 835–36. http://dx.doi.org/10.1093/bja/81.6.835.
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Leslie, Frances M., Yiling Chen, and Ursula H. Winzer-Serhan. "Opioid receptor and peptide mRNA expression in proliferative zones of fetal rat central nervous system." Canadian Journal of Physiology and Pharmacology 76, no. 3 (1998): 284–93. http://dx.doi.org/10.1139/y98-028.
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There is increasing evidence to suggest that opioid peptides may have widespread effects as regulators of growth. To evaluate the hypothesis that endogenous opioids control cellular proliferation during neural development, we have used in situ hybridization to examine opioid peptide and receptor mRNA expression in neuroepithelial zones of fetal rat brain and spinal cord. Our data show that proenkephalin mRNA is widely expressed in forebrain germinal zones and choroid plexus during the second half of gestation. In contrast, prodynorphin mRNA expression is restricted to the periventricular region of the ventral spinal cord. Little µ or delta receptor mRNA expression was detected in any regions of neuronal proliferation prior to birth. However, kappa receptor mRNA is widely expressed in hindbrain germinal zones during the 3rd week of gestation. Our present findings support the hypothesis that endogenous opioids may regulate proliferation of both neuronal and non-neuronal cells during central nervous system development. Given the segregated expression of proenkephalin mRNA in forebrain neuroepithelium and kappa receptor mRNA within hindbrain, different opioid mechanisms may regulate cell division in rostral and caudal brain regions.Key words: enkephalin, dynorphin, ontogeny, neurogenesis.
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Phan, Michael, Courtney Wong, Daniel Tomaszewski, et al. "Evaluating Opioid Dispensing Rates among Pediatrics and Young Adults based on CURES Data Reporting in California from 2015-2019." Journal of Contemporary Pharmacy Practice 67, no. 4 (2021): 23–32. http://dx.doi.org/10.37901/jcphp20-00012.
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Background Receipt of opioid prescriptions in pediatric and young adult patients may be a risk factor for future opioid misuse. Data from prescription drug monitoring programs provide insight on outpatient opioid use. In our study, we analyzed the opioid dispensing rates for pediatrics and young adults in California. Methods A secondary analysis was performed from 2015-2019 using Controlled Utilization Review and Evaluation System data. This database provides dispensing data of controlled substances in California. Patients younger than 25 years who were prescribed opiates were analyzed by county. We further divided them into two groups (children: ≤14 years; adolescents and young adult: 15-24 years). Descriptive statistics and heat maps were used to illustrate the trends in opioid usage among different age groups. Results The overall percentages for the number of opioids being dispensed to patients aged <25 years have decreased over the past four years. In 2015, 6 out of 58 counties in California were considered “high-rate” with >2.9% of opioids dispensed to patients younger than 25 years old; in 2019, this number reduced to zero. Patients 25 and older received a higher proportion of opioids compared to younger populations; in 2019, 35.91% of opioids were dispensed to patients 45-64, and 8.92% to patients younger than 25. Conclusion Pediatric opioid prescriptions have declined over the recent years. However, a high degree of variability of prescription rates between demographic counties was noted. More studies are warranted in order to understand this discrepancy in opioid prescribing among pediatric and young adult patients.