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1
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 (October 18, 2018): 192. http://dx.doi.org/10.3390/pharmaceutics10040192.
Повний текст джерелаАнотація:
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.
2
Sehgal, Nalini. "Peripherally Acting Opioids and Clinical Implications for Pain Control." Pain Physician 3;14, no. 3;5 (May 14, 2011): 249–58. http://dx.doi.org/10.36076/ppj.2011/14/249.
Повний текст джерелаАнотація:
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
3
Hellman, Kevin M., Thaddeus S. Brink, and Peggy Mason. "Activity of Murine Raphe Magnus Cells Predicts Tachypnea and On-Going Nociceptive Responsiveness." Journal of Neurophysiology 98, no. 6 (December 2007): 3121–33. http://dx.doi.org/10.1152/jn.00904.2007.
Повний текст джерелаАнотація:
In rats, opioids produce analgesia in large part by their effects on two cell populations in the medullary raphe magnus (RM). To extend our mechanistic understanding of opioid analgesia to the genetically tractable mouse, we characterized behavioral reactions and RM neural responses to opioid administration. d-Ala2, N-Me-Phe4-Gly5ol-enkephalin, a mu-opioid receptor agonist, microinjected into the murine RM produced cardiorespiratory depression and reduced slow wave electroencephalographic activity as well as increased the noxious heat-evoked withdrawal latencies. As in rat, RM cell types that were excited and inhibited by noxious stimuli, termed on and off cells, respectively, were observed in mice. However, in contrast to findings in rat, opioid doses that suppressed withdrawals did not alter the background discharge rate of murine on and off cells, suggesting that the cellular mechanisms by which the murine RM generates opioid analgesia are substantially different from those in rats. Murine on cell discharge did not predict the latency or magnitude of an ensuing withdrawal but did correlate to the magnitude and latency of concurrent withdrawals. Although opioids failed to alter the background discharge of on and off cells, they reduced the responses of RM neurons to noxious stimulation, further evidence that RM modulates on-going withdrawals. In characterizing the role of RM in respiratory modulation, we found that on cells burst and off cells paused during tachypneic events. The effects of opioids in the murine RM on homeostasis and the association of on and off cell discharge with tachypnea corroborate roles for opioid signaling in RM beyond analgesia.
4
Peterson, P. K., B. Sharp, G. Gekker, C. Brummitt, and W. F. Keane. "Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity." Journal of Immunology 138, no. 11 (June 1, 1987): 3907–12. http://dx.doi.org/10.4049/jimmunol.138.11.3907.
Повний текст джерелаАнотація:
Abstract Opiate addiction and stress have been associated with altered immune responses. In this study, we evaluated the influence of morphine and the stress responsive opioid peptide beta-endorphin (beta-END) on O-2 and H2O2 production by cultured human peripheral blood mononuclear cells. Exposure of these cells during 48 hr of culture to morphine and beta-END at pharmacologically (10(-8) M) and physiologically (10(-12) M) relevant concentrations, respectively, markedly suppressed peripheral blood mononuclear cell O-2 and H2O2 release in response to the respiratory burst stimuli opsonized zymosan and phorbol myristate acetate. Both opioids also induced a minimal, but statistically significant, increase in resting O-2 and H2O2 generation. The modulatory effects of morphine and beta-END on peripheral blood mononuclear cell oxygen metabolism appeared to involve a classical opioid receptor, because opioid activity was blocked by naloxone and was not observed with N-acetylated-beta-END. Using purified lymphocyte and monocyte preparations, we determined that although opioids directly increase monocyte-resting oxygen metabolism, lymphocytes are the primary target cell in opioid-mediated suppression of monocyte respiratory burst activity. The release of a suppressive product from opioid-triggered lymphocytes was inhibited by cyclosporine. Based on the results of this study, we propose that opioid-mediated suppression of mononuclear phagocyte respiratory burst activity is another factor to be considered in the immunodeficiency of opiate addiction and stress.
5
Cannaert, Annelies, Lakshmi Vasudevan, Melissa Friscia, Amanda L. A. Mohr, Sarah M. R. Wille, and Christophe P. Stove. "Activity-Based Concept to Screen Biological Matrices for Opiates and (Synthetic) Opioids." Clinical Chemistry 64, no. 8 (August 1, 2018): 1221–29. http://dx.doi.org/10.1373/clinchem.2018.289496.
Повний текст джерелаАнотація:
Abstract BACKGROUND Detection of new highly potent synthetic opioids is challenging as new compounds enter the market. Here we present a novel screening method for the detection of opiates and (synthetic) opioids based on their activity. METHODS A cell-based system was set up in which activation of the μ-opioid receptor (MOR) led to recruitment of β-arrestin 2, resulting in functional complementation of a split NanoLuc luciferase and allowing readout via bioluminescence. Assay performance was evaluated on 107 postmortem blood samples. Blood (500 μL) was extracted via solid-phase extraction. Following evaporation and reconstitution in 100 μL of Opti-MEM® I, 20 μL was analyzed in the bioassay. RESULTS In 8 samples containing synthetic opioids, in which no positive signal was obtained in the bioassay, quadrupole time-of-flight mass spectrometry revealed the MOR antagonist naloxone, which can prevent receptor activation. Hence, further evaluation did not include these samples. For U-47700 (74.5–547 ng/mL) and furanyl fentanyl (<1–38.8 ng/mL), detection was 100% (8/8) for U-47700 and 95% (21/22) for furanyl fentanyl. An analytical specificity of 93% (55/59) was obtained for the opioid negatives. From an additional 10 samples found to contain other opioids, 5 were correctly scored positive. Nondetection in 5 cases could be explained by very low concentrations (<1 ng/mL alfentanil/sufentanil) or presence of inactive enantiomers. CONCLUSIONS The MOR reporter assay allows rapid identification of opioid activity in blood. Although the cooccurrence of opioid antagonists is currently a limitation, the bioassay's high detection capability, specificity, and untargeted nature may render it a useful first-line screening tool to investigate potential opioid intoxications.
6
Ozdemir, Ercan. "The Role of the Cannabinoid System in Opioid Analgesia and Tolerance." Mini-Reviews in Medicinal Chemistry 20, no. 10 (May 27, 2020): 875–85. http://dx.doi.org/10.2174/1389557520666200313120835.
Повний текст джерелаАнотація:
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.
7
Ronström, Joakim W., Natalie L. Johnson, Stephen T. Jones, Sara J. Werner, Hillary A. Wadsworth, James N. Brundage, Valerie Stolp, et al. "Opioid-Induced Reductions in Amygdala Lateral Paracapsular GABA Neuron Circuit Activity." International Journal of Molecular Sciences 24, no. 3 (January 18, 2023): 1929. http://dx.doi.org/10.3390/ijms24031929.
Повний текст джерелаАнотація:
Opioid use and withdrawal evokes behavioral adaptations such as drug seeking and anxiety, though the underlying neurocircuitry changes are unknown. The basolateral amygdala (BLA) regulates these behaviors through principal neuron activation. Excitatory BLA pyramidal neuron activity is controlled by feedforward inhibition provided, in part, by lateral paracapsular (LPC) GABAergic inhibitory neurons, residing along the BLA/external capsule border. LPC neurons express µ-opioid receptors (MORs) and are potential targets of opioids in the etiology of opioid-use disorders and anxiety-like behaviors. Here, we investigated the effects of opioid exposure on LPC neuron activity using immunohistochemical and electrophysiological approaches. We show that LPC neurons, and other nearby BLA GABA and non-GABA neurons, express MORs and δ-opioid receptors. Additionally, DAMGO, a selective MOR agonist, reduced GABA but not glutamate-mediated spontaneous postsynaptic currents in LPC neurons. Furthermore, in LPC neurons, abstinence from repeated morphine-exposure in vivo (10 mg/kg/day, 5 days, 2 days off) decrease the intrinsic membrane excitability, with a ~75% increase in afterhyperpolarization and ~40–50% enhanced adenylyl cyclase-dependent activity in LPC neurons. These data show that MORs in the BLA are a highly sensitive targets for opioid-induced inhibition and that repeated opioid exposure results in impaired LPC neuron excitability.
8
Bril, Silviu, Yoav Shoham, and Jeremy Marcus. "The ‘Mystery’ of Opioid-Induced Diarrhea." Pain Research and Management 16, no. 3 (2011): 197–99. http://dx.doi.org/10.1155/2011/309685.
Повний текст джерелаАнотація:
Bowel dysfunction, mainly constipation, is a well-known and anticipated side effect of opioids. The physician prescribing an opioid frequently confronts the challenge of preventing and treating bowel dysfunction. Different strategies have emerged for managing opioid-induced constipation. These strategies include physical activity, maintaining adequate fluid intake, adhering to regular daily bowel habits, using laxatives and other anticonstipation medications and, recently, using a peripheral opioid antagonist, either as a separate drug or in the form of an opioid agonist-antagonist combination pill. What options exist for the physician when a patient receiving opioids complains of diarrhea, cramps and bloating, rather than the expected constipation? The present article describes a possible cause of opioid-induced diarrhea and strategies for management.
9
Kaczyńska, Katarzyna, and Piotr Wojciechowski. "Non-Opioid Peptides Targeting Opioid Effects." International Journal of Molecular Sciences 22, no. 24 (December 19, 2021): 13619. http://dx.doi.org/10.3390/ijms222413619.
Повний текст джерелаАнотація:
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity—such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)—we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.
10
Michaud, Veronique, Ravil Bikmetov, Matt K. Smith, Pamela Dow, Lucy I. Darakjian, Malavika Deodhar, Brian Cicali, Kevin T. Bain, and Jacques Turgeon. "Use of Drug Claims Data and a Medication Risk Score to Assess the Impact of CYP2D6 Drug Interactions among Opioid Users on Healthcare Costs." Journal of Personalized Medicine 11, no. 11 (November 10, 2021): 1174. http://dx.doi.org/10.3390/jpm11111174.
Повний текст джерелаАнотація:
Cytochrome P450 2D6 (CYP2D6) activity is highly variable due to several factors, including genetic polymorphisms and drug-drug-gene interactions. Hydrocodone, oxycodone, codeine, and tramadol the most commonly prescribed CYP2D6-activated opioids for pain. However, the co-administration of CYP2D6 interacting drugs can modulate CYP2D6-medicated activation of these opioids, affecting drug analgesia, effectiveness, and safety, and can impact healthcare costs. A retrospective, observational cohort analysis was performed in a large (n = 50,843) adult population. This study used drug claims data to derive medication risk scores and matching propensity scores to estimate the effects of opioid use and drug-drug interactions (DDIs) on medical expenditures. 4088 individuals were identified as opioid users; 95% of those were prescribed CYP2D6-activated opioids. Among those, 15% were identified as being at risk for DDIs. Opioid users had a significant increase in yearly medical expenditure compared to non-opioid users ($2457 vs. $1210). In matched individuals, average healthcare expenditures were higher for opioid users with DDIs compared to those without DDIs ($7841 vs. $5625). The derived medication risk score was higher in CYP2D6 opioid users with interacting drug(s) compared to no DDI (15 vs. 12). Higher costs associated with CYP2D6 opioid use under DDI conditions suggest inadequate CYP2D6 opioid prescribing practices. Efforts to improve chronic opioid use in adults should reduce interacting drug combinations, especially among patients using CYP2D6 activated opioids.
11
Gintzler, PhD, Alan R., and Nai-Jiang Liu, MD, PhD. "Harnessing endogenous opioids for pain relief: Fantasy vs reality." Journal of Opioid Management 16, no. 1 (January 1, 2020): 67–72. http://dx.doi.org/10.5055/jom.2020.0552.
Повний текст джерелаАнотація:
Objective: To review evidence demonstrating efficacy and feasibility of harnessing the activity of endogenous opioid analgesic systems for pain management.Methods: The authors sought to summarize a wealth of data that establish proof of concept that the analgesic activity of endogenous opioids can be exploited to clinically benefit from the enormous pain-relieving abilities of these peptides without contributing to the current crisis of death by synthetic opioid overdose.Results: There is a plethora of studies demonstrating that not only can endogenous opioids mediate placebo-induced antinociception but they are also active in modulating clinical pain. Earlier studies convincingly demonstrate the effectiveness of psychological strategies to coopt endogenous opioid analgesic systems to produce pain relief. The challenge is to define pharmacological targets for activating endogenous opioid analgesia reliably in a clinical setting. Based on insights gleaned from mechanisms underlying the ebb and flow of analgesic responsiveness to the spinal application of endomorphin 2, multiple signaling proteins were identified that activate endogenous spinal opioid analgesia. Notably, this was achieved in the absence of any exogenous synthetic opioid.Conclusions: Utilization of drugs that harness endogenous opioid antinociception in accordance with varying physiological states represents a novel approach for effective pain management while mitigating the present epidemic of death by synthetic opioid overdose.
12
Rullo, Laura, Francesca Felicia Caputi, Loredana Maria Losapio, Camilla Morosini, Luca Posa, Donatella Canistro, Fabio Vivarelli, Patrizia Romualdi, and Sanzio Candeletti. "Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells." Molecules 27, no. 23 (November 29, 2022): 8321. http://dx.doi.org/10.3390/molecules27238321.
Повний текст джерелаАнотація:
Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects.
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Rocchi, Giulio, Bruno Sterlini, Samuele Tardito, Matilde Inglese, Anna Corradi, Gilberto Filaci, Mario Amore, Paola Magioncalda, and Matteo Martino. "Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders." Neuroscientist 26, no. 4 (March 5, 2020): 343–58. http://dx.doi.org/10.1177/1073858420902360.
Повний текст джерелаАнотація:
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.
14
Henshaw, MBBS, MMed, FANZCA, FFPMANZCA, John S. "Do transdermal opioids reduce healthcare use in an Australian rural pain population? A comparison with oral opioids." Journal of Opioid Management 7, no. 2 (January 15, 2018): 135–44. http://dx.doi.org/10.5055/jom.2011.0056.
Повний текст джерелаАнотація:
Objective: To determine whether transdermal (TD) opioids reduce healthcare contacts when compared with oral opioids in a rural population with chronic noncancer pain (CNCP).Design: An observational longitudinal study to measure the changes in selfreported healthcare use by the route of opioid administration over time (monthly for 1 year). Subjects were opioid-treated CNCP patients from North West Tasmania. The subjects completed the monthly datasheets by recording all healthcare contacts and the routes of opioid administration. The outcome measures of mean monthly healthcare contacts (MHCs) by the routes of opioid administration were analyzed using generalized estimating equations with robust standard errors.Results: The details of 10,564 healthcare contacts from 198 subjects were obtained during the study. General practitioner (GP) mean MHCs were 2.01 (95% confidence intervals [CI] = 1.58-2.45) for oral opioids and significantly (p = 0.02) lower by 0.38 (95% CI = −0.70 to −0.05) contacts for TD opioids. Pharmacy mean MHCs were 2.44 (95% CI = 1.88-3.00) for oral opioids and unchanged (p = 0.86) by −0.04 (95% CI = −0.44-0.37) for TD opioids. Total mean MHCs with oral opioid use were 5.98 (95% CI = 4.93-7.03). With TD opioid use, this was nonsignificantly lower (p = 0.12) by 0.62 (95% CI = −1.40-0.15) contacts.Conclusions: The use of TD opioid preparations, with their prolonged analgesic effect, may reduce total healthcare activity and significantly reduce GP contact. This may particularly benefit a rural population where there is a relative shortage of doctors.
15
Cheng, P. Y., D. Wu, Y. Soong, S. McCabe, J. A. Decena, and H. H. Szeto. "Role of mu 1- and delta-opioid receptors in modulation of fetal EEG and respiratory activity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 265, no. 2 (August 1, 1993): R433—R438. http://dx.doi.org/10.1152/ajpregu.1993.265.2.r433.
Повний текст джерелаАнотація:
Recent evidence suggests that administration of low doses of morphine causes respiratory stimulation, along with a more active electroencephalogram (EEG) in the fetal lamb. The present study used selective opioid agonists and antagonists to determine the role mu 1- and delta-opioid receptor subtypes play in the response as well as determine if endogenous opioid peptides exert a tonic influence at the mu 1- and delta-opioid receptors to maintain normal EEG and respiratory activity under control, physiological conditions. Both morphine (2.5 mg/h iv) and [D-Pen2,D-Pen5]enkephalin (DPDPE) (46 nmol/h icv) resulted in a significant activation of fetal EEG, which was blocked by naloxonazine (NALZ, mu 1-opioid antagonist) and naltrindole (NTI, delta-opioid antagonist), respectively. Administration of NALZ alone, but not NTI, resulted in a slowing of the EEG. Morphine and [D-Ala2]deltorphin I (0.36 nmol/h icv) significantly increased breath number and were blocked by NALZ and NTI respectively. Both NALZ and NTI alone resulted in a reduction in breath number. These results suggest that the activation of the delta- or mu 1-opioid receptors will stimulate fetal respiratory and EEG activity. Furthermore, the endogenous opioids play a tonic role at both the delta- and mu 1-opioid receptors in the regulation of respiratory timing and EEG activity.
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Takeda, Shinhiro, Lars I. Eriksson, Yuji Yamamoto, Henning Joensen, Hiroshi Onimaru, and Sten G. E. Lindahl. "Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats." Anesthesiology 95, no. 3 (September 1, 2001): 740–49. http://dx.doi.org/10.1097/00000542-200109000-00029.
Повний текст джерелаАнотація:
Background Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists. Methods Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory). Results Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses. Conclusions Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.
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Inagaki, Masanao, Toshiyuki Kanemasa, and Takaaki Yokota. "Naldemedine: Peripherally Acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects." Current Topics in Medicinal Chemistry 20, no. 31 (December 3, 2020): 2830–42. http://dx.doi.org/10.2174/1568026620666200710105953.
Повний текст джерелаАнотація:
Opioids are widely used for pain management in moderate-to-severe pain. However, opioids are associated with adverse events, such as constipation and emesis/vomiting. To reduce these undesired effects, a structure–activity relationship study of morphinan derivatives was conducted, and a promising lead compound with inhibitory effects on opioid receptors was obtained. Further improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine’s analgesic effect. Naldemedine was launched in Japan and the USA in 2017 and in the EU in 2019, for treating opioid-induced constipation.
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DINTE, Elena, Radu BORZA, and Oana MOCAN GURKA. "Evaluating the activity of dispensing opioid analgesic medication." Romanian Journal of Pharmaceutical Practice 14, no. 3 (September 30, 2021): 139–44. http://dx.doi.org/10.37897/rjphp.2021.3.5.
Повний текст джерелаАнотація:
Objectives. The purpose of this paper was to evaluate the drug dispensing activity of analgesic opioids in pharmacies. Materials and methods. The study was conducted in an observational and retrospective manner, based on a questionnaire distributed in different pharmacies across Romania. Results. The dispensing activity of opioid analgesics is conducted in 71 out of the 100 pharmacies that have received the questionnaire. These pharmacies are located in 12 out of the 41 counties, mostly in the urban area and 96% of them are community pharmacies. The most prescribed and dispensed pharmaceutical forms are solid forms, the injectable products and transdermic systems being dispensed in a high percentage, up to 40% respectively, only in 25% of the questioned pharmacies. The average time spent by a pharmacist for the entire activity of dispensing an opioid analgesic prescribed by a doctor was estimated at 17.82± 0.58 minutes. Conclusions. The activity regarding opioid analgesics in the community pharmacy is limited by the low rentability, high costs and time consumption. The results of the study impose a further analysis on the impact that this service has upon public health, in order to this activity be sustained by the national health insurance system. Measures must be implemented to ensure that patients from rural or unprivileged areas are able to get their analgesics from the nearest community pharmacy constantly.
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Pattullo, Gavin G. "Clinical implications of opioid-induced ventilatory impairment." Anaesthesia and Intensive Care 50, no. 1-2 (February 21, 2022): 52–67. http://dx.doi.org/10.1177/0310057x211070292.
Повний текст джерелаАнотація:
Opioid-induced ventilatory impairment is the primary mechanism of harm from opioid use. Opioids suppress the activity of the central respiratory centres and are sedating, leading to impairment of alveolar ventilation. Respiratory physiological changes induced with acute opioid use include depression of the hypercapnic ventilatory response and hypoxic ventilatory response. In chronic opioid use a compensatory increase in hypoxic ventilatory response maintains ventilation and contributes to the onset of sleep-disordered breathing patterns of central sleep apnoea and ataxic breathing. Supplemental oxygen use in those at risk of opioid-induced ventilatory impairment requires careful consideration by the clinician to prevent failure to detect hypoventilation, if oximetry is being relied on, and the overriding of hypoxic ventilatory drive. Obstructive sleep apnoea and opioid-induced ventilatory impairment are frequently associated, with this interrelationship being complex and often unpredictable. Monitoring the patient for opioid-induced ventilatory impairment poses challenges in the areas of reliability, avoidance of alarm fatigue, cost, and personnel demands. Many situations remain in which patients cannot be provided effective analgesia without opioids, and for these the clinician requires a comprehensive knowledge of opioid-induced ventilatory impairment.
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Cowan, Alan. "Mechanisms of opioid activity." Current Opinion in Anaesthesiology 5, no. 4 (August 1992): 529–34. http://dx.doi.org/10.1097/00001503-199208000-00012.
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CHRUBASIK, JOACHIM, and FLORELLA MAGORA. "Antinociceptive Opioid Activity Ratio." Anesthesiology 72, no. 6 (June 1, 1990): 1097. http://dx.doi.org/10.1097/00000542-199006000-00026.
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De Montis, Maria Graziella, Paola Devoto, Alessandro Bucarelli, and Alessandro Tagliamonte. "Opioid activity of lefetamine." Pharmacological Research Communications 17, no. 5 (May 1985): 471–78. http://dx.doi.org/10.1016/0031-6989(85)90082-7.
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Marrone, Gina F., Steven G. Grinnell, Zhigang Lu, Grace C. Rossi, Valerie Le Rouzic, Jin Xu, Susruta Majumdar, Ying-Xian Pan, and Gavril W. Pasternak. "Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS." Proceedings of the National Academy of Sciences 113, no. 13 (March 14, 2016): 3663–68. http://dx.doi.org/10.1073/pnas.1523894113.
Повний текст джерелаАнотація:
The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia.
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Langford, Dale J., Jacob B. Gross, Ardith Z. Doorenbos, David J. Tauben, John D. Loeser, and Debra B. Gordon. "Evaluation of the Impact of an Online Opioid Education Program for Acute Pain Management." Pain Medicine 21, no. 1 (January 25, 2019): 55–60. http://dx.doi.org/10.1093/pm/pny300.
Повний текст джерелаАнотація:
Abstract Objective The University of Washington instituted a policy requiring all credentialed clinicians who prescribe opioids to complete a one-time education activity about safe and responsible opioid prescribing. A scenario-based, interactive online learning module was developed for opioid management of acute pain in hospitalized adults. This study examined the impact of the education module on learners’ knowledge, perceived competence, and use of guideline-adherent practices. Methods Clinicians who completed the education module participated in a voluntary de-identified online survey approximately six months after the learning activity. Survey questions were related to 1) the perception of improved knowledge; 2) impact on learner’s use of three guideline-adherent practices; and 3) perceived competence in managing opioids for acute pain. Descriptive statistics were generated, and multiple linear regression models were used for analysis. Results Clinicians (N = 167) reported improvement in knowledge and perceived competence. Controlling for other aspects of knowledge evaluated, learning to construct a safe opioid taper plan for acute pain, distinguishing between short- and long-acting opioids, and safely initiating opioids for acute pain were significantly associated with increased self-reported likelihood of incorporating the Washington state Prescription Monitoring Program (P = 0.003), using multimodal analgesia (P = 0.022), and reducing the duration of opioids prescribed (P = 0.016). Only improvement in knowledge of how to construct a safe opioid taper plan was significantly associated with increased perceived competence (P = 0.002). Conclusions Our findings suggest that this online education module about safe opioid prescribing for acute pain management was effective at improving knowledge, increasing the likelihood of using guideline-adherent clinical practices, and increasing perceived competence.
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Vigil, Jacob M., Sarah S. Stith, and Anthony P. Reeve. "Accuracy of Patient Opioid Use Reporting at the Time of Medical Cannabis License Renewal." Pain Research and Management 2018 (January 28, 2018): 1–4. http://dx.doi.org/10.1155/2018/5704128.
Повний текст джерелаАнотація:
The decision to authorize a patient for continued enrollment in a state-sanctioned medical cannabis program is difficult in part due to the uncertainty in the accuracy of patient symptom reporting and health functioning including any possible effects on other medication use. We conducted a pragmatic convenience study comparing patient reporting of previous and current prescription opioid usage to the opioid prescription records in the Prescription Monitoring Program (PMP) among 131 chronic pain patients (mean age = 54; 54% male) seeking the first annual renewal of their New Mexico Medical Cannabis Program (NMMCP) license. Seventy-six percent of the patients reported using prescription opioids prior to enrollment in the NMMCP, however, the PMP records showed that only 49% of the patients were actually prescribed opioids in the six months prior to enrollment. Of the 64 patients with verifiable opioid prescriptions prior to NMMCP enrollment, 35 (55%) patients reported having eliminated the use of prescription opioids by the time of license renewal. PMP records showed that 26 patients (63% of patients claiming to have eliminated the use of opioid prescriptions and 41% of all patients with verifiable preenrollment opioid use) showed no prescription opioid activity at their first annual NMMCP renewal visit.
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Lee, MD, MHS, Jiha, Lisa Gale Suter, MD, and Liana Fraenkel, MD, MPH. "Opioid dispensation among systemic lupus erythematosus patients who persistently frequent the emergency department." Journal of Opioid Management 16, no. 1 (January 1, 2020): 23–31. http://dx.doi.org/10.5055/jom.2020.0547.
Повний текст джерелаАнотація:
Objective: To understand prevalence and factors associated with opioid dispensation among systemic lupus erythematosus (SLE) patients who persistently frequent the emergency department (ED) to improve quality of care.Methods: In this retrospective observational cohort study, the authors identified SLE patients who persistently frequented the ED, defined as having three or more ED visits over 12 months, for at least 2 out of 4 years between 2013 and 2016. The authors collected patient-level variables including demographics and long-term opioid therapy (LTOT). Each encounter was categorized as: SLE-, infection-, pain-related, or “other.” Additional encounter-level variables such as healthcare resource utilization and disposition were recorded. The authors used mixed effects multivariate logistic regression to analyze factors associated with (1) opioid administration in the ED and (2) opioid prescription upon discharge from the ED. Results: Seventy-seven SLE patients having 1,143 encounters were identified as persistently frequent ED users. Opioids were administered in the ED for 38 percent of all encounters. Medicaid, LTOT, physician as the ED provider versus advanced-practice providers, more imaging tests, and rheumatology specialty consultation were associated with increased odds of opioid administration in the ED. Opioids were prescribed on discharge for 17 percent of encounters discharged from the ED. African American patients, those on Medicaid, and patients utilizing the ED for SLE-related activity/complications compared to “other” reasons were more likely to receive opioid prescription upon discharge from the ED than their respective counterparts.Conclusion: Opioids are commonly dispensed in the ED for SLE patients. This is true even for patients utilizing the ED for SLE-related disease activity/complications.
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Trescot, Andrea M. "A Review of the Role of Genetic Testing in Pain Medicine." Pain Physician 5;17, no. 5;9 (September 14, 2014): 425–45. http://dx.doi.org/10.36076/ppj.2014/17/425.
Повний текст джерелаАнотація:
Background: Pain clinicians have always been challenged by the variability of response to pain treatment. Differences in the degree of pain stimulation and pain sensitivity, weight and age differences, prior opioid use and tolerance, as well as the differences in bioavailability of various opioid formulations have been cited as causes for the wide variability in analgesia seen with opioids. Genetics may explain the variability of responses and help to predict more effective (or less dangerous) medication choices and doses. Genetics may also help to predict the response to specific opioids and antidepressants. Objectives: In this review article, we discuss the genetic influence of nociception, analgesia, and hyoanalgesia. The CYP450 enzymes involved in the metabolism and activity of opioids and adjuvant analgesics are genetically controlled, as are the opioid receptors and a variety of brain chemistries. Methods: This article discusses the specific pain implications of genetic variations in CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A7, OPRM1, OPRK1, OPRD1, COMT, GABA, UGT, MC1R, GCH1, ABCB1, P-glycoprotein, 5HTR1A, 5HTR2A, MTHFR, CACNA2D2, and 5-HTTLPR. Results: Recent research findings suggest the relationship between genetic predisposition and clinical behavior, including the risk of opioid misuse and addiction. While urine drug testing may hint at genetic issues regarding opioid metabolism, cheek swab DNA testing has become economically viable, and we review the current and future genetic pain issues that may influence the decisions that pain clinicians make every day. Conclusion: Genetic testing may explain and predict many of the clinical responses seen with opioids and adjuvant medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction. Key words: Genetics, genetic testing, opioid metabolism, drug interactions, urine drug testing, opioid risk evaluation, opioid receptors
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Wang, Dandan, Hannah M. Stoveken, Stefano Zucca, Maria Dao, Cesare Orlandi, Chenghui Song, Ikuo Masuho, et al. "Genetic behavioral screen identifies an orphan anti-opioid system." Science 365, no. 6459 (August 15, 2019): 1267–73. http://dx.doi.org/10.1126/science.aau2078.
Повний текст джерелаАнотація:
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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Root-Bernstein, Robert. "Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction." Pharmaceuticals 15, no. 2 (February 10, 2022): 214. http://dx.doi.org/10.3390/ph15020214.
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This paper proposes the design of combination opioid–adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Combinations of adrenergic and opioid drugs are sometimes used to improve analgesia, decrease opioid doses required to achieve analgesia, and to prolong the duration of analgesia. Recent mechanistic research suggests that these enhanced functions result from an allosteric adrenergic binding site on opioid receptors and, conversely, an allosteric opioid binding site on adrenergic receptors. Dual occupancy of the receptors maintains the receptors in their high affinity, most active states; drops the concentration of ligand required for full activity; and prevents downregulation and internalization of the receptors, thus inhibiting tolerance to the drugs. Activation of both opioid and adrenergic receptors also enhances heterodimerization of the receptors, additionally improving each drug’s efficacy. Tethering adrenergic drugs to opioids could produce new drug candidates with highly desirable features. Constraints—such as the locations of the opioid binding sites on adrenergic receptors and adrenergic binding sites on opioid receptors, length of tethers that must govern the design of such novel compounds, and types of tethers—are described and examples of possible structures provided.
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Fennell, Gillian. "CONTINUED OPIOID USE REDUCES PERCEIVED CHANCE OF LIVING TO AGE 75 AMONG YOUNG-OLD INDIVIDUALS WITH CHRONIC PAIN." Innovation in Aging 6, Supplement_1 (November 1, 2022): 366. http://dx.doi.org/10.1093/geroni/igac059.1446.
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Abstract Pain limits older adults’ predictions of their own life expectancies. Due to their analgesic properties and simultaneous linkages to depression, poor subjective health, and functional disability, it is uncertain if the use of opioids augments or contributes to limitations in subjective life expectancy (SLE). This study uses 2016 and 2018 data from the Health and Retirement study to assess the predictive value of prescription opioid use transitions on perceived chances of living to age 75 (SLE). Our sample includes 50 to 62 year-olds who reported pain in both waves (N=1,977). The OLS model controls for pain intensity and activity interference, socio-demographic factors, six chronic conditions, depression, and the 2016 baseline outcome measure. Relative to non-opioid users, respondents who transitioned off of opioids after 2016 reported significantly higher SLEs in 2018 (b=5.56, p=.05). Respondents who used opioids in both waves reported significantly lower SLEs relative to non-opioid users (b=-4.17, p=.02). Individuals who began using opioids following the 2016 wave were no different on SLE than non-opioid users (p=.11). Higher 2016 SLE predictions and being female were associated with higher SLEs. Being never married and ever having diabetes were negatively associated with SLE. Continued opioid use among individuals with chronic pain reduced anticipated chances of living to 75 whereas transitioning off of such medications had the opposite effect. Despite their analgesic properties, prescribed opioid use has negative effects on future outlook independent of pain, health status, and depression. As a consequence, continued opioid users may poor health and/or financial planning decisions.
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Golovko, A. I., M. B. Ivanov, V. L. Rejniuk, Yu Yu Ivnitsky, V. A. Barinov, and V. K. Borodavko. "TOXICOLOGICAL CHARACTERISTIC OF DESIGNER DRUGS FROM THE GROUP OF SYNTHETIC OPIOIDS." Toxicological Review, no. 1 (February 28, 2019): 3–11. http://dx.doi.org/10.36946/0869-7922-2019-1-3-11.
Повний текст джерелаАнотація:
Toxicological characteristic of designer drugs from the group of synthetic opioids is presented. The historical aspects of illicit drug trafficking are considered. In the illicit drug market of EU countries 38 synthetic opioids, 22 of them belonging to fentanyl derivatives, have been revealed for the period 2005-2017. The widespread use of synthetic opioids among drug addicts has been accompanied by an increase in the number of fatal overdoses. In the United States the number of fatal poisonings by synthetic opioids of fentanyl series increased by 40.3 times between 1999 and 2017. The similar situation is emerging in other countries. This is due to the fact that the biological activity and toxicity of synthetic opioids far exceed those of morphine and heroin. The differences between the metabolism of heroin and synthetic opioids are considered. Data on the toxicity of synthetic opioids are presented. The neurotransmitter mechanisms of their respiratory depression, including disorders of opioid, GABAergic, glutamatergic and serotoninergic neurotransmitter systems are discussed. A brief description of the antidote activity of opioid receptor antagonists in acute poisoning by synthetic opioids is given.
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Żylicz, Zbigniew. "Opioid-induced Hyperalgesia complicates treatment of pain: concept, diagnosis and treatment." BÓL 19, no. 2 (November 30, 2018): 33–37. http://dx.doi.org/10.5604/01.3001.0012.8300.
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Opioid induced hyperlagesia (OIH) is caused by excitation of the neurons and microglia in the spinal cord after exposure to opioids. All opioids are able to produce OIH, but some of them do it stronger than others. In this article the concept of OIH as well as the diagnosis and treatment strategies will be discussed. The most successful strategy is the dose reduction and modification of NMDA receptor activity in the spinal cord. This can be secured by the use of ketamine, gabapentinoids, propofol, magnesium salts, paracetamol and experimentally, ultra-low doses of opioid antagonists.
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Mercadante, Sebastiano, Giampiero Porzio, and Vittorio Gebbia. "New Opioids." Journal of Clinical Oncology 32, no. 16 (June 1, 2014): 1671–76. http://dx.doi.org/10.1200/jco.2013.51.8662.
Повний текст джерелаАнотація:
Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. Therefore, there is a significant need for more effective treatment options. New opioids have been marketed in the past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: μ-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain.
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Jashinski, Julia, Ellie Grossman, Aurora Quaye, Corinne Cather, Kevin Potter, David A. Schoenfeld, A. Eden Evins, and Jodi M. Gilman. "Randomised, pragmatic, waitlist controlled trial of cannabis added to prescription opioid support on opioid dose reduction and pain in adults with chronic non-cancer pain: study protocol." BMJ Open 12, no. 6 (June 2022): e064457. http://dx.doi.org/10.1136/bmjopen-2022-064457.
Повний текст джерелаАнотація:
IntroductionChronic, non-cancer pain impacts approximately 50 million adults in the USA (20%), approximately 25% of whom receive chronic prescription opioids for pain despite limited empirical efficacy data and strong dose-related risk for opioid use disorder and opioid overdose. Also despite lack of efficacy data, there are many reports of people using cannabis products to manage chronic pain and replace or reduce chronic opioids. Here we describe the protocol for a randomised trial of the effect of cannabis, when added to a behavioural pain management and prescription opioid taper support programme, on opioid utilisation, pain intensity and pain interference.MethodsThis is a pragmatic, single-blind, randomised, wait-list controlled trial that aims to enrol 250 adults taking prescription opioids at stable doses of ≥25 morphine milligram equivalents per day for chronic non-cancer pain who express interest in using cannabis to reduce their pain, their opioid dose or both. All participants will be offered a weekly, 24-session Prescription Opioid Taper Support group behavioural pain management intervention. Participants will be randomly assigned in 1:1 ratio to use cannabis products, primarily from commercial cannabis dispensaries or to abstain from cannabis use for 6 months. Coprimary outcomes are change in prescription monitoring programme-verified opioid dose and change in Pain, Enjoyment, General Activity scale scores. Secondary outcomes include quality of life, depression, anxiety, self-reported opioid dose and opioid and cannabis use disorder symptoms. All other outcomes will be exploratory. We will record adverse events.Ethics and disseminationThis study has ethical approval by the Massachusetts General Brigham Institutional Review Board (#2021P000871). Results will be published in peer-reviewed journals and presented at national conferences.Trial registration numberNCT04827992.
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Hutchinson, Mark R., Sondra T. Bland, Kirk W. Johnson, Kenner C. Rice, Steven F. Maier, and Linda R. Watkins. "Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward." Scientific World JOURNAL 7 (2007): 98–111. http://dx.doi.org/10.1100/tsw.2007.230.
Повний текст джерелаАнотація:
This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.
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Natalini, Cláudio Corrêa, Anderson Fávaro da Cunha, and Renata Lehn Linardi. "Multi-drug resistance gene (MDR1) and opioid analgesia in horses." Ciência Rural 36, no. 1 (February 2006): 330–35. http://dx.doi.org/10.1590/s0103-84782006000100055.
Повний текст джерелаАнотація:
Opioid absorption in the intestinal tract as well as its effects in the central nervous system is modulated by the P-glycoprotein (P-gp) encoded in the Multi-drug Resistance gene (MDR1) also named ATP-binding cassete, subfamily B, member 1 (ABCB1). This MDR1 gene acts as a selective pump. The expression of this protein in humans and rodents inhibits cellular uptake of substrate opioids. The presence of the intestinal iso-enzyme CYP3A4 associated with MDR1 gene decreases the opioid analgesic activity due to an increase in intestinal metabolism, with a predicted intestinal first pass extraction around 20% which significantly influences the oral availability of opioids. In the central nervous system, P-gp expression decreases opioid neuronal uptake diminishing the analgesic effects. It is unknown if horses have the MDR1 gene and P-gp and what are the effects on opioid absorption, metabolism, and analgesia. Identifying the MDR1 gene and P-gp status in horses is of great importance in order to better understand opioid pharmacologic effects in horses.
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Carter, Jason R., Charity L. Sauder, and Chester A. Ray. "Effect of morphine on sympathetic nerve activity in humans." Journal of Applied Physiology 93, no. 5 (November 1, 2002): 1764–69. http://dx.doi.org/10.1152/japplphysiol.00462.2002.
Повний текст джерелаАнотація:
There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 ± 2 to 22 ± 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 ± 2 to 91 ± 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 ± 4 to 59 ± 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug × exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.
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Abram, Stephen E., George A. Mampilly, and Douglas Milosavljevic. "Assessment of the Potency and Intrinsic Activity of Systemic versus Intrathecal Opioids in Rats." Anesthesiology 87, no. 1 (July 1, 1997): 127–34. http://dx.doi.org/10.1097/00000542-199707000-00017.
Повний текст джерелаАнотація:
Background One measure of an opioid's efficacy is its ability to retain its analgesic effect as the intensity of a noxious stimulus is increased. A few studies have assessed the ability of either spinal or systemic opioids to produce analgesia using low- and high-intensity stimulation. There are little data available to show whether there are differences in efficacy between systemic and intrathecal opioid administration. The purpose of this study was to assess the relative efficacy of several clinically useful opioids systemically and spinally and to determine whether intrathecal administration resulted in greater efficacy than systemic administration. Methods Groups of rats were administered multiple doses of meperidine, morphine, hydromorphone, fentanyl, sufentanil, or buprenorphine either subcutaneously or intrathecally via implanted catheters. Noxious radiant heat was applied sequentially to each hindpaw, one at low intensity (adjusted to a mean withdrawal latency of 10 s) and one at high intensity (adjusted to a mean withdrawal latency of 5 s). Paw withdrawal latencies were recorded; dose-response curves for each intensity and each route of administration were graphically recorded, and ED50s were calculated. Ratios of high-to low-stimulus intensity ED50s were calculated for both routes of administration for each drug, and the ratios of subcutaneous-to-intrathecal ED50s for low-intensity stimulation were calculated to assess the relative systemic versus spinal potencies for each drug. Results The ratios of the high-to-low intensity ED50s were meperidine, 11.8, morphine, 6.1, hydromorphone, 2.6, fentanyl, 2.3, sufentanil, 1.8, and buprenorphine, 24.0. For intrathecal administration, there was uniformity of the high- to low-intensity ED50 ratios for the agonist drugs (meperidine, 2.1; morphine, 2.1; hydromorphone, 1.9; fentanyl, 1.8; sufentanil, 1.6). For morphine and hydromorphone, the systemic ED50 doses were several hundred times the intrathecal ED50s whereas the systemic-to-spinal ED50 ratios for the other drugs were 20 or less. Conclusions As intensity of noxious stimulation is increased, the more potent opioid agonists, administered systemically, produce antinociception with lesser increases in dose compared with lower potency drugs such as meperidine or morphine. When given spinally all opioid agonists tested, including morphine and meperidine, demonstrated good efficacy, as measured by their ability to provide antinociception for high versus low intensity stimulation.
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Klein, Amanda H., Husam K. Mohammad, Rabiah Ali, Brad Peper, Steven P. Wilson, Srinivasa N. Raja, Matthias Ringkamp, and Sarah Sweitzer. "Overexpression of µ-Opioid Receptors in Peripheral Afferents, but Not in Combination with Enkephalin, Decreases Neuropathic Pain Behavior and Enhances Opioid Analgesia in Mouse." Anesthesiology 128, no. 5 (May 1, 2018): 967–83. http://dx.doi.org/10.1097/aln.0000000000002063.
Повний текст джерелаАнотація:
Abstract Background The current study used recombinant herpes simplex virus type I to increase expression of µ-opiate receptors and the opioid ligand preproenkephalin in peripheral nerve fibers in a mouse model of neuropathic pain. It was predicted that viral vector delivery of a combination of genes encoding the µ-opioid receptor and preproenkephalin would attenuate neuropathic pain and enhance opioid analgesia. The behavioral effects would be paralleled by changes in response properties of primary afferent neurons. Methods Recombinant herpes simplex virus type 1 containing cDNA sequences of the µ-opioid receptor, human preproenkephalin, a combination, or Escherichia coli lacZ gene marker (as a control) was used to investigate the role of peripheral opioids in neuropathic pain behaviors. Results Inoculation with the µ-opioid receptor viral vector (n = 13) reversed mechanical allodynia and thermal hyperalgesia and produced leftward shifts in loperamide (ED50 = 0.6 ± 0.2 mg/kg vs. ED50 = 0.9 ± 0.2 mg/kg for control group, n = 8, means ± SD) and morphine dose-response curves (ED50 = 0.3 ± 0.5 mg/kg vs. ED50 = 1.1 ± 0.1 mg/kg for control group). In µ-opioid receptor viral vector inoculated C-fibers, heat-evoked responses (n = 12) and ongoing spontaneous activity (n = 18) were decreased after morphine application. Inoculation with both µ-opioid receptor and preproenkephalin viral vectors did not alter mechanical and thermal responses. Conclusions Increasing primary afferent expression of opioid receptors can decrease neuropathic pain-associated behaviors and increase systemic opioid analgesia through inhibition of peripheral afferent fiber activity.
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Paice, Judith A., Li Chen, Elizabeth Garrett-Mayer, Karen S. Hagerty, Kristina Lynne Maletz Novick, Danielle Potter, Mark Riffon, Whitney Rhodes, Liya Wang, and Suanna S. Bruinooge. "Annual trends in opioid prescribing for patients (Pts) with metastatic non-small cell lung cancer (mNSCLC): Cancerlinq data analysis, 2010 to 2017." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 2076. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.2076.
Повний текст джерелаАнотація:
2076 Background: Despite opioid misuse and abuse, opioids remain a mainstay for management of cancer pain. Government, payers, and institutions have implemented policies to reduce opioid use. The impact of these restrictions on oncologist prescriptions (Rx) of opioids and management of cancer pain in pts with cancer is not well known. Methods: A retrospective, observational analysis used deidentified EHR data from ASCO’s CLQ Discovery database. Study cohort included pts with mNSCLC diagnosis and >1 clinical encounter (including opioid Rx) from CLQ clinician during 2010-2017. Opioids included DEA schedule II and III opioid drugs prescribed for cancer pain, excluding cough suppressants. Annual Rx rates were defined as the number of mNSCLC pts who had ≥ 1 opioid Rx dated 2010-2017 per CLQ total mNSCLC pts who had ≥1 clinical encounter in the year. Annual rates demonstrate trends in opioid prescribing patterns over time. Results: 18,106 pts with mNSCLC clinical activity between 2010 and 2017 were identified. Overall, 39.8% of pts had opioid Rx in 2010-2017. Annual Rx rates increased from 2010-2015 and fell 2016-2017 (see table). Hydrocodone was the second most frequently prescribed opioid overall (N=4211 pts), but Rx rates began to decline in 2012. Tramadol and acetaminophen + codeine Rx rates gradually increased throughout the time period. DEA initially scheduled Tramadol as schedule IV in 2014. Conclusions: Opioids are commonly prescribed by oncologists for patients with mNSCLC. Rx rates have declined since 2015, likely due to increased government, payer, and institutional restrictions on access. Hydrocodone Rx declined since 2012, perhaps exacerbated by reclassification from schedule III to schedule II by the DEA (October 2014). Rxs for schedule IV and III opioids (known to be of lower potency) increased modestly, likely due to comparatively fewer prescribing restrictions. Additional research is needed to understand whether the decline continues and the impact on management of cancer pain, particularly among metastatic patients. [Table: see text]
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Hugo F Miranda, Viviana Noriega, Valeria Valdivia, Fernando Sierralta, and Juan Carlos Prieto. "Opioid antagonism in fentanyl antinociception experimental." GSC Advanced Research and Reviews 13, no. 2 (November 30, 2022): 009–14. http://dx.doi.org/10.30574/gscarr.2022.13.2.0292.
Повний текст джерелаАнотація:
Among the most commonly used drugs to reduce pain and inflammation are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Opioids are a wide group of drugs including fentanyl a fully synthetic opioid that is more potent that morphine. The aim of the present study was to evaluate the fentanyl antinociception in two pain murine tests, the acetic acid writhing (WT) and the formalin hind paw (FHP). Likewise, the involvement of opioids antagonists: naltrexone, naltrindole and nor-binaltorphimine in the induced activity of fentanyl was estimated. The antinociceptive activity of fentanyl was evaluated from dose-response curves. The intraperitoneal administration of fentanyl induced a dose related antinociceptive effects with different potencies in both tests. The data revealed a significant decrease in the analgesic effect of fentanyl by action of naltrexone, naltrindole and nor-binaltorphimine in the WT and FHP tests with the exception of nor-binaltorphimine in the WT. The effect of opioids antagonist in reducing the efficacy of fentanyl could possibly be related to other multiple mechanisms added to the inhibition of the activation of the MOR, DOR, and KOR opioid receptors. This study demonstrates that there is a functional interaction modulatory between fentanyl antinociception fentanyl and naltrexone, naltrindole and nor-binaltorphimine in the murine assays of acetic acid writhing and formalin hind paw. This modulation seems to be mediated by the multiple mechanisms of action of fentanyl. These results suggest than fentanyl is able to be effective in models of nociception and the inflammatory pain.
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Milligan, C. E., L. Webster, E. T. Piros, C. J. Evans, T. J. Cunningham, and P. Levitt. "Induction of opioid receptor-mediated macrophage chemotactic activity after neonatal brain injury." Journal of Immunology 154, no. 12 (June 15, 1995): 6571–81. http://dx.doi.org/10.4049/jimmunol.154.12.6571.
Повний текст джерелаАнотація:
Abstract Macrophages have a prominent role in the injury response of the brain, yet the molecular mechanisms that control their invasion to the site of neuronal degeneration is unknown. After removal of the posterior cortex at birth, there is massive and specific targeting of nonresident macrophages to axotomized neurons in the lateral thalamus. The present study has identified an injury-induced, brain-derived chemotactic factor (BDCF) capable of eliciting chemotactic responses from resident peritoneal macrophages and brain macrophages. Conditioned media collected from tissue slices containing the axotomized central nervous system neurons exhibit BDCF activity. Initial experiments indicated that BDCF is a small peptide and, thus, we used specific pharmacologic reagents to characterize further BDCF activity. Naloxone, a pan opioid receptor antagonist, completely blocks BDCF activity. Although both kappa and mu opioid receptor antagonists failed to modify BDCF-induced macrophage chemotaxis, two specific delta receptor antagonists blocked BDCF. Analysis of BDCF by reverse phase HPLC and RIA revealed peak chemotactic activity in fractions consistent with the presence of an opioid peptide. The results suggest that cells in the brain respond to neuronal injury by producing and releasing opioids that can initiate a specific macrophage response.
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Gomes, Ivone, Salvador Sierra, Lindsay Lueptow, Achla Gupta, Shawn Gouty, Elyssa B. Margolis, Brian M. Cox, and Lakshmi A. Devi. "Biased signaling by endogenous opioid peptides." Proceedings of the National Academy of Sciences 117, no. 21 (May 11, 2020): 11820–28. http://dx.doi.org/10.1073/pnas.2000712117.
Повний текст джерелаАнотація:
Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The “Opioid Epidemic” has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([35S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.
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McDonough, Paul G., and Marcello Negri. "Opioid Activity in Menstrual Disorders." Fertility and Sterility 46, no. 3 (September 1986): 534–37. http://dx.doi.org/10.1016/s0015-0282(16)49604-4.
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Pereira, Jose L., and Eduardo D. Bruera. "Comment: Opioid-Induced Muscle Activity." Annals of Pharmacotherapy 30, no. 9 (September 1996): 1042–43. http://dx.doi.org/10.1177/106002809603000931.
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Kearse, L. A., G. Koski, M. V. Husain, D. M. Philbin, and K. McPeck. "Epileptiform activity during opioid anesthesia." Electroencephalography and Clinical Neurophysiology 87, no. 6 (December 1993): 374–79. http://dx.doi.org/10.1016/0013-4694(93)90150-t.
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Aurich, C., S. Schlote, H.-O. Hoppen, E. Klug, H. Hoppe, and J. E. Aurich. "Effects of the opioid antagonist naloxone on release of luteinizing hormone in mares during the anovulatory season." Journal of Endocrinology 142, no. 1 (July 1994): 139–44. http://dx.doi.org/10.1677/joe.0.1420139.
Повний текст джерелаАнотація:
Abstract To investigate an involvement of endogenous opioids in the regulation of circannual changes in reproductive activity, effects of the opioid antagonist naloxone on the concentration of immunoreactive and bioactive luteinizing hormone (LH) in plasma were measured in mares during the anovulatory season. Naloxone (0·5 mg/kg i.v.) caused a significant increase (P<0·05) in immunoreactive as well as bioactive LH concentration in plasma. The amplitude of the increase in LH concentrations measured with an in vitro bioassay was more pronounced than the amplitude of the increase in LH secretion determined by radioimmunoassay. This indicates that although in seasonal anovulatory mares the bioactivity of LH in plasma is low, highly bioactive LH is present in the anterior pituitary and can be released by naloxone. The LH response to naloxone did not depend on the degree of ovarian follicular activity. It can be concluded that a tonic opioid inhibition of LH release is present in mares during at least part of the anovulatory season and that endogenous opioids seem to be involved in the regulation of seasonal reproductive activity in the horse. In contrast to the situation during the breeding season, the opioid systems regulating LH release are activated independently of luteal progesterone. Journal of Endocrinology (1994) 142, 139–144
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Bond, Cherie, K. Steven LaForge, Mingting Tian, Dorothy Melia, Shengwen Zhang, Lisa Borg, Jianhua Gong та ін. "Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: Possible implications for opiate addiction". Proceedings of the National Academy of Sciences 95, № 16 (4 серпня 1998): 9608–13. http://dx.doi.org/10.1073/pnas.95.16.9608.
Повний текст джерелаАнотація:
Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds β-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, β-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.
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Rao, Anita G., Heather A. Prentice, Priscilla Hannah Chan, Liz W. Paxton, Tadashi Ted Funahashi, and Gregory B. Maletis. "Risk Factors for Opioid Use Following Anterior Cruciate Ligament Reconstruction (ACLR) in a Cohort of 21,202 ACLR." Orthopaedic Journal of Sports Medicine 7, no. 7_suppl5 (July 2019): 2325967119S0025. http://dx.doi.org/10.1177/2325967119s00257.
Повний текст джерелаАнотація:
Objectives: The misuse of opioid medication has contributed to a significant national crisis affecting public health, as well as patient morbidity and medical costs. We sought to determine baseline opioid utilization in patients undergoing ACLR and examine demographic, patient characteristics, and medical factors associated with postoperative opioid utilization. Methods: Primary elective ACLR were identified using an integrated healthcare system’s ACLR registry (January 2005-January 2015). Patients with cancer or those who had other knee surgery in the preceding year were excluded. We studied the effect of preoperative and intraoperative risks factors on number of dispensed opioid medication prescriptions (Rx) in the early (0-90 days) and late (91-360 days) postoperative periods using logit regression. Risk factors studied included: number of opioid Rx in preceding year, age, gender, race, American Society of Anesthesiologists (ASA) classification, body mass index (BMI), activity at the time of injury, time from injury to ACLR, concomitant procedure or injury, medical comorbidities, and opioid-use comorbidities. Results: Of 21202 ACLR from 20813 patients, 25.5% used at least 1 opioid Rx in the one-year preoperative period. 17.7% and 2.7% used ≥2 opioid Rx in the early and late recovery periods, respectively. The risk factors associated with greater opioid Rx in both the early and late periods included: preoperative opioid use, age >20 years, ASA classification of ≥3, other activity at the time of injury, repaired cartilage injury, chronic pulmonary disease, and substance abuse. Risk factors associated with opioid Rx use during the early period only included: other race, acute ACL injury, repaired meniscal injury, multi-ligament injury, and dementia/psychoses. Risk factors associated with greater opioid Rx during the late period included: female gender, BMI >25 kg/m2, motor vehicle accident as the mechanism of injury, and hypertension. Conclusion: We identified several risk factors for postoperative opioid usage after ACLR. The strongest predictors of postoperative prescription opioid usage after ACLR included preoperative opioid use, increasing age, ASA classification of 3 or more, other activity at the time of injury, repaired meniscal injury, cartilage repair, chronic pulmonary disease, and substance abuse. Awareness of risk factors for postoperative opioid usage may encourage more targeted utilization of opioids in pain management. Surgeons may consider additional support or referral to a pain specialist for patients with these risk factors. [Figure: see text]
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Root-Bernstein, Robert, Beth Churchill, and Miah Turke. "Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse." International Journal of Molecular Sciences 21, no. 17 (August 28, 2020): 6230. http://dx.doi.org/10.3390/ijms21176230.
Повний текст джерелаАнотація:
Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions.