Perinatal morphine but not buprenorphine affects gestational and offspring neurobehavioral outcomes in mice.

Within the national opioid epidemic, there has been an increase in the number of infants exposed to opioids in utero. Additionally, opioid agonist medications are the standard of care for women with opioid use disorder during pregnancy. Buprenorphine (BUP), a partial µ -opioid receptor agonist, has been successful in improving gestational and neonatal outcomes. However, in utero exposure has been linked to childhood cognitive and behavioral problems. Therefore, we sought to compare offspring cognitive and behavioral outcomes after prenatal exposure to a clinically relevant low dose of BUP compared to morphine (MO), a full µ -opioid receptor agonist and immediate metabolite of heroin. We used a mouse model to assess gestational and offspring outcomes. Mouse dams were injected once daily s.c. with saline (SAL, n = 12), MO (10 mg/kg, n = 15), or BUP (0.1 mg/kg, n = 16) throughout pre-gestation, gestation, and lactation until offspring were weaned on postnatal day (P)21. Offspring social interaction and exploratory behavior were assessed, along with executive function via the touchscreen 5 choice serial reaction time task (5CSRTT). We then quantified P1 brain gene expression in the frontal cortex and amygdala (AMG). Perinatal MO but not BUP exposure decreased gestational weight gain and was associated with dystocia. In adolescent offspring, perinatal MO but not BUP exposure increased social exploration in males and grooming behavior in females. In the 5CSRTT, male MO exposed offspring exhibited increased impulsive action errors compared to male BUP offspring. In the AMG of P1 MO exposed offspring, we observed an increase in gene expression of targets related to activity of microglia. Importantly, both MO and BUP caused acute hyperlocomotion in the dams to a similar degree, indicating that the selected doses are comparable, in accordance with previous dose comparisons on analgesic and reward efficacy. These data suggest that compared to MO, low dose BUP improves gestational outcomes and has less of an effect on the neonatal offspring brain and later adolescent and adult behavior.

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the µ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a µ-opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.

The Role of Opioid Receptors in Cancer.

Opioids are one of the most potent drugs for treating moderate to severe pain. Despite irrefutable clinical application in chronic pain management, the long-term use of opioids has been increasingly questioned due to undesired side effects that demand attention. Opioids such as morphine mediate clinically relevant effects primarily through the µ-opioid receptor that go beyond their classical role as analgesics, causing potentially fatal side effects such as tolerance, dependence, and addiction. Furthermore, there is growing evidence that opioids affect immune system function, cancer progression, metastasis, and recurrence. Though a biological plausibility, the clinical evidence for the action of opioids on cancer is mixed, revealing a more complex picture as researchers struggle to establish a vital link between opioid receptor agonists, cancer progression, and suppression, or both. Thus, in light of the uncertainty of opioid effects on cancer, in this review, a focused overview of the role of opioid receptors in modulating cancer progression, their underlying signaling mechanisms, and the biological activity of opioid receptor agonists and antagonists is provided.

[Kratom (Mitragyna Speciosa): a Psychoactive Plant with Opportunities and Risks]. / Kratom (Mitragyna speciosa): eine psychoaktive Pflanze mit Chancen und Risiken.

Kratom is an evergreen tree that is native to Southeast Asia. Its leafs are traditionally used as a stimulant, a remedy for various health problems and for religious purposes. Especially in the US (in a lesser extent also in Europe) kratom use is significantly prevalent. In Western countries, kratom is used predominantly as an analgesic and stimulant, for the treatment of opioid use disorders, and for improving mental health (e. g., in depression, anxiety disorders). Main molecular constituents of kratom are alkaloids of which mitragynine and 7-hydroxymitragynine appear to be most important. Pharmacodynamics and -kinetics of kratom are complex and insufficiently studied. It is known that mitragynine and 7-hydroxymitragynine are partial agonist at human µ-opioid receptors and antagonists at κ- and δ-opioid receptors with additional effects at other central receptors. Tolerability of kratom is presumably better than that of classical opioids; this is probably due to missing effects of kratom on ß-arrestin and discussed as a starting point for the development of opioids with improved tolerability. Some alkaloids of kratom are inhibitors of CYP26 and to a somewhat lesser degree of CYP2C19 and CYP3A4. The addictive potential of kratom appears to be lower than that of classical opioids; however, corresponding data is limited and kratom use disorders appear to occur primarily in Western countries. Several cases of severe health-related problems and deaths are known in the US; in these cases, however, polysubstance use was usually present. Kratom use is likely associated with hepatotoxicity and cardiotoxicity. Kratom-associated mortality and morbidity in Western countries are quantitatively significantly different from Southeast Asia, where kratom use is no public health problem. The reasons for this may be the combined use of substances (which is more prevalent in Western countries), higher dosages of consumed kratom, adulterations and contaminations of commercially available kratom in Western countries, pharmacokinetic interactions, and higher concentrations of 7-hydroxymitragynine in dried kratom leafs (that are typically consumed in Western countries) in comparison to fresh leafs (that are typically consumed in Southeast Asia).

Designed to Do Good: Key Findings on the Development and Operation of First Responder Deflection Programs.

Opioids and drug overdoses have claimed more than 750 000 American lives since the late 1990s. Overdoses since the mid-2010s have risen dramatically, due to synthetic opioids such as fentanyl whose lethality is disproportionately greater than street drugs of earlier decades. Until recently, most police and other first responders lacked resources beyond arrest to respond to overdoses and other nonviolent crimes. Largely in response to the opioid crisis and synthetic opioid-related overdoses, first responder deflection (FRD) has emerged as an alternative. First responder deflection has enabled first responders across the United States to save lives by training them to administer naloxone, a medication that blocks opioid receptors after overdose, then linking these individuals to community-based treatment and services. Consequently, FRD has helped keep many citizens out of the justice system entirely, giving them a chance to rebuild their lives and become productive members of their communities. To this end, TASC's Center for Health and Justice and National Opinion Research Center at The University of Chicago collaborated on a national FRD survey encompassing a comprehensive overview of the field and its role in responding to the opioid crisis. The findings reveal how FRD offers alternatives to traditional policing, including its role in advancing racial and social equity by aligning public health and public safety for those who otherwise might enter the justice system. This article will discuss the methodology, key findings, and policy implications of this national survey (encompassing more than 300 active FRD programs). We will present results on the development of FRDs and how they operate. Results will cover the extensive involvement of law enforcement agencies in initiating FRD initiatives; the role of non-first responder partners in providing treatment and services through FRD; and the scope of Medication-Assisted Treatment in these programs, among other important findings.

The current and emerging treatment landscape for chronic cough.

Cough serves a protective physiologic function as a vital defensive reflex preventing aspiration. However, exposure to viral infections or other triggers induces, in some individuals, a chronic cough (CC) that causes a significant symptomatic burden. Most cases of CC are due to conditions that respond to appropriate therapeutic trials (upper airway cough syndrome; asthma; reflux). Unfortunately, a significant subgroup of patients will have refractory CC, which does not respond to treatment of known underlying causes of CC. Currently, available therapeutic options for refractory CC are inadequate due to limited efficacy and frequently intolerable adverse effects. Current professional society guideline recommendations are discussed, and a promising pipeline of antitussive drugs in development is introduced, including purinergic 2X3 receptor antagonists, neurokinin-1 receptor antagonists, oral mixed ĸ-opioid receptor agonists/µ-opioid receptor antagonists, and voltage-gated sodium channel blockers.

Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR.

BACKGROUND: Fentanyl is an opioid analgesic and is widely used in ovarian cancer patients for pain management. Although increasing evidence has suggested the direct role of fentanyl on cancer, little is known on the effect of fentanyl on ovarian cancer cells. METHODS: Proliferation, migration and apoptosis assays were performed in ovarian cancer cells after fentanyl treatment. Xenograft mouse model was generated to investigate the in vivo efficacy of fentanyl. Combination index was analyzed for the combination of fentanyl and chemotherapeutic drugs. Immunoblotting approach was used to analyze signaling involved in fentanyl's action focusing on EGFR. RESULTS: Fentanyl at nanomolar concentration does-dependently increased migration and proliferation of a panel of ovarian cancer cell lines. Fentanyl at the same concentrations either did not or stimulated proliferation to a less extent in normal cells than in ovarian cancer cells. Consistently, fentanyl significantly promoted ovarian cancer growth in vivo. The combination of fentanyl with cisplatin or paclitaxel was antagonist in inhibiting cell proliferation. Although fentanyl did not affect cell apoptosis, it significantly alleviated ovarian cancer cell death induced by chemotherapeutic drugs. Mechanistically, fentanyl specifically activated EGFR and its-mediated downstream pathways. Knockdown of EGFR abolished the stimulatory effects of fentanyl on ovarian cancer cells. We finally demonstrated that the activation of EGFR by fentanyl is associated with opioid µ receptor system. CONCLUSIONS: Fentanyl activates ovarian cancer via simulating EGFR signaling pathways in an opioid µ receptor-dependent manner. The activation of EGFR signaling by fentanyl may provide a new guide in clinical use of fentanyl in ovarian cancer patients.

Opioid receptor activation suppresses the neuroinflammatory response by promoting microglial M2 polarization.

Activation of microglia is considered the most important component of neuroinflammation. Microglia can adopt a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. Opioid receptors (ORs) have been shown to control neurotransmission of various peptidergic neurons, but their potential role in regulating microglial function is largely unknown. Here, we aimed to investigate the effect of the OR agonists DAMGO, DADLE and U-50488 on the polarization of C8-B4 microglial cells. We observed that opioids suppressed lipopolysaccharide (LPS)-triggered M1 polarization and promoted M2 polarization. This was reflected in lower phagocytic activity, lower production of NO, lower expression of TNF-α, IL-1ß, IL-6, IL-86 and IL-12 beta p40 together with higher migration rate, and increased expression of IL-4, IL-10, arginase 1 and CD 206 in microglia, compared to cells affected by LPS. We demonstrated that the effect of opioids on microglial polarization is mediated by the TREM2/NF-κB signaling pathway. These results provide new insights into the anti-inflammatory and neuroprotective effects of opioids and highlight their potential in combating neurodegenerative diseases.

Development of a Translational Model to Assess the Impact of Opioid Overdose and Naloxone Dosing on Respiratory Depression and Cardiac Arrest.

In response to a surge of deaths from synthetic opioid overdoses, there have been increased efforts to distribute naloxone products in community settings. Prior research has assessed the effectiveness of naloxone in the hospital setting; however, it is challenging to assess naloxone dosing regimens in the community/first-responder setting, including reversal of respiratory depression effects of fentanyl and its derivatives (fentanyls). Here, we describe the development and validation of a mechanistic model that combines opioid mu receptor binding kinetics, opioid agonist and antagonist pharmacokinetics, and human respiratory and circulatory physiology, to evaluate naloxone dosing to reverse respiratory depression. Validation supports our model, which can quantitatively predict displacement of opioids by naloxone from opioid mu receptors in vitro, hypoxia-induced cardiac arrest in vivo, and opioid-induced respiratory depression in humans from different fentanyls. After validation, overdose simulations were performed with fentanyl and carfentanil followed by administration of different intramuscular naloxone products. Carfentanil induced more cardiac arrest events and was more difficult to reverse than fentanyl. Opioid receptor binding data indicated that carfentanil has substantially slower dissociation kinetics from the opioid receptor compared with nine other fentanyls tested, which likely contributes to the difficulty in reversing carfentanil. Administration of the same dose of naloxone intramuscularly from two different naloxone products with different formulations resulted in differences in the number of virtual patients experiencing cardiac arrest. This work provides a robust framework to evaluate dosing regimens of opioid receptor antagonists to reverse opioid-induced respiratory depression, including those caused by newly emerging synthetic opioids.

Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer identifies an adaptation pathway mediated by opioid receptor kappa 1.

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease.

Modulatory Effects of Stem Cells on Opioid Receptors and Neuroinflammation.

PURPOSE OF REVIEW: This narrative review examines stem cell therapy and its effect on opioid therapy in neuropathic pain. RECENT FINDINGS: Stem cell therapy has shown promise in neuropathic pain and opioid tolerance, with a notable common pathway (the P2X4 receptor). Opioid therapy frequently has poor efficacy in patients who suffer from neuropathic pain. There is evidence that the presence of neuropathic pain itself causes changes to the opioid receptor, decreasing the therapeutic potential of this modality. The efficacy of opioid therapy is further decreased in this patient population after chronic opioid exposure, which leads to opioid tolerance and in some cases opioid-induced hyperalgesia. There is growing evidence that stem cell therapy has potential to treat neuropathic pain and may simultaneously decrease opioid tolerance and hyperalgesia. Opioid-induced hyperalgesia occurs via mu-opioid receptor-dependent expression of P2X4 receptors on microglia. Intrathecal stem cell therapy provides analgesic properties due to the significant reduction of P2X4R expression in spinal cord microglia, thereby directly decreasing chronic neuropathic pain.

Recent Advances in Peripheral Opioid Receptor Therapeutics.

PURPOSE OF REVIEW: Although opioids are excellent analgesics, they are associated with severe short- and long-term side effects that are especially concerning for the treatment of chronic pain. Peripherally acting opioid receptor agonists promise to mitigate the more serious centrally mediated side effects of opioids, and the goal of this paper is to identify and elaborate on recent advances in these peripheral opioid receptor therapeutics. RECENT FINDINGS: Peripheral opioid receptor agonists are effective analgesics that at the same time circumvent the problem of centrally mediated opioid side effects by (1) preferentially targeting peripheral opioid receptors that are often the source of the pain and (2) their markedly diminished permeability or activity across the blood-brain barrier. Recent novel bottom-up approaches have been notable for the design of therapeutics that are either active only at inflamed tissue, as in the case of fentanyl-derived pH-sensitive opioid ligands, or too bulky or hydrophilic to cross the blood-brain barrier, as in the case of morphine covalently bound to hyperbranched polyglycerols. Recent innovations in peripheral opioid receptor therapeutics of pH-sensitive opioid ligands and limiting opioid permeability across the blood-brain barrier have had promising results in animal models. While this is grounds for optimism that some of these therapeutics will be efficacious in human subjects at a future date, each drug must undergo individualized testing for specific chronic pain syndromes to establish not only the nuances of each drug's therapeutic effect but also a comprehensive safety profile.

Electroacupuncture decreases inflammatory pain through a pro-resolving mechanism involving the peripheral annexin A1-formyl peptide receptor 2/ALX-opioid receptor pathway.

The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10 Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.

Targeting the Opioid Receptors: A Promising Therapeutic Avenue for Treatment in "Heavy Drinking Smokers".

AIMS: Despite a general decline in tobacco use in the last decades, the prevalence of tobacco smoking in individuals with alcohol use disorder (AUD) remains substantial (45-50%). Importantly, the co-use of both substances potentiates the adverse effects, making it a significant public health problem. Substantial evidence suggests that AUD and Tobacco use disorder (TUD) may share common mechanisms. Targeting these mechanisms may therefore provide more effective therapy. Numerous studies describe a potential role of the endogenous opioid system in both AUD and TUD. Reviewing this literature, we aim to evaluate the efficacy of molecules that target the opioid system as promising therapeutic interventions for treating alcohol and tobacco co-use disorders. METHODS: We provide a synthesis of the current epidemiological knowledge of alcohol and tobacco co-use disorders. We evaluate clinical and preclinical research that focuses on the regulation of the endogenous opioid system in alcohol, nicotine, and their interactions. RESULTS: The epidemiological data confirm that smoking stimulates heavy drinking and facilitates alcohol craving. Pharmacological findings suggest that treatments that are efficacious in the dual addiction provide a beneficial treatment outcome in comorbid AUD and TUD. In this regard, MOP, DOP and NOP-receptor antagonists show promising results, while the findings prompt caution when considering KOP-receptor antagonists as a treatment option in alcohol and tobacco co-use disorders. CONCLUSIONS: Existing literature suggests a role of the opioid system in sustaining the high comorbidity rates of AUD and TUD. Molecules targeting opioid receptors may therefore represent promising therapeutic interventions in 'heavy drinking smokers.'

Urgencias por drogas de abuso. El papel de las salas de consumo supervisado / Emergences related to recreational drug abuse: the role of medically supervised drug consumption rooms

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Multivalent peptide and peptidomimetic ligands for the treatment of pain without toxicities and addiction.

The current opioid crisis has created a tragic problem in medicine and society. Pain is the most ubiquitous and costly disease in society and yet all of our "treatments" have toxicities, especially for prolonged use. However, there are several alternatives that have been discovered in the past fifteen years that have been demonstrated in animals to have none of the toxicities of current drugs. Many of the compounds are multivalent and have novel biological activity profiles. Unfortunately, none of these have been in clinical trials in humans, perhaps because they were discovered in academic laboratories. A review of these novel chemicals are given in this paper.

Modulation of the central opioid system as an antidepressant target in rodent models.

There has been a resurgence in interest in the central opioid system as a target in the treatment of depression. Using a range of laboratory rodent tests, potential antidepressant properties have been most associated with kappa opioid receptor antagonists, delta opioid receptor agonists, and nociceptin/orphanin FQ receptor antagonists. Although most studies to date have assessed acute behavioral effects, more elaborate investigations have demonstrated activity following repeated administration. Concerns over adverse effects have meant that opioid candidates need to be examined for their abuse potential, locomotor stimulant, and other adverse effects that might reside by activating a certain receptor subtype. The interplay between the central opioid and monoaminergic systems has been established with many clinically used antidepressants exhibiting affinity for opioid receptors that could contribute to their therapeutic effect. Similarly currently marketed opioid drugs such as tramadol possess antidepressant properties. More recent investigations have begun to examine combining of opioid agents, conferring unique profiles. This approach acknowledges that targeting a single opioid receptor may not be sufficient to produce the balanced profile of therapeutic effects, while minimizing adverse effects. As these compounds begin to reach the clinical stage, hopefully they will represent an important addition to the armamentarium to treat depression.

Eluxadoline en el tratamiento del síndrome de intestino irritable con predominio de diarrea. Punto de vista SEPD / Eluxadoline in the treatment of diarrhea-predominant irritable bowel syndrome. The SEPD perspective

Los trastornos funcionales del tubo digestivo, entre los que se encuentra el síndrome de intestino irritable con predominio de diarrea, constituyen una patología muy prevalente en todo el mundo, con un gran impacto tanto económico como en la calidad de vida de los pacientes, que no cuenta con alternativas terapéuticas completamente satisfactorias. Estas circunstancias han propiciado la investigación de diferentes moléculas con unas dianas terapéuticas más específicas como los receptores opioides. Eluxadoline (Vibercy(R) en Estados Unidos/Truberzi® en Europa, de Allergan) es una molécula agonista con efectos locales mixtos tanto agonista de los receptores opioides μ- y κ- como antagonista del receptor δ-opioide, que fue aprobada en 2015 por la Food and Drug Administration (FDA) y en 2016 por la Agencia Europea del Medicamento (EMA) para su indicación en el síndrome de intestino irritable con predominio de diarrea. Eluxadoline es un fármaco que ofrece, con ventaja sobre los que se utilizan en esta patología, el control tanto de la consistencia de las deposiciones como del dolor abdominal, con una buena tolerancia en la mayoría de los casos y una mejoría en la calidad de vida de estos pacientes, por lo que es una molécula a considerar en el abordaje de esta patología. Como en todo producto de reciente incorporación terapéutica, es de esperar una farmacovigilancia adecuada así como que se vaya generando conocimiento de estudios que nos ofrezcan información sobre diferentes escenarios tales como el tratamiento a demanda, la valoración de la pérdida de respuesta, la utilización del tratamiento como rescate a otras moléculas y la valoración del coste-eficacia del fármaco, para caracterizar y posicionar de una manera más precisa eluxadoline dentro del espectro terapéutico (AU)

Functional gut disorders, including diarrhea-predominant irritable bowel syndrome, are highly prevalent conditions worldwide that significantly impact health economy and patient quality of life, yet lacking fully satisfactory therapeutic options. These circumstances fostered research on various molecules with more specific therapeutic targets, including opioid receptors. Eluxadoline (Allergan’s Vibercy® in the USA, Truberzi® in Europe) is a locally-acting mixed mu- and kappa-opioid receptor agonist, and delta-opioid receptor antagonist, that was licensed in 2015 by the Food and Drug Administration (FDA) and in 2016 by the European Medicines Agency (EMA) for use in diarrhea-predominant irritable bowel syndrome. Eluxadoline provides, with advantage over the current standard of care, control of both stool consistency and abdominal pain, good tolerability in most cases, and improved quality of life, hence it deserves consideration when approaching a patient with this disorder. As with any recently approved therapy, adequate pharmacovigilance is to be expected, as well as studies to inform on different scenarios such as on-demand therapy, loss of response assessment, use as rescue therapy for other molecules, and cost-effectiveness, to further characterize and more accurately position eluxadoline within the therapeutic spectrum (AU)

Síndrome de la bolsa de orina púrpura / Purple urine bag syndrome

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Guía CDC para la prescripción de opioides en dolor crónico / CDC guidelines for prescribing opioids for chronic pain

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