RESUMEN
Introduction: Deaths due to overdose of fentanyls result primarily from depression of respiration. These potent opioids can also produce muscle rigidity in the diaphragm and the chest muscles, a phenomenon known as Wooden Chest Syndrome, which further limits ventilation. Methods: We have compared the depression of ventilation by fentanyl and morphine by directly measuring their ability to induce muscle rigidity using EMG recording from diaphragm and external and internal intercostal muscles, in the rat working heart-brainstem preparation. Results: At equipotent bradypnea-inducing concentrations fentanyl produced a greater increase in expiratory EMG amplitude than morphine in all three muscles examined. In order to understand whether this effect of fentanyl was a unique property of the phenylpiperidine chemical structure, or due to fentanyl's high agonist intrinsic efficacy or its lipophilicity, we compared a variety of agonists with different properties at concentrations that were equipotent at producing bradypnea. We compared carfentanil and alfentanil (phenylpiperidines with relatively high efficacy and high to medium lipophilicity, respectively), norbuprenorphine (orvinolmorphinan with high efficacy and lipophilicity) and levorphanol (morphinan with relatively low efficacy and high lipophilicity). Discussion: We observed that, agonists with higher intrinsic efficacy were more likely to increase expiratory EMG amplitude (i.e., produce chest rigidity) than agonists with lower efficacy. Whereas lipophilicity and chemical structure did not appear to correlate with the ability to induce chest rigidity.
RESUMEN
Synthetic cannabinoid receptor agonists (SCRAs) have been associated with QT interval prolongation. Limited preclinical information on SCRA effects on cardiac electrogenesis results from the rapid emergence of new compounds and restricted research availability. We used two machine-learning-based tools to evaluate seven novel SCRAs' interaction potential with the hERG potassium channel, an important drug antitarget. Five SCRAs were predicted to have the ability to block the hERG channel by both prediction tools; ADB-FUBIATA was predicted to be a strong hERG blocker. ADB-5Br-INACA and ADB-4en-PINACA showed varied predictions. These findings highlight potentially proarrhythmic hERG block by novel SCRAs, necessitating detailed safety evaluations.
RESUMEN
BACKGROUND AND PURPOSE: The illicit use of fentanyl-like drugs (fentanyls), which are µ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls. EXPERIMENTAL APPROACH: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with µ opioid receptors, to assess Gi protein activation and ß-arrestin 2 recruitment. Agonist-induced cell surface receptor loss was assessed using an enzyme-linked immunosorbent assay, whilst agonist-induced G protein-coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the µ opioid receptor were determined in silico using molecular dynamics simulations. KEY RESULTS: Relative to the reference ligand DAMGO, carfentanil was ß-arrestin-biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias. CONCLUSIONS AND IMPLICATIONS: Carfentanil is a ß-arrestin-biased opioid drug at the µ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.
Asunto(s)
Canales de Potasio de Rectificación Interna , Receptores Opioides mu , Ratas , Humanos , Animales , Receptores Opioides mu/metabolismo , beta-Arrestinas/metabolismo , Arrestina/metabolismo , Ligandos , Células HEK293 , Fentanilo/farmacología , Analgésicos Opioides/farmacología , Proteínas de Unión al GTP/metabolismo , beta-Arrestina 1/metabolismoRESUMEN
BACKGROUND AND PURPOSE: G protein-biased µ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased µ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones. EXPERIMENTAL APPROACH: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells. Desensitisation of opioid-induced currents were studied in rat locus coeruleus neurones using whole-cell patch-clamp electrophysiology. The mechanism of Compound 1-induced µ receptor desensitisation was probed using kinase inhibitors. KEY RESULTS: Compound 1 has similar intrinsic activity for G protein signalling as morphine. As predicted for a G protein-biased µ agonist, Compound 1 induced minimal agonist-induced internalisation and phosphorylation at intracellular µ receptor serine/threonine residues known to be involved in G protein-coupled receptor kinase (GRK)-mediated desensitisation. However, Compound 1 induced robust rapid µ receptor desensitisation in locus coeruleus neurons, to a greater degree than morphine. The extent of Compound 1-induced desensitisation was unaffected by activation or inhibition of protein kinase C (PKC) but was significantly reduced by inhibition of GRK. CONCLUSION AND IMPLICATIONS: Compound 1 is a novel G protein-biased µ agonist that induces substantial rapid receptor desensitisation in mammalian neurons. Surprisingly, Compound 1-induced desensitisation was demonstrated to be GRK dependent despite its G protein bias. Our findings refute the assumption that G protein-biased agonists will evade receptor desensitisation and tolerance. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
Asunto(s)
Analgésicos Opioides , Receptores Opioides mu , Ratas , Humanos , Animales , Analgésicos Opioides/farmacología , Receptores Opioides mu/metabolismo , Proteínas de Unión al GTP/metabolismo , Morfina/farmacología , Transducción de Señal , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Mamíferos/metabolismoRESUMEN
In ligand bias different agonist drugs are thought to produce distinct signaling outputs when activating the same receptor. If these signaling outputs mediate therapeutic versus adverse drug effects, then agonists that selectively activate the therapeutic signaling pathway would be extremely beneficial. It has long been thought that µ-opioid receptor agonists that selectively activate G protein- over ß-arrestin-dependent signaling pathways would produce effective analgesia without the adverse effects such as respiratory depression. However, more recent data indicate that most of the therapeutic and adverse effects of agonist-induced activation of the µ-opioid receptor are actually mediated by the G protein-dependent signaling pathway, and that a number of drugs described as G protein biased in fact may not be biased, but instead may be low-intrinsic-efficacy agonists. In this review we discuss the current state of the field of bias at the µ-opioid receptor and other opioid receptor subtypes.
Asunto(s)
Analgésicos Opioides , Transducción de Señal , Humanos , Analgésicos Opioides/efectos adversos , Proteínas de Unión al GTP/metabolismo , Dolor/tratamiento farmacológico , beta-Arrestinas/metabolismoRESUMEN
Fentanyl is a key therapeutic, used in anaesthesia and pain management. It is also increasingly used illicitly and is responsible for a large and growing number of opioid overdose deaths, especially in North America. A number of factors have been suggested to contribute to fentanyl's lethality, including rapid onset of action, in vivo potency, ligand bias, induction of muscle rigidity and reduced sensitivity to reversal by naloxone. Some of these factors can be considered to represent 'anomalous' pharmacological properties of fentanyl when compared with prototypical opioid agonists such as morphine. In this review, we examine the nature of fentanyl's 'anomalous' properties, to determine whether there is really a pharmacological basis to support the existence of such properties, and also discuss whether such properties are likely to contribute to overdose deaths involving fentanyls. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
Asunto(s)
Sobredosis de Droga , Fentanilo , Humanos , Fentanilo/farmacología , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Antagonistas de Narcóticos , Naloxona/farmacología , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/epidemiologíaRESUMEN
Overdose deaths from fentanyl have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist that is less well reversed by naloxone than morphine. Due to fentanyl's high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by its interactions with the lipid membrane on route to binding to the µ-opioid receptor (MOPr). Through coarse-grained molecular dynamics simulations, electrophysiological recordings and cell signalling assays, we determined how fentanyl and morphine access the orthosteric pocket of MOPr. Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl may take a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices. In electrophysiological recordings fentanyl-induced currents returned after washout, suggesting fentanyl deposits in the lipid membrane. However, mutation of residues forming the potential MOPr transmembrane access site did not alter fentanyl's pharmacological profile in vitro. A high local concentration of fentanyl in the lipid membrane, possibly in combination with a novel lipophilic binding route, may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.
RESUMEN
Background: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression. Methods: Tolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively. Results: Morphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment. Conclusion: These data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration.
RESUMEN
BACKGROUND AND AIMS: This qualitative study aimed to explore how the development of tolerance to both the psychoactive and respiratory depressant effects of heroin on re-exposure are experienced by people who use heroin. METHODS: Semi-structured one-to-one interviews were conducted with 20 adults who currently or previously used heroin (for at least 6 months), with any type of administration (injected, smoked) and experience of abstinence (at least 2 weeks) and relapse. Topic guides explored the participants understanding of tolerance, their experience of developing tolerance to heroin and of tolerance following relapse. Interviews were audio-recorded and transcribed. Thematic analysis was used to generate salient themes. RESULTS: The analysis produced three broad themes: lay understanding of tolerance; tolerating tolerance; and rapid tolerance development following relapse. Tolerance was defined as the body adapting to regular drug use, so that the drug no longer produced the same level of effect. Tolerance was experienced as interacting and co-developing with physical dependence and the symptoms of withdrawal. Indeed, several participants did not differentiate between tolerance and dependence. Most participants did not notice tolerance to respiratory depression. Tolerance levels fluctuated-increasing over periods of regular use and reducing when abstinent. Using more drug was the most common response to increasing tolerance to the desired effects. On re-use following abstinence, tolerance was experienced as developing more quickly in the most recent relapse compared to the first. Tolerance was also perceived to return more quickly with each abstinence-relapse cycle. CONCLUSIONS: Qualitative accounts of tolerance report that tolerance returns more quickly with each relapse episode. By elucidating the mechanism(s) involved and potentially discovering how they could be switched on prior to relapse occurring we might be able to develop a beneficial harm reduction treatment for people in abstinence that would protect against overdose occurring on subsequent relapse.
Asunto(s)
Dependencia de Heroína , Heroína , Adulto , Analgésicos Opioides , Tolerancia a Medicamentos , Heroína/efectos adversos , Humanos , RecurrenciaRESUMEN
BACKGROUND AND AIMS: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26th May 2016, made the production, supply and sale of all non-exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA. DESIGN: Observational study. SETTING: Thirty-four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study. PARTICIPANTS: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure. MEASUREMENTS: Toxicological analyses of patient samples were conducted using liquid-chromatography tandem mass-spectrometry. Time-series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression. FINDINGS: SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99-1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94-1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non-SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98-1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98-1.04; P = 0.478) implementation of the PSA. CONCLUSIONS: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Personalidad , Agonistas de Receptores de Cannabinoides/efectos adversos , Cromatografía Liquida , Femenino , Hospitales , Humanos , Masculino , Reino Unido/epidemiologíaRESUMEN
G protein-biased agonists of the µ-opioid receptor (MOPr) have been proposed as an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the ß-arrestin2-knockout mouse that led to this proposal, and alternative genetic models do not support the G protein-biased MOPr agonist hypothesis. Furthermore, assessment of putatively biased ligands has been confounded by several factors, including assay amplification. As such, the extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that ß-arrestin2 mediates deleterious opioid effects. Addressing these current challenges represents a pressing issue to successfully advance drug development at this receptor and improve upon current opioid analgesics.
Asunto(s)
Analgésicos Opioides , Receptores Opioides mu , Animales , Proteínas de Unión al GTP/metabolismo , Ligandos , Ratones , Receptores Opioides mu/metabolismo , Arrestina beta 2/metabolismoRESUMEN
BACKGROUND AND PURPOSE: GPCRs can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor, early experimental evidence from a single study suggested that G protein signalling mediates analgesia, whereas ß-arrestin2 signalling mediates respiratory depression and constipation. Consequently, for more than a decade, much research effort has been focused on developing biased µ-opioid agonists that preferentially target G protein signalling over ß-arrestin signalling, as it was believed that such drugs would be analgesics devoid of respiratory depressant activity. However, the prototypical compounds that have been developed based on this concept have so far failed in clinical and preclinical development. EXPERIMENTAL APPROACH: The present study was set up to re-examine opioid-induced respiratory depression in ß-arrestin2 knockout mice. To this end, a consortium was formed consisting of three different laboratories located in different countries to evaluate independently opioid-induced respiratory depression. KEY RESULTS: Our consensus results unequivocally demonstrate that the prototypical µ-opioid agonist morphine (3.75-100 mg·kg-1 s.c. or 3-30 mg·kg-1 i.p.) as well as the potent opioid fentanyl (0.05-0.35 mg·kg-1 s.c.) do indeed induce respiratory depression and constipation in ß-arrestin2 knockout mice in a dose-dependent manner indistinguishable from that observed in wild-type mice. CONCLUSION AND IMPLICATIONS: Our findings do not support the original suggestion that ß-arrestin2 signalling plays a key role in opioid-induced respiratory depression and call into question the concept of developing G protein-biased µ-opioid receptor agonists as a strategy for the development of safer opioid analgesic drugs.
Asunto(s)
Morfina , Insuficiencia Respiratoria , Analgésicos Opioides/toxicidad , Animales , Fentanilo , Ratones , Morfina/farmacología , Receptores Opioides mu/metabolismo , Insuficiencia Respiratoria/inducido químicamente , Arrestina beta 2/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Fentanyl overdose deaths have reached "epidemic" levels in North America. Death in opioid overdose invariably results from respiratory depression. In the present work, we have characterized how fentanyl depresses respiration, and by comparing fentanyl with heroin and morphine, the active breakdown product of heroin, we have sought to determine the factors, in addition to high potency, that contribute to the lethality of fentanyl. EXPERIMENTAL APPROACH: Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole body plethysmography. KEY RESULTS: Intravenously administered fentanyl produced more rapid depression of respiration than equipotent doses of heroin or morphine. Fentanyl depressed both respiratory rate and tidal volume. Fentanyl did not depress respiration in µ-opioid receptor knockout mice. Naloxone, the opioid antagonist widely used to treat opioid overdose, reversed the depression of respiration by morphine more readily than that by fentanyl, whereas diprenorphine, a more lipophilic antagonist, was equipotent in reversing fentanyl and morphine depression of respiration. Prolonged treatment with morphine induced tolerance to respiratory depression, but the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself. CONCLUSION AND IMPLICATIONS: We propose that several factors (potency, rate of onset, lowered sensitivity to naloxone, and lowered cross tolerance to heroin) combine to make fentanyl more likely to cause opioid overdose deaths than other commonly abused opioids. Lipophilic antagonists such as diprenorphine may be better antidotes than naloxone to treat fentanyl overdose.
Asunto(s)
Analgésicos Opioides/toxicidad , Fentanilo/toxicidad , Heroína/toxicidad , Pulmón/efectos de los fármacos , Morfina/toxicidad , Respiración/efectos de los fármacos , Insuficiencia Respiratoria/inducido químicamente , Analgésicos Opioides/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Sobredosis de Droga , Tolerancia a Medicamentos , Femenino , Fentanilo/administración & dosificación , Heroína/administración & dosificación , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Pulmón/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/administración & dosificación , Antagonistas de Narcóticos/farmacología , Receptores Opioides mu/agonistas , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/metabolismo , Insuficiencia Respiratoria/fisiopatología , Frecuencia Respiratoria/efectos de los fármacos , Medición de Riesgo , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
Agonists at the δ opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some δ opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the δ opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signaling pathways and potentially improve the therapeutic profile of δ opioid agonists. Here, we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide), a novel G protein-biased and selective δ opioid agonist. In cell-based assays, PN6047 fully engages G protein signaling but is a partial agonist in both the arrestin recruitment and internalization assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test, and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, δ opioid ligands with limited arrestin signaling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states. SIGNIFICANCE STATEMENT: PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide) is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment, and PN6047 does not display proconvulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signaling will be beneficial in the treatment of chronic pain.
Asunto(s)
Analgésicos Opioides/metabolismo , Antidepresivos/química , Benzamidas/química , Benzamidas/farmacocinética , Dolor Crónico/tratamiento farmacológico , Proteínas de Unión al GTP/metabolismo , Receptores Opioides delta/metabolismo , Animales , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Arrestina/metabolismo , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Tolerancia a Medicamentos , Células HEK293 , Humanos , Masculino , Ratones , Modelos Animales , Ratas Wistar , Resultado del TratamientoRESUMEN
BACKGROUND: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression. METHODS: Mice were fed control or ethanol (5%) liquid diet for 16 days. On days 9-16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance. RESULTS: Prolonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol. CONCLUSIONS: Prolonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Tolerancia a Medicamentos , Etanol/administración & dosificación , Morfina/administración & dosificación , Insuficiencia Respiratoria/inducido químicamente , Mecánica Respiratoria/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Sobredosis de Droga/fisiopatología , Sobredosis de Droga/prevención & control , Tolerancia a Medicamentos/fisiología , Masculino , Ratones , Distribución Aleatoria , Insuficiencia Respiratoria/fisiopatología , Mecánica Respiratoria/fisiologíaRESUMEN
We summarise the evidence for medicinal uses of opioids, harms related to the extramedical use of, and dependence on, these drugs, and a wide range of interventions used to address these harms. The Global Burden of Diseases, Injuries, and Risk Factors Study estimated that in 2017, 40·5 million people were dependent on opioids (95% uncertainty interval 34·3-47·9 million) and 109â500 people (105â800-113â600) died from opioid overdose. Opioid agonist treatment (OAT) can be highly effective in reducing illicit opioid use and improving multiple health and social outcomes-eg, by reducing overall mortality and key causes of death, including overdose, suicide, HIV, hepatitis C virus, and other injuries. Mathematical modelling suggests that scaling up the use of OAT and retaining people in treatment, including in prison, could avert a median of 7·7% of deaths in Kentucky, 10·7% in Kiev, and 25·9% in Tehran over 20 years (compared with no OAT), with the greater effects in Tehran and Kiev being due to reductions in HIV mortality, given the higher prevalence of HIV among people who inject drugs in those settings. Other interventions have varied evidence for effectiveness and patient acceptability, and typically affect a narrower set of outcomes than OAT does. Other effective interventions focus on preventing harm related to opioids. Despite strong evidence for the effectiveness of a range of interventions to improve the health and wellbeing of people who are dependent on opioids, coverage is low, even in high-income countries. Treatment quality might be less than desirable, and considerable harm might be caused to individuals, society, and the economy by the criminalisation of extramedical opioid use and dependence. Alternative policy frameworks are recommended that adopt an approach based on human rights and public health, do not make drug use a criminal behaviour, and seek to reduce drug-related harm at the population level.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Sobredosis de Droga/mortalidad , Trastornos Relacionados con Opioides/epidemiología , Analgésicos Opioides/envenenamiento , Sobredosis de Droga/epidemiología , Salud Global , Conocimientos, Actitudes y Práctica en Salud , Humanos , Trastornos Relacionados con Opioides/prevención & control , Trastornos Relacionados con Opioides/terapia , Prevalencia , Factores de RiesgoAsunto(s)
Sobredosis de Droga/mortalidad , Fentanilo/farmacología , Narcóticos/farmacología , Receptores Opioides mu/agonistas , Sobredosis de Droga/tratamiento farmacológico , Fentanilo/análogos & derivados , Fentanilo/envenenamiento , Humanos , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Narcóticos/envenenamiento , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/fisiopatología , Músculos Respiratorios/fisiopatologíaRESUMEN
This themed section of the British Journal of Pharmacology stems from an International Narcotics Research Conference (INRC) meeting held in July 2016 at The Assembly Rooms in Bath, UK. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.