Étude du mécanisme des overdoses aux opioïdes : apport de l’expérimental à la clinique

doi:10.1016/j.pharma.2009.06.005

Annales Pharmaceutiques Françaises

Volume 67, Issue 5, September 2009, Pages 353-359

https://doi.org/10.1016/j.pharma.2009.06.005 Get rights and content

Résumé

L’overdose désigne un effet, l’intoxication par opioïde, et un mécanisme, le surdosage. De façon surprenante, la compréhension physiopathologique de cette complication grave reste très limitée. Dans le cadre des polyconsommations, notre approche a été triple : (1) améliorer les connaissances de la toxicité respiratoire aiguë de ces médicaments ; (2) préciser les mécanismes des interactions médicamenteuses ; (3) identifier des facteurs de variabilité et de vulnérabilité. La veille sanitaire et l’étude clinique des intoxications en réanimation a confirmé l’existence d’intoxications par la buprénorphine de mécanisme plus complexe que la simple overdose et surtout de gravité moindre que l’overdose à l’héroïne en posant la question de l’innocuité relative de la méthadone. Des études expérimentales ont permis de répondre à certaines interrogations soulevées par la clinique mettant aussi en évidence quelques discordances. Les opioïdes à doses pharmacologiques diminuent la réponse ventilatoire au CO₂ mais celle-ci n’explique pas la morbimortalité des intoxications aux opioïdes. Les mécanismes de morbimortalité toxique des opioïdes sont différents. La buprénorphine à des doses proches de sa DL₅₀, n’induit pas d’insuffisance respiratoire définie par une baisse de la PaO₂ qui est provoquée par l’association à une benzodiazépine, le flunitrazépam. L’interaction délétère n’apparaît pas avec d’autres benzodiazépines, sauf une très forte dose de nordiazépam. L’interaction apparaît de nature pharmacocinétique, métabolique. La méthadone induit une hypoxémie dose dépendante, précédant l’hypercapnie et des modifications significatives et particulières de la ventilation de repos. Nous étudions les relations entre les perturbations de l’hématose et de la ventilation de repos et les différents types de récepteurs opiacés.

Summary

The widely used term “overdose” denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO₂. However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO₂). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO₂. This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO_2, even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.

Section snippets

Veilles sanitaires des intoxications

En raison du développement de l’usage du Temgésic^® et de l’évidence du développement des polyconsommations nous avions mis en place en 1995 un programme de détection urinaire des substances pour tout syndrome opiacé admis en réanimation toxicologique à l’hôpital Fernand-Widal. Le syndrome opiacé est composé d’une triade associant troubles de la conscience, bradypnée, voire apnée et myosis. Il possède une forte valeur prédictive clinique vis-à-vis de la prise de produits à action

Problèmes d’interprétations des résultats

Il faut souligner l’extrême difficulté dans l’établissement d’une relation causale entre, d’une part, un effet observé qui peut être soit la découverte d’un sujet décédé, soit d’un syndrome opioïde et, d’autre part, des principes actifs détectés dans les urines ou des concentrations sanguines mesurées. C’est ainsi qu’une étude rétrospective a été réalisée sous la direction du Pr Ricordel, chef du laboratoire de toxicologie de la préfecture de police, portant sur les cas de décès avec détection

Overdose ou surdose aux opioïdes

Parler d’overdose, de surdose aux opioïdes, pose un problème nosologique. En effet, le terme d’overdose signifie à la fois une maladie et un mécanisme ; une maladie, l’existence d’un syndrome opioïde et un mécanisme, le surdosage. Le terme d’overdose pose la question de savoir si la toxicité des opioïdes n’est que dose dépendante. L’effet dépresseur respiratoire de la méthadone à dose thérapeutique est connu depuis longtemps. Il avait été mis en évidence par Santiago dès 1977, qui avait montré

Buprénorphine

À partir de tels résultats, il devenait nécessaire de séparer, au moins pour un temps, l’étude des mécanismes de toxicité respiratoire induits par la méthadone de ceux induits par la buprénorphine. Il apparaissait urgent de préciser les mécanismes de toxicité de la buprénorphine. Possédant un modèle reproductible, nous avons dans un premier temps étudié l’interaction de la buprénorphine avec d’autres benzodiazépines. En effet, la fréquence de l’association de substances psychoactives au cours

Méthadone

Ces études nous ont encouragés à préciser la toxicité intrinsèque de la méthadone. Après détermination de sa DL₅₀ chez le rat mâle Sprague-Dawley, nous nous sommes intéressés à la relation dose–effet dans un éventail de dose allant de 8 à 80 % de la DL₅₀. Ce modèle expérimental montre un effet seuil de la méthadone sur la PaCO₂ avec augmentation de celle-ci seulement pour la dose égale à 80 % de la DL₅₀. En revanche, il existe une diminution dose dépendante, sans effet seuil, de la PaO₂. Ces

Conclusion

Compte tenu de la complexité et de la diversité des mécanismes mis en jeu, le terme d’intoxication opioïde apparaît plus approprié que celui de surdosage opioïde. Lors de surdosages, certains opioïdes, tels la méthadone, ont une toxicité dose dépendante, d’autres, comme la buprénorphine, n’ont pas de toxicité dépendante de la dose. Certaines benzodiazépines peuvent faire apparaître cette toxicité (buprénorphine) ou l’augmenter (méthadone). Dans l’interaction opioïdes–benzodiazépines, il existe

Conflits d’intérêts

Aucun.

Remerciements

Je souhaiterais exprimer mes sincères remerciements à mes collaboratrices, techniciennes Inserm, Mme Patricia Risède et notre très regrettée Claire Monier, sans lesquelles ces travaux n’auraient jamais vu le jour et à mes collaborateurs, étudiants, qui ont concrétisé ces hypothèses dans leurs thèses soutenues brillamment : Mmes les Dr Gueye, Pirnay, sans oublier le Pr Mégarbane. Une pensée à Melle Chevillard dont les résultats sont particulièrement prometteurs et qui soutiendra sa thèse cette

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Cited by (14)

Effects of alcohol on brain oxygenation and brain hypoxia induced by intravenous heroin
2021, Neuropharmacology
Alcohol is the most commonly used psychoactive drug, often taken in conjunction with opioid drugs. Since both alcohol and opioids can induce CNS depression, it is often assumed that alcohol potentiates the known hypoxic effects of opioid drugs. To address this supposition, we used oxygen sensors to examine the effects of alcohol on brain oxygenation and hypoxic responses induced by intravenous heroin in awake, freely moving rats. To eliminate robust sensory effects of alcohol following its oral or intraperitoneal delivery, alcohol was administered directly into the stomach via chronically implanted intragastric catheters at human relevant doses. Alcohol delivered at a 0.5 g/kg dose did not affect brain oxygen levels, except for a weak transient increase during drug delivery. This phasic oxygen increase was stronger at a 2.0 g/kg alcohol dose and followed by a weaker tonic increase. Since alcohol absorption from intragastric delivery is much slower and more prolonged than with intraperitoneal or intravenous injections, the rapid rise of brain oxygen levels suggests that alcohol has a direct action on sensory afferents in the stomach well before the drug physically reaches brain tissue via circulation. Despite slow tonic increases in brain oxygen, alcohol at the 2.0 g/kg dose strongly potentiates heroin-induced oxygen responses, increasing both the magnitude and duration of oxygen decrease. Therefore, under the influence of alcohol, the use of opioid drugs becomes much more dangerous, increasing brain hypoxia and enhancing the probability of serious health complications, including coma and death.
Cocaine added to heroin fails to affect heroin-induced brain hypoxia
2020, Brain Research
Citation Excerpt :
It has been found that one in five heroin overdose deaths also involved cocaine (Warner et al., 2016). Since respiratory depression followed by brain hypoxia is the most dangerous effect of opioid drugs (Baud, 2009; Dahan et al., 2005; Jaffe et al., 1997; Pattinson, 2008), this study was designed to examine how brain hypoxic effects of heroin are affected by co-injected cocaine. Similar to our previous studies (Solis et al., 2017a,b; Solis et al., 2018a,b), drug-induced effects on brain oxygen were assessed by directly monitoring oxygen levels in the NAc by using oxygen sensors coupled with high-speed amperometry in freely moving rats.
Heroin and cocaine are both highly addictive drugs that cause unique physiological and behavioral effects. These drugs are often co-administered and cocaine has been found in ~20% of cases of opioid overdose death. Respiratory depression followed by brain hypoxia is the most dangerous effect of high-dose opioids that could result in coma and even death. Conversely, cocaine at optimal self-administering doses increases brain oxygen levels. Considering these differences, it is unclear what pattern of oxygen changes will occur when these drugs are co-administered. Here, we used high-speed amperometry with oxygen sensors to examine changes in oxygen concentrations in the nucleus accumbens (NAc) induced by intravenous (iv) cocaine, heroin, and their mixtures in freely-moving rats. Cocaine delivered at a range of doses, both below (0.25 mg/kg) and within the optimal range of self-administration (0.5 and 1.0 mg/kg) modestly increased NAc oxygen levels. In contrast, heroin increased oxygen levels at a low reinforcing dose (0.05 mg/kg), but induced a biphasic down-up change at higher reinforcing doses (0.1 and 0.2 mg/kg), and caused a strong monophasic oxygen decrease during overdose (0.6 mg/kg). When combined at moderate doses, cocaine (0.25, 0.5 mg/kg) slightly increased and prolonged oxygen increases induced by heroin alone (0.5 and 0.1 mg/kg), but oxygen decreases were identical when cocaine (1 mg/kg) was combined with heroin at large doses (0.2 and 0.6 mg/kg). Therefore, health dangers of speedball may result from de-compensation of vital functions due to diminished intra-brain oxygen inflow induced by high-dose heroin coupled with enhanced oxygen use induced by cocaine.
Interactions of benzodiazepines with heroin: Respiratory depression, temperature effects, and behavior
2019, Neuropharmacology
Citation Excerpt :
Opioids are important therapeutic drugs that alleviate pain of different origins, but these drugs have strong addictive properties and their abuse can result in serious health complications and death (Compton et al., 2016; McLaughlin, 2017). While opioids induce multiple physiological effects, respiratory depression, which results in brain hypoxia, appears to be the most dangerous one (Baud, 2009; Jaffe et al., 1997; Simon, 1997). This effect is minor and can be controlled following therapeutic use of opioid analgesics, but it can be robust and life-threatening when highly potent opioids such as heroin or fentanyl are administered intravenously at higher doses (Solis et al., 2017b, 2018).
Benzodiazepines are important therapeutic drugs, but they are often abused and co-abused with opioids. Clinical evidence suggests that benzodiazepines can inhibit respiration, and when combined with the respiratory-depressive effects of opioids, may increase likelihood of death. In this study we used oxygen sensors coupled with high-speed amperometry and multi-site thermorecording to examine how intravenous (iv) midazolam, a potent benzodiazepine, modulates the brain hypoxic and temperature effects of iv heroin in freely-moving rats. Oxygen levels and brain temperature were assessed with high temporal resolution in the nucleus accumbens (NAc), an important structure in the motivational-reinforcement circuit. When administered alone, midazolam (2 mg/kg) modestly decreased NAc temperature but had no evident effects on oxygen levels in this structure. In contrast, heroin (0.4 mg/kg) induced a strong decrease in NAc oxygen that was followed by a weaker, rebound-like oxygen increase. Midazolam pretreatment did not affect heroin-induced brain hypoxia but potentiated the initial hypothermia induced by heroin. However, co-administration of these drugs potentiated the heroin-induced oxygen decrease and enhanced heroin-induced brain hypothermia. Co-administration of heroin and midazolam also resulted in enhanced locomotor inhibition and loss of motor control. This effect caused some rats to collapse, resulting in nose and mouth occlusion, which caused a secondary hypoxic phase. These results could have important implications for human drug users, as the combined use of benzodiazepines with potent opioids not only results in sustained brain hypoxia but creates conditions of loss of motor control which could result in asphyxia and death.
This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.
Respiratory depression and brain hypoxia induced by opioid drugs: Morphine, oxycodone, heroin, and fentanyl
2019, Neuropharmacology
Citation Excerpt :
As shown in latter study, centrally administered oxycodone was 2–3-fold less potent than morphine and its effects were shorter than those for morphine. Respiratory depression appears to be a basic effect of all μ-opioid receptor agonists (Baud, 2009; Jaffe et al., 1997; Simon, 1997). As shown above, each of four opioids considered in this review decreased NAc oxygen levels, indicating brain hypoxia.
Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in serious health complications. Respiratory depression that leads to brain hypoxia is perhaps the most dangerous symptom of acute intoxication with opioids, and it could result in lethality. The development of substrate-specific sensors coupled with amperometry made it possible to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely-moving rats. The goal of this review paper is to consider changes in brain oxygen levels induced by several opioid drugs (heroin, fentanyl, oxycodone, morphine). While some of these drugs are widely used in clinical practice, they all are abused, often at doses exceeding the clinical range and often resulting in serious health complications. First, we consider some basic knowledge regarding brain oxygen, its physiological fluctuations, and mechanisms involved in regulating its entry into brain tissue. Then, we present and discuss data on brain oxygen changes induced by each opioid drug within a wide range of doses, from low, behaviorally relevant, to high, likely to be self-administered by drug users. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-course, and their potential danger when used at high doses via rapid-onset administration routes. While most data discussed in this work were obtained in rats, we believe that these data have clear human relevance in addressing the alarming rise in lethality associated with the opioid abuse.
This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.
Interest of take-home naloxone for opioid overdose
2018, Therapie
Ces dernières décennies, on a observé un changement du panorama des opioïdes consommés avec la commercialisation des médicaments de substitution aux opiacés, une augmentation de la consommation d’analgésiques opioïdes et récemment l’émergence des opioïdes de synthèse. L’Organisation mondiale de la santé (OMS) recense environ 70 000 décès par surdosage d’opioïdes dans le monde chaque année. En France, d’après le dispositif de surveillance et de veille sanitaire du réseau français d’addictovigilance « décès en relation avec l’abus de médicaments et de substances » (DRAMES), la majorité des décès sont liés à un opioïde (majoritairement la méthadone, suivi de l’héroïne, la buprénorphine et des médicaments analgésiques opioïdes). La naloxone, antagoniste des récepteurs aux opioïdes, est utilisée dans le traitement d’urgence de surdosage d’opioïdes. Depuis quelques années, différents pays ont mis à disposition des kits de naloxone à des personnes susceptibles d’être témoins d’un surdosage d’opioïdes. En 2014, l’OMS a publié des recommandations pour cette mise à disposition et sur la nécessité de former les usagers et leur entourage à la prise en charge de ces surdosages. Dans ce contexte, l’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a mis à disposition un dispositif intranasal Nalscue^® dans le cadre d’une autorisation temporaire d’utilisation (ATU) de cohorte en juillet 2016. Au vu de la diversité des caractéristiques des opioïdes actuellement consommés (pharmacodynamiques, pharmacocinétiques, physicochimique, galénique…), le risque de surdosage peut différer d’un opioïde à l’autre et il peut être nécessaire en fonction du contexte clinique, d’administrer des doses plus élevées de naloxone et les réitérer pour prolonger son action.
Over the course of these last decades, we observed a change on opioid use with the marketing of opiate maintenance treatment, an increase of opioids used for pain management and recent concerns have arisen around the use of synthetic opioid. The World Health Organization (WHO) reports around 70,000 people opioid overdose death each year. In France, according to the DRAMES program (fatalities in relation with abuse of licit or illicit drugs) of the French addictovigilance network, most of deaths are related to opioids overdose (especially methadone, following by heroin, buprenorphine and opioid used for pain management). Opioid overdose is treatable with naloxone, an opioid antagonist which rapidly reverses the effects of opioids. In recent years, a number of programs around the world have shown that it is feasible to provide naloxone to people likely to witness an opioid overdose. In 2014, the WHO published recommendations for this provision and the need to train users and their entourage in the management of opioid overdose. In this context, in July 2016, French drug agency has granted a temporary authorization for use of a naloxone nasal spray Nalscue^®. Because different opioids can be used and because each opioid has specific characteristics (pharmacodynamics, pharmacokinetics, galenic form…), the risk of overdose may differ from one opioid to another and it may be necessary, depending on the clinical context, to use larger and repeated doses of naloxone.
Robustness of arterial blood gas analysis for assessment of respiratory safety pharmacology in rats
2016, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
Morphine, oxycodone and fentanyl all produced decreases in oxygen tension, saturation and pH as well as an increase in CO2 tension. In line with previous reports (Chevillard, Megarbane, Risede, & Baud, 2009; Kuo, Wyse, Meutermans, & Smith, 2015; Meert & Vermeirsch, 2005), the profile of each compound is unique, although general trends can be drawn for morphine, fentanyl, hydrocodone and oxycodone. In contrast, the profile for buprenorphine is inherently distinct from the other opioids tested; buprenorphine produced a hypoxia consistent with literature reports (Chevillard, Megarbane, Risede, & Baud, 2009) although the magnitude of effect was low and the variability was high.
Whole body plethysmography using unrestrained animals is a common technique for assessing the respiratory risk of new drugs in safety pharmacology studies in rats. However, wide variations in experimental technique make cross laboratory comparison of data difficult and raise concerns that non-appropriate conditions may mask the deleterious effects of test compounds — in particular with suspected respiratory depressants. Therefore, the objective of this study was to evaluate the robustness of arterial blood gas analysis as an alternative to plethysmography in rats. We sought to do this by assessing the effect of different vehicles and times post-surgical catheterization on blood gas measurements, in addition to determining sensitivity to multiple opioids. Furthermore, we determined intra-lab variability from multiple datasets utilizing morphine and generated within a single lab and lastly, inter-lab variability was measured by comparing datasets generated in two separate labs. Overall, our data show that arterial blood gas analysis is a measure that is both flexible in terms of experimental conditions and highly sensitive to respiratory depressants, two key limitations when using plethysmography. As such, our data strongly advocate the adoption of arterial blood gas analysis as an investigative approach to reliably examine the respiratory depressant effects of opioids.

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^☆: Communication présentée à l’Académie de pharmacie lors de la séance thématique : « Traitements de substitution aux opiacés » du 28 janvier 2009.

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Séance thématique : « Traitements de substitution aux opiacés »Étude du mécanisme des overdoses aux opioïdes : apport de l’expérimental à la cliniqueMechanisms of opioid-induced overdose: Experimental approach to clinical concerns☆

Résumé

Summary

Section snippets

Veilles sanitaires des intoxications

Problèmes d’interprétations des résultats

Overdose ou surdose aux opioïdes

Buprénorphine

Méthadone

Conclusion

Conflits d’intérêts

Remerciements

Forensic Sci Int

Am J Med

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Vet Anaesth Analg

Fundam Appl Toxicol

Toxicol Lett

Traitement d’urgence de l’overdose à l’héroïne

Rev Prat

Analgésiques centraux

Intoxications aiguës par traitement substitutif à base de buprénorphine haut dosage. 29 observations cliniques-20 cas mortels

Presse Med

Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995–99

Addiction

Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities

J Anal Toxicol

Deaths attributable to methadone vs buprenorphine in France

JAMA

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths

Addiction

Séance thématique : « Traitements de substitution aux opiacés »
Étude du mécanisme des overdoses aux opioïdes : apport de l’expérimental à la cliniqueMechanisms of opioid-induced overdose: Experimental approach to clinical concerns☆