Toleranzentwicklung unter Opioidgabe - Molekulare Mechanismen und klinische Bedeutung

Zusammenfassung

Eine unter langfristiger Opioidgabe gelegentlich zu beobachtende Wirkung ist die Toleranzentwicklung der analgetischen Wirkung. Dies geht mit einer Dosissteigerung einher und kann im Rahmen der Anästhesie, Intensivmedizin und Schmerztherapie beobachtet werden. Zwar liegt bei tumorbedingten Schmerzen in den meisten Fällen eine mit der Grunderkrankung einhergehende Zunahme der Schmerzintensität vor. Es gibt jedoch auch Fälle, bei denen sich im Rahmen einer medikamentösen Antinozizeption eine Toleranz auf das Opioid entwickelt. Als Auslöser kommen weniger pharmakokinetische Ursachen als vielmehr Adaptationsmechanismen an den mit dem Opioid interagierenden Bindestellen und die nach Bindung ausgelösten intrazellulären Prozesse infrage. So führt eine Desensibilisierung des Rezeptors zu einer verminderten Ansprechbarkeit auf das Opioid, „taucht der Opioidrezeptor” in das Zellinnere (Internalisierung) ab, wird die Nitritoxydsynthetase mit anschließender Bildung von dem pronozizeptiven NO aktiviert, führen Unterschiede in der Rezeptoraffinität verschiedener Opioide zu einer unterschiedlich schnellen Toleranzentwicklung, oder kann eine langfristige Benzodiazepingabe eine antiopioidartige Wirkung induzieren. Vorherrschender Mechanismus einer Toleranzentwicklung im anästhesiologischen Bereich sind jedoch intrazelluläre, durch das Opioid induzierte Aktivierungsprozesse (Phospholipase C, Proteinkinase C) die über den N-Methyl-D-Aspartat-(NMDA)-Rezeptor eine antiopioidartige Wirkung zur Folge haben. Um eine Toleranzentwicklung zu vermeiden bzw. ihr entgegenzutreten ist die zusätzliche Gabe von Liganden indiziert, die am NMDA-Rezeptor eine antagonistische Wirkung vermitteln (z. B. Dextromethorphan, Ketamin). Des Weiteren sollte das Konzept der multimodalen Analgesie verfolgt werden, indem die im Rahmen des operativen Eingriffs aktivierte Zyklooxygenase (COX-2), durch Coxibe gehemmt wird. Im Rahmen der Therapie chronischer Schmerzen kann ein Opioidwechsel (Opioidrotation) angezeigt sein, wenn trotz Dosissteigerung von Morphin der Schmerz nicht beherrschbar ist bzw. die Nebenwirkungen eine weitere Dosiserhöhung verbieten. So kann von Morphin auf Methadon, das auch am NMDA-Rezeptor bindet, oder auf wirkstärkere Liganden wie Fentanyl TTS oder Oxycodon umgestiegen werden. Die zu wählende Dosierung orientiert sich hierbei weniger an den Äquivalenztabellen als an der individuellen Wirkung. Eine Toleranzentwicklung im Rahmen der Analgosedierung kann durch die simultane Gabe eines α₂-Agonisten (Clonidin, Dexmedetomidin), respektive durch ein intermittierendes Sistieren der Benzodiazepingabe hinausgezögert werden. Zwar weisen alle experimentelle Daten darauf hin, dass mit jeder Opioidgabe adaptive Prozesse einsetzen, die einer Toleranzentwicklung Vorschub leisten. Es sollte deswegen jedoch nicht auf eine Opioidgabe verzichtet werden, zumal eine Toleranzentwicklung mit Hilfe des Konzepts einer multimodalen Analgesie vermieden werden kann.

Abstract

Introduction: One often identified effect of opioid administration is that of the development of tolerance to the analgesic effect. While it is generally agreed that tolerance to opioid analgesia does occur, it does not appear to be a limiting factor. Dose escalation in chronic pain therapy is considered to be predominantly a consequence of increasing pain, which is a result of increasing nociceptive input as the disease progresses. The underlying cause of tolerance to opioids, however, as commonly identified in the ICU can be identified as an adaptation process. When the opioid is given continuously several causes of adaptation can be identified, all of which can be traced back to the cellular and molecular level. Receptor related changes involved in tolerance: Initial effects of opioid administration in most individuals are analgesia, sedation, nausea/vomiting, respiratory depression, pupillary constriction, constipation and euphoria or dysphoria. However, numerous studies and clinical experience suggest that tolerance to different opioid effects develop at different rates, which has been termed selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation and miosis. Such diversity suggest receptor-related differences in the speed of development of tolerance. In the ICU other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of tolerance of the latter. Such an effect very likely is due to a reduction in activity of the descending inhibitory nervous system. In addition, there is surmountable data suggesting that the higher the intrinsic activity of the opioid at only one receptor site, lesser receptors are needed in order to induce a potent analgesic effect. As a net result the incidence of tolerance is less likely to become clinically apparent when potent ligands such as fentanyl or sufentanil are administered. N-methyl-D-aspartate (NMDA) activation, opioid receptor internalization and desensitization: An altered metabolism has little effect on the rate of development of tolerance. In chronic pain treatment with morphine, however, an increased ratio of the metabolite morphine-3-glucuronide, with antiopioid effects, to morphine-6-glucuronide is associated with staggering doses of the analgesic. Opioids which interact with µ- and/or κ-binding sites, demonstrate an adaptation process called desensitization which is due to a reduced interaction with the internal second messenger system called G-protein. This is only a short-lived phenomenon following binding of the ligand. Another underlying mechanism of tolerance development is that of internalization of the opioid receptors. This short-lived phenomenon, termed endocytosis, results in lesser binding sites available for the mediation of analgesia. Another and more relevant mechanism of long-term opioid binding is that of subsequent protein kinase C (PKC), phospholipase C (PLC) translocation and activation of nitric oxide synthetase (NOS). All of this contributes to a N-methyl-D-aspartate (NMDA) receptor activation with ensuing antiopioid effect and tolerance. Clinical consequences following the development of tolerance: Most likely genetic difference in opioid receptor synthesis and difference in their affinities for various ligands is the cause for the wide margin of dose variability in patients (genetic polymorphism). Once tolerance to the analgesic effect of the opioid is observed and in order to avoid unnecessary further development of tolerance, simultaneous administration of other receptor mediated analgesics is advocated. In the perioperative period strategies like the multimodal analgesic concept is fostered. It consists of the simultaneous administration of low-dose ketamine, co-administration of an α₂-agonist, and the administration of a selective COX-2 inhibitor (refecoxib, parecoxib) respectively. In chronic pain therapy combined administration with either dextromethorphane, or opioid rotation of a more potent ligand such as methadone, fentanyl TTS or oxycodone is suggested. Since conversion factors are not reliable in opioid rotation, it is best to start off with 50 % of the equivalent dose and rapidly titrate to the desired effect. With regard to tolerance development in the ICU, co-administration of an α₂-agonist (clonidine, dexmedetomidine), and daily intermittent cessation of benzodiazepine administration are advocated. Since continuous dosing of an opioid, commonly handled in the ICU setting is more likely to induce tolerance, intermittent administration is advocated. Taken together, there is an abundance of experimental data which suggests, that with every dose of an opioid several adaptive processes are being initiated. Due to genetic polymorphism such adaptation is seen clinically with striking individual different dosages, the degree and the time of onset of tolerance. Although tolerance development may result in staggering doses of an opioid, there is no reason to evade the use of such agents. On the contrary, the concept of multimodal analgesia consisting of the simultaneous use of analgesics with a different mode of action can counteract tolerance development.

Schlüsselwörter

Opioidtoleranz - Rezeptor-Desensibilisierung - -Internalisierung - NMDA-Aktivierung - Ketamin - Clonidin - COX-2 Hemmer

Key words

Opioid tolerance - receptor desensitization - internalization - NMDA-activation - opioid rotation - ketamine - clonidine - COX-2 inhibitor

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