Über das Abhängigkeitspotential von Gabapentinoiden

Zusammenfassung

Die Verschreibungshäufigkeit der Gabapentinoide Gabapentin und Pregabalin hat in den letzten 10 Jahren auch in Deutschland stark zugenommen. Insbesondere Warnungen aus mehreren nationalen und internationalen Pharmakovigilanz-Registern sowie der Handel von Gabapentoiden auf Schwarzmärkten und im Internet haben zu einer anhaltenden Debatte über das Gefährdungs- und Abhängigkeitsrisiko dieser Substanzen geführt. Da klinische Zulassungsstudien bisher keine bedeutsamen Hinweise auf eine Abhängigkeitsentwicklung zeigten, haben wir systematisch in PubMed und Scopus nach Kasuistiken und klinischen Studien zu Missbrauch und Abhängigkeit von Gabapentin und Pregabalin gesucht. Wir fanden 14 klinisch-epidemiologische Studien und 38 Kasuistiken. Diese wurden durchsucht nach Hinweisen auf i) erfüllte Abhängigkeitskriterien nach ICD-10, ii) nicht-medizinische Einnahmen und deren Dauer, iii) Rückfälle, iv) soziale Folgeschäden und v) Fälle mit Behandlung wegen eines nicht-medizinischen Konsums von Gabapentinoiden. Missbrauch und Abhängigkeit von Gabapentinoiden waren regelhaft assoziiert mit anderen Substanzabhängigkeiten, meistens mit Opiatabhängigkeit oder Politoxikomanie. Drogenabhängige bevorzugten Pregabalin wegen einer schnelleren und stärkeren Euphorisierung („liking“) als mit Gabapentin oral möglich. Beide Gabapentinoide sind in therapeutischen Dosen anxiolytisch, in geringeren Dosen stimulierend und in höheren Dosen sedierend. Todesfälle sind primär bei Opiatabhängigen und Politoxikomanen hauptsächlich im Zusammenhang mit massiven Pregabalin-Überdosierungen beschrieben worden. Noch ist umstritten, ob Gapapentinoide hier eine tragende kausale Rolle spielten oder eher weniger gefährliche „Mitläufer“ waren. Toleranzentwicklung und Entzugssymptome (körperliche Abhängigkeit) sind häufig verbunden mit dem medizinischen und nicht-medizinischen Gebrauch von Gabapentin oder Pregabalin. Es konnten nur 4 Fälle mit psychischen Abhängigkeitssymptomen (ausschließlich von Pregabalin) identifiziert werden, die keine Verbindung zu Missbrauch und Abhängigkeit von anderen Substanzen hatten (mit Ausnahme von Nikotin). Unter Berücksichtigung der Häufigkeit des Übertrittes von ärztlichen Verschreibungen zu nicht-medizinischen Einnahmen, der Häufigkeit und Dauer dieser Selbsteinnahmen sowie der Anzahl von beschriebenen Rückfällen kann Pregabalin als stärker abhängigkeitserzeugend gelten als Gabapentin. Allerdings waren solche Ereignisse eher selten im Vergleich zu denen bei Gebrauch von traditionellen psychoaktiven Drogen. Schließlich konnten keine Berichte über soziale Folgeschäden durch einen medizinischen oder nicht-medizinischen Gabapentinoid-Konsum oder behandlungssuchende Gabapentinoid-Konsumenten gefunden werden. Deshalb kann ein geringeres „wanting“ von Gabapentinoiden im Vergleich zu traditionellen psychoaktiven Substanzen vor dem Hintergrund von Berridgeʼs und Robinsonʼs Anreiz-Sensiblisierungs-Theorie zur Pathogenese von Abhängigkeitserkrankungen angenommen werden. Auch wird die Möglichkeit einer anti-adversen Selektion von Gabapentinoiden bei Opioidabhängigen und Abhängigen von anderen Drogen diskutiert. Abschließend schätzen wir das relative Abhängigkeitsrisiko von Gabapentin und Pregabalin anhand eines Algorithmus ein, der ursprünglich von Griffith und Johnson zur Bestimmung des Abhängigkeitsrisikos von Sedativa entwickelt wurde. In der Bilanz erscheint das Gefährdungs- und Abhängigkeitspotential der Gabapentinoide geringer als das von anderen Sedativa (und Stimulantien). Im Vergleich zu Gabapentin scheint Pregabalin stärker addictogen zu wirken. Wenn nicht ohnehin vermeidbar, sollten beide Gabapentinoide bei Risikopopulationen wie Suchtpatienten nur unter engmaschiger Kontrolle ihrer therapeutischen Wirksamkeit und Überwachung der Verschreibungen über einen begrenzten Zeitraum eingesetzt werden.

Abstract

In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international pharmacovigilance-databases have warned for abuse liabilities and overdose fatalities in association with both gabapentinoids, which moreover, became to be sold on internet and black-markets, their addictive power has been subject to an ongoing clinical debate. As pre- and post-approval clinical trials did not reveal significant signs of dependence on gabapentin or pregabalin, we systematically searched in PubMed and Scopus for clinical studies and case reports being associated with abuse of and dependence on these drugs. We found 14 clinical-epidemiologic studies and 38 case reports/series. These were evaluated for i) fulfilled dependence criteria according to ICD-10, ii) non-medical self-administration and their duration, iii) relapses, iv) social sequels, and v) cases seeking treatment for misusing gabapentin or pregabalin. Mostly, the cases of abuse of and dependence on gabapentinoids appeared to be associated with other substance dependencies, primarily opiate dependence and polyvalent drug use. Drug users preferred pregabalin citing a faster and stronger euphoria (“liking”) than achievable with oral gabapentin. Both gabapentinoids were anxiolytic in therapeutic doses, stimulating in lower and sedating along with increasing doses. Fatalities have been described mainly in the population of opiate dependents and polyvalent drug users, predominantly together with excessive pregabalin overdosing. It is debated whether the gabapentinoids were indeed the main cause of death in these cases or whether gabapentin and pregabalin had been only bystanders. Tolerance and withdrawal symptoms (physical dependence) of gabapentinoids appeared to be common in medical and non-medical use of gabapentinoids. There were only 4 persons who had fulfilled behavioral dependence criteria of gabapentinoids (all had used pregabalin) and had no association with other substance use disorders (apart from nicotine). Regarding the transitions from prescription to non-medical self-administration, the frequency and duration of self-administrations as well as the number of reported relapses, pregabalin appeared also to be more addictive than gabapentin. However, all these events were reported rather infrequently compared with traditional substances of abuse. We did not find a case with social sequalea due to the use of gabapentinoids or a person who sought treatment for his gabapentin or pregabalin use. Therefore, the gabapentinoids were assumed to possess a lower “wanting” in consideration of Berridge’s and Robinsons’s incentive-sensitization theory of addiction. Also, anti-adverse selection of gabapentinoids is discussed to be present in the population of opioid and multi-drug users. Based upon all these results and assumptions, we have estimated the relative risk of dependence on gabapentinoids by using an algorithm which was previously developed by Griffith and Johnson for evaluation of the abuse liabilities of sedatives. Overall, the risk of harm and dependence on gabapentinoids appeared to be lower than that of other sedatives (and stimulants). In addition, pregabalin appeared to be somewhat riskier than gabapentin. We think that in patients with current or past substance use disorders, the treatment with gabapentinoids should be avoided or if indispensable, these drugs should be administered exclusively over a limited time span with caution by using a therapeutic and prescription monitoring.

Schlüsselwörter

Abhängigkeitsrisiko - Gesundheitsschädigung - Selbsteinnahme - „wanting“ - „liking“ - Rausch - Pregabalin - Gabapentin

Key words

abuse liability - health hazard - self-administration - „wanting“ - „liking“ - high - pregabalin - gabapentin

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