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Langzeittherapie mit Opioiden bei chronischem nicht-tumorbedingtem Schmerz

Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in offenen Anschlussstudien über mindestens 26 Wochen

Long-term opioid therapy in chronic noncancer pain

A systematic review and meta-analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks

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An Erratum to this article was published on 29 May 2015

Zusammenfassung

Hintergrund

Die Wirksamkeit und Sicherheit der Langzeittherapie mit Opioiden (≥ 6 Monate) bei chronischem nicht-tumorbedingtem Schmerz (CNTS) ist umstritten. Eine systematische Übersichtsarbeit mit Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in offenen Anschlussstudien randomisierter, kontrollierter Studien (RCT) wurde bisher nicht durchgeführt.

Methoden

Bis Dezember 2013 wurden MEDLINE und clinicaltrials.gov wie auch die Literaturverzeichnisse von systematischen Übersichtsbeiträgen zu Langzeit-RCT mit Opioiden bei CNTS durchsucht. Wir schlossen offene Anschlussstudien mit einer Studiendauer von ≥ 26 Wochen von RCT mit einer Dauer von ≥ 2 Wochen ein. Mithilfe eines Random-effects-Modells wurden für kategoriale Daten gepoolte Schätzungen von Ereignisraten und für kontinuierliche Variablen standardisierte Mittelwertdifferenzen (SMD) berechnet.

Ergebnisse

Eingeschlossen wurden 11 offene Anschlussstudien mit 2445 Teilnehmern, die nozizeptive (Kreuzschmerz, Arthrose) und neuropathische Schmerzen (radikulär, Polyneuropathie) hatten. Die Studiendauer betrug im Median 26 Wochen (26–108 Wochen). In 4 Studien wurde Oxycodon getestet, in 2 Tramadol und Buprenorphin. Jeweils in einer Studie wurden Hydromorphon, Morphin, Oxymorphon und Tapentadol untersucht. Von den bei Studienbeginn randomisierten Patienten schlossen 28,5 % [95 %-Konfidenzintervall (KI): 17,9 %; 39,2 %) die offene Phase ab; 53,5 % der Patienten (95 %-KI: 38,1 %; 68,2 %), die in die offene Phase eintraten, beendeten sie auch. Der Gesamtverlust lag bei 71,5 % (95 %-KI: 60,9 %; 83,1 %) aller Patienten, die anfänglich in die RCT eingeschlossen worden waren. Insgesamt 4,9 % der Patienten (95 %-KI: 2,9 %; 8,2 %) brachen die Anschlussstudie wegen fehlender Wirksamkeit ab, 16,8 % (95 %-KI: 11,0 %; 24,8 %) wegen unerwünschter Ereignisse in der offenen Phase. Ein Anteil von 0,08 % (95 %-KI: 0,001 %; 0,05 %) verstarb in der offenen Phase. Lediglich eine Studie beinhaltete systematische Untersuchungen eines Fehlverhaltens im Umgang mit den Medikamenten: Nach Einschätzung der Untersucher zeigten 5,7 % (95 %-KI: 3,4 %; 9,6 %) ein solches Verhalten, nach unabhängiger Expertenmeinung waren es 2,6 % (95 %-KI: 1,2 %; 5,8 %). Es fand sich keine signifikante Veränderung der Schmerzintensität zwischen dem Ende der randomisierten Phase und dem Ende der offenen Phase [SMD: 0,19 (− 0,03; 0,41); p = 0,50; 6 Studien mit 1360 Teilnehmern).

Schlussfolgerungen

Nur eine Minderheit der Patienten, die bei der Randomisierung für eine Opioidtherapie ausgewählt worden waren, beendete die offene Langzeitstudie. Bei diesen Patienten konnten allerdings anhaltende Effekte einer Schmerzreduktion gezeigt werden. Eine Langzeittherapie mit Opioiden kann bei sorgfältig ausgewählten und überwachten CNTS-Patienten erwogen werden, die in der kurzfristigen Therapie mit Opioiden bei zumindest tolerablen unerwünschten Ereignissen eine klinisch bedeutsame Schmerzreduktion erfahren haben.

Abstract

Background

The efficacy and safety of long-term (≥ 6 months) opioid therapy (LtOT) in chronic noncancer pain (CNCP) is under debate. A systematic review with meta-analysis of the efficacy and harms of opioids in open-label extension studies of randomized controlled trials (RCTs) has not been conducted until now.

Methods

We screened MEDLINE and clinicaltrials.gov (through to December 2013), as well as reference sections of systematic reviews of long-term RCTs of opioids in CNCP. We included open-label extension trials with a study duration ≥ 26 weeks of RCTs of ≥ 2 weeks duration. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables were calculated.

Results

We included 11 open-label extension studies with 2445 participants with nociceptive (low back, osteoarthritis) and neuropathic (radicular, polyneuropathy) pain. Median study duration was 26 (range 26–108) weeks. Four studies tested oxycodone, two studies tramadol and buprenorphine; hydromorphone, morphine, oxymorphone and tapentadol were each tested in one study. Of the patients randomized at baseline, 28.5 % (95 % confidence interval, CI, 17.9–39.2 %) finished the open-label period; 53.5 % (95 % CI 38.1–68.2 %) of patients entering the open-label period finished the open-label period. In sum, the total loss was 71.5 % (95 % CI 60.9–83.1 %) of all patients primarily included into the RCT. A total of 4.9 % (95 % CI 2.9–8.2 %) of patients dropped out due lack of efficacy; 16.8 % (95 % CI 11.0–24.8 %) dropped out to due adverse events (AE) in the open-label period and 0.08 % (95 % CI 0.001–0.05 %) of patients died during the open-label period. Only one study systematically assessed aberrant drug behavior of the patients: 5.7 % (95 % CI 3.4–9.6 %) showed aberrant drug behavior in the opinion of the investigators and 2.6 % (95 % CI 1.2–5.8 %) were judged to show aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [− 0.03, 0.41]; six studies with 1360 participants).

Conclusion

Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy.

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Danksagungen

Wir danken Frau Dr. Lindena (Kleinmachnow) und Herrn Prof. Treede (Mannheim) für die hilfreichen Anmerkungen zum Manuskript.

Einhaltung ethischer Richtlinien

Interessenkonflikt.

W. Häuser erhielt Vortragshonorare für nicht-produktgebundene Vorträge von Abbott, Janssen-Cilag, MSD Sharp & Dohme und Pfizer und ein Beratungshonorar (Studiendesign) von Daiichi Sankyo. C. Maier war in den wissenschaftlichen Advisory Boards von Mundipharma und Pfizer tätig; er erhielt Vortragshonorare von Pfizer, Mundipharma, MSD, Lilly und Grünenthal. K. Bernardy erhielt Reiseunterstützung von Eli-Lilly. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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Authors and Affiliations

  1. Innere Medizin I, Klinikum Saarbrücken gGmbH, Winterberg 1, 66119, Saarbrücken, Deutschland

    W. Häuser

  2. Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Technische Universität München, München, Deutschland

    W. Häuser

  3. Abteilung für Schmerztherapie, Berufsgenossenschaftliche Universitätsklinik Bergmannsheil GmbH, Ruhr-Universität Bochum, Bochum, Deutschland

    K. Bernardy & C. Maier

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482_2014_1452_MOESM1_ESM.pdf

English version of "Langzeitopioidtherapie bei chronischem nicht-tumorbedingtem Schmerz. Systematische Übersicht und Metaanalyse der Wirksamkeit, Verträglichkeit und Sicherheit in offenen Anschlussstudien über mindestens 26 Wochen“ (PDF 0,7MB)

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Evidenzbericht: Forest Plots der standardisierten Mittelwertdifferenzen und Risikoreduktionen zwischen Opioiden für ausgewählte Endpunkte (PDF 0,2MB)

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Evidence report: forest plots of standardized mean differences and risk differences between opioids for selected outcomes (PDF 0,2MB)

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Evidenzbericht: Tabellen - Charakteristiken der Studien, die in qualitative und/oder quantitative Analyse einbezogen wurden (PDF 0,5MB)

Evidence report: Tables - Characteristics of studies included into qualitative and/or quantitative analysis (PDF 0,5MB)

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Häuser, W., Bernardy, K. & Maier, C. Langzeittherapie mit Opioiden bei chronischem nicht-tumorbedingtem Schmerz. Schmerz 29, 96–108 (2015). https://doi.org/10.1007/s00482-014-1452-0

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