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Efficacy, tolerability and safety of cannabis-based medicines for cancer pain

A systematic review with meta-analysis of randomised controlled trials

Wirksamkeit, Verträglichkeit und Sicherheit von Cannabispräparaten bei Tumorschmerz

Eine systematische Übersichtsarbeit mit Metaanalyse randomisierter, kontrollierter Studien

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Abstract

Background

The importance of medical cannabis and cannabis-based medicines for cancer pain management needs to be determined.

Methods

A systematic literature search until December 2018 included CENTRAL, PubMed, SCOPUS and trial registers. Randomised controlled trials (RCTs) investigating medical cannabis and/or pharmaceutical cannabinoids for pain control in cancer patients with a study duration of at least 2 weeks and a sample size of at least 20 participants per study arm were included. Clinical outcomes comprised efficacy (pain intensity, patient impression of improvement, combined responder, sleep problems, psychological distress, opioid maintenance and breakthrough dosage), tolerability (dropout rate due to adverse events) and safety (nervous system, psychiatric and gastrointestinal side effects; serious adverse events). The quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Results

Five RCTs with oromucosal nabiximols or tetrahydrocannabinol (THC) including 1534 participants with moderate and severe pain despite opioid therapy were identified. Double blind period of the RCTs ranged between 2 and 5 weeks. Four studies with a parallel design and 1333 patients were available for meta-analysis. The quality of evidence was very low for all comparisons. Oromucosal nabiximols and THC did not differ from placebo in reducing pain, sleep problems, opioid dosages and in the frequency of combined responder, serious adverse events and psychiatric disorders side effects. The number of patients who reported to be much or very much improved was higher with oromucosal nabiximols and THC than with placebo (number needed to treat for an additional benefit 16; 95% confidence interval [CI] 8 to infinite). The dropout rates due to adverse events (number needed to treat for an additional harm [NNTH]: 20; 95% CI 11–100), the frequency of nervous system (NNTH: 10; 95% CI 7–25) and of gastrointestinal side effects (NNTH: 11; 95% CI 7–33) was higher with oromucosal nabiximols and THC than with placebo.

Conclusions

Very low quality evidence suggests that oromucosal nabiximols and THC have no effect on pain, sleep problems and opioid consumption in patients with cancer pain with insufficient pain relief from opioids. The complete manuscript is written in English.

Zusammenfassung

Hintergrund

Der Stellenwert von Cannabispräparaten (medizinischer Cannabis und cannabisbasierte Arzneimittel) zur Behandlung von Tumorschmerzen muss geklärt werden.

Methoden

Systematische Literatursuche bis Dezember 2018 in CENTRAL, PubMed, SCOPUS und Studienregistern. Randomisierte, kontrollierte Studien (RCT) mit medizinischem Cannabis und/oder cannabisbasierten Arzneimitteln zur Behandlung von Tumorschmerzen, mit einer Studiendauer von mindestens 2 Wochen und mit mindestens 20 Patienten pro Behandlungsarm wurden eingeschlossen. Klinische Endpunkte waren Wirksamkeit (Schmerzintensität, subjektive globale Besserung, kombinierte Ansprechraten, Schlafstörungen, psychische Symptombelastung, Dosis der Opioiderhaltungs- und Opioidbedarfsmedikation), Verträglichkeit (Abbruchraten wegen Nebenwirkungen) und Sicherheit (Nebenwirkungen im Nervensystem, psychiatrische, gastrointestinale und schwere Nebenwirkungen). Die Qualität der Evidenz wurde mit Grading of Recommendations Assessment, Development and Evaluation (GRADE) bestimmt.

Ergebnisse

Fünf RCT mit bukkalem Nabiximols oder Tetrahydrocannabinol (THC) und 1534 Teilnehmern mit mäßigen oder starken Schmerzen trotz Opioidtherapie wurden gefunden. Die Doppelblindperiode der RCT lag zwischen 2 und 5 Wochen. Vier RCT mit einem Paralleldesign und 1333 Patienten wurden in die Metaanalyse eingeschlossen. Die Qualität der Evidenz war für alle Vergleiche sehr gering. Bukkales Nabiximols und THC unterschieden sich von Placebo weder in der Reduktion von Schmerzen, Schlafstörungen und Opioiddosierungen noch in der Häufigkeit von kombinierten Ansprechraten sowie schweren bzw. psychiatrischen Nebenwirkungen. Die Zahl der Patienten, die eine starke oder sehr starke globale Besserung berichteten, war unter bukkalem Nabiximols und THC höher als unter Placebo (Anzahl der behandelten Patienten, um einen zusätzlichen Nutzen zu erzielen: 16; 95 %-Konfidenzintervall [95 %-KI]: 8 bis unendlich). Die Abbruchrate wegen Nebenwirkungen war unter Nabiximols und THC höher als unter Placebo (Anzahl der behandelten Patienten, um einen zusätzlichen Schaden zu erzielen [NNTH]: 20; 95 %-KI: 11–100). Für Nebenwirkungen des Nervensystems betrug die NNTH 10 (95 %-KI: 7–25), für gastrointestinale Nebenwirkungen 11 (95 %-KI: 7–33).

Schlussfolgerungen

Es besteht eine Evidenz sehr niedriger Qualität, dass bukkales Nabiximols und THC keinen Effekt auf Schmerz, Schlafstörungen und Opioidverbrauch bei Patienten mit Tumorschmerzen mit unzureichender Schmerzreduktion durch Opioide haben.

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Correspondence to Winfried Häuser.

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Conflict of interest

W. Häuser was reimbursed for travel and accommodation fees by Bioevents for organising a congress on controversies on cannabis-based medicines. He is the head of the steering committee of the European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. L. Radbruch is the president of the Geram Society for Palliative care. P. Welsch and P. Klose have no academic conflict of interests to declare. M.-A. Fitzcharles is the head of the steering committee of a position statement of the Canadian Rheumatology Association (“A Pragmatic Approach for Medical Cannabis and Patients with Rheumatic Diseases”). All authors declare that they have no financial conflicts of interest.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

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Häuser, W., Welsch, P., Klose, P. et al. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain. Schmerz 33, 424–436 (2019). https://doi.org/10.1007/s00482-019-0373-3

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