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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References
Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti CI, ESMO Guidelines Committee (2018) Management of cancer pain in adult patients: ESMO clinical practice guidelines. Ann Oncol 29(Supplement_4):iv166–iv191
World Health Organization (WHO) (1986) Cancer pain relief. WHO, Genf
Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA (2017) Opioids for cancer pain—An overview of Cochrane reviews. Cochrane Database Syst Rev 7:CD12592
Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S (2017) A selective review of medical cannabis in cancer pain management. Ann Palliat Med 6(Suppl 2):S215–S222
Vyas MB, LeBaron VT, Gilson AM (2018) The use of cannabis in response to the opioid crisis: A review of the literature. Nurs Outlook 66:56–65
Carter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L (2011) Cannabis in palliative medicine: Improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care 28:297–303
Karst M (2018) Cannabinoids in pain medicine. Schmerz 32:381–396
Martell K, Fairchild A, LeGerrier B, Sinha R, Baker S, Liu H, Ghose A, Olivotto IA, Kerba M (2018) Rates of cannabis use in patients with cancer. Curr Oncol 25:219–225
Bar-Lev Schleider L, Mechoulam R, Lederman V, Hilou M, Lencovsky O, Betzalel O, Shbiro L, Novack V (2018) Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med 49:37–43
Krcevski-Skvarc N, Wells C, Häuser W (2018) Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: A survey of the status in the chapters of the European Pain Federation. Eur J Pain 22(3):440–454
Fitzcharles MA, Eisenberg E (2018) Medical cannabis: A forward vision for the clinician. Eur J Pain 22:485–491
Mücke M, Carter C, Cuhls H, Prüß M, Radbruch L, Häuser W (2016) Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety. Schmerz 30:25–36
Nugent SM, Morasco BJ, O’Neil ME et al (2017) The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Ann Intern Med 16:319–331
Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W (2018) Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 3:CD12182
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Open Med 3:e123–e130
Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions. http://handbook.cochrane.org/. Accessed 21 Dec 2018
Derry S, Wiffen PJ, Moore RA et al (2017) Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults. Cochrane Database Syst Rev 7:CD12638
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT et al (2008) Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 9:105–121
International Council for Harmonisation. (2016) Medical dictionary for regulatory activities. Version 19.1. www.meddra.org/news-and-events/news/all-translationsmeddra-version-191-are-now-available. Accessed 8 Aug 2016
Schaefert R, Welsch P, Klose P, Sommer C, Petzke F, Häuser W (2015) Opioids in chronic osteoarthritis pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration. Schmerz 29:47–59
Moore RA, Barden J, Derry S, McQuay HJ (2008) Managing potential publication bias. In: McQuay HJ, Kalso E, Moore RA (eds) Systematic reviews in pain research: Methodology refined. IASP Press, Seattle, pp 15–24
Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum, Hillsdale
Fayers PM, Hays RD (2014) Don’t middle your MIDs: Regression to the mean shrinks estimates of minimally important differences. Qual Life Res 23:1–4
Furukawa TA, Cipriani A, Barbui C, Brambilla P, Watanabe N (2005) Imputing response rates from means and standard deviations in meta-analyses. Int Clin Psychopharmacol 20:49–52
Review Manager (RevMan) (2014) Computer program, Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen
Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P (2011) Interpreting results and drawing conclusions. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions. Version 5.1.0 (updated march 2011). The Cochrane Collaboration, London (available from http://handbook.cochrane.org)
Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P (2013) GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol 66:151–157
Fallon MT, Lux EA, McQuade R et al (2017) Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: Two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain 11:119–133
Lichtman AH, Lux EA, McQuade R et al (2018) Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symptom Manage 55:179–188.e1
Johnson JR, Burnell-Nugent M, Lossignol D et al (2010) Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39:167–179
Portenoy RK, Ganae-Motan ED, Allende S et al (2012) Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, gradeddose trial. J Pain 13:438–449
Jochimsen PR, Lawton RL, VerSteeg K, Noyes R Jr (1978) Effect of benzopyranoperidine, a delta-9-THC congener, on pain. Clin Pharmacol Ther 24:223–227
Noyes R, Brunk SF, Avery DA, Canter AC (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89
Noyes R, Brunk SF, Baram DA, Canter AC (1975) Analgesic effect of delta-9-tetrahydrocannabinol. Clin Pharmacol Ther 15:139–143
Staquet M, Gantt C, Machin D (1978) Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 23:397–401
Turcotte JG, del Rocío Guillen Núñez M, Flores-Estrad D, Oñate-Ocaña LF, Zatarain-Barrón ZL, Barrón A, Arrieta O (2018) The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: A randomized, double-blind clinical trial. Support Care Cancer 26:3029–3038
Davies BH, Weatherstone RM, Graham JD, Griffiths RD (1974) A pilot study of orally administered ∆(1)-trans-tetrahydrocannabinol in the management of patients undergoing radiotherapy for carcinoma of the bronchus. Br J Clin Pharmacol 1:301–306
Côté M, Trudel M, Wang C, Fortin A (2016) Improving quality of life with nabilone during radiotherapy treatments for head and neck cancers: A randomized double-blind placebo-controlled trial. Ann Otol Rhinol Laryngol 125:317–324
Lynch ME, Cesar-Rittenberg P, Hohmann AG (2014) A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47:166–173
Tetra Bio-Pharma (2018) Safety and efficacy of smoked cannabis for improving quality of life in advanced cancer patients. https://clinicaltrials.gov/ct2/show/NCT03339622. Accessed 31 Dec 2018 (ClinicalTrials.gov Identifier: NCT03339622)
Martinez D (2019) Inhaled cannabis versus fentanyl buccal tablets for management of breakthrough pain in cancer patients. https://clinicaltrials.gov/ct2/show/NCT02675842?term=02675842&rank=1. Accessed 31 Dec 2018 (ClinicalTrials.gov Identifier: NCT02675842)
GW Pharmaceuticals (2018) Sativex oromucosal spray. https://www.medicines.org.uk/emc/product/602/smpc. Accessed 6 Apr 2019
Moore A, Derry S, Eccleston C, Kalso E (2013) Expect analgesic failure; pursue analgesic success. BMJ 346:f2690
Andersohn F, Garbe E (2008) Pharmacoepidemiological research with large health databases. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 51:1134–1155
Aviram J, Samuelly-Leichtag G (2017) Efficacy of cannabis-based medicines for pain management: A systematic review and meta-analysis of randomized controlled trials. Pain Physician 20:E755–E796
Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S (2017) A selective review of medical cannabis in cancer pain management. Ann Palliat Med 6(Suppl 2):S215–S222
Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrell M, Weier M, Degenhardt L (2018) Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: A systematic review and meta-analysis of controlled and observational studies. Pain 159:1932–1954
Grotenhermen F, Müller-Vahl K (2012) The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 109:495–501
Allan GM, Ramji J, Perry D, Ton J, Beahm NP, Crisp N, Dockrill B, Dubin RE, Findlay T, Kirkwood J, Fleming M, Makus K, Zhu X, Korownyk C, Kolber MR, McCormack J, Nickel S, Noël G, Lindblad AJ (2018) Simplified guideline for prescribing medical cannabinoids in primary care. Can Fam Physician 64:111–120
Deutsche Gesellschaft für Palliativmedizin (2015) S3-Leitlinie Palliativmedizin für Patienten mit einer nicht heilbaren Krebserkrankung. https://www.dgpalliativmedizin.de/allgemein/s3-leitlinie.html. Accessed 2 Jan 2019
Häuser W, Finn DP, Kalso E, Krcevski-Skvarc N, Kress HG, Morlion B, Perrot S, Schäfer M, Wells C, Brill S (2018) European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur J Pain 2018(22):1547–1564
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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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DOI: https://doi.org/10.1007/s00482-019-0373-3