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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    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

    CAS  Article  Google Scholar 

  2. 2.

    World Health Organization (WHO) (1986) Cancer pain relief. WHO, Genf

    Google Scholar 

  3. 3.

    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

    PubMed  Google Scholar 

  4. 4.

    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

    Article  Google Scholar 

  5. 5.

    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

    Article  Google Scholar 

  6. 6.

    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

    Article  Google Scholar 

  7. 7.

    Karst M (2018) Cannabinoids in pain medicine. Schmerz 32:381–396

    CAS  Article  Google Scholar 

  8. 8.

    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

    CAS  Article  Google Scholar 

  9. 9.

    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

    Article  Google Scholar 

  10. 10.

    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

    CAS  Article  Google Scholar 

  11. 11.

    Fitzcharles MA, Eisenberg E (2018) Medical cannabis: A forward vision for the clinician. Eur J Pain 22:485–491

    CAS  Article  Google Scholar 

  12. 12.

    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

    Article  Google Scholar 

  13. 13.

    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

    Article  Google Scholar 

  14. 14.

    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

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    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

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions. http://handbook.cochrane.org/. Accessed 21 Dec 2018

    Google Scholar 

  17. 17.

    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

    PubMed  Google Scholar 

  18. 18.

    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

    Article  Google Scholar 

  19. 19.

    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

    Google Scholar 

  20. 20.

    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

    CAS  Article  Google Scholar 

  21. 21.

    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

    Google Scholar 

  22. 22.

    Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum, Hillsdale

    Google Scholar 

  23. 23.

    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

    Article  Google Scholar 

  24. 24.

    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

    Article  Google Scholar 

  25. 25.

    Review Manager (RevMan) (2014) Computer program, Version 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen

  26. 26.

    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)

    Google Scholar 

  27. 27.

    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

    Article  Google Scholar 

  28. 28.

    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

    Article  Google Scholar 

  29. 29.

    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

    Article  Google Scholar 

  30. 30.

    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

    Article  Google Scholar 

  31. 31.

    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

    CAS  Article  Google Scholar 

  32. 32.

    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

    CAS  Article  Google Scholar 

  33. 33.

    Noyes R, Brunk SF, Avery DA, Canter AC (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89

    Article  Google Scholar 

  34. 34.

    Noyes R, Brunk SF, Baram DA, Canter AC (1975) Analgesic effect of delta-9-tetrahydrocannabinol. Clin Pharmacol Ther 15:139–143

    Google Scholar 

  35. 35.

    Staquet M, Gantt C, Machin D (1978) Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 23:397–401

    CAS  Article  Google Scholar 

  36. 36.

    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

    Article  Google Scholar 

  37. 37.

    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

    CAS  Article  Google Scholar 

  38. 38.

    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

    Article  Google Scholar 

  39. 39.

    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

    Article  Google Scholar 

  40. 40.

    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)

    Google Scholar 

  41. 41.

    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)

    Google Scholar 

  42. 42.

    GW Pharmaceuticals (2018) Sativex oromucosal spray. https://www.medicines.org.uk/emc/product/602/smpc. Accessed 6 Apr 2019

    Google Scholar 

  43. 43.

    Moore A, Derry S, Eccleston C, Kalso E (2013) Expect analgesic failure; pursue analgesic success. BMJ 346:f2690

    Article  Google Scholar 

  44. 44.

    Andersohn F, Garbe E (2008) Pharmacoepidemiological research with large health databases. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 51:1134–1155

    Article  Google Scholar 

  45. 45.

    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

    CAS  PubMed  Google Scholar 

  46. 46.

    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

    Article  Google Scholar 

  47. 47.

    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

    CAS  Article  Google Scholar 

  48. 48.

    Grotenhermen F, Müller-Vahl K (2012) The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 109:495–501

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    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

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    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

    Google Scholar 

  51. 51.

    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

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Winfried Häuser.

Ethics declarations

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.

Caption Electronic Supplementary Material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Medical cannabis
  • Nabiximols
  • Cancer pain
  • Systematic review
  • Randomised controlled trial

Schlüsselwörter

  • Medizinischer Cannabis
  • Nabiximols
  • Tumorschmerz
  • Systematische Übersichtsarbeit
  • Randomisierte, kontrollierte Studie