301
Views
6
CrossRef citations to date
0
Altmetric
Review

Safety and tolerability of nabiximols oromucosal spray: a review of more than 15 years” accumulated evidence from clinical trials

&
Pages 755-778 | Received 28 Jan 2021, Accepted 25 May 2021, Published online: 21 Jul 2021

References

  • Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234–246.
  • Sativex Oromucosal Spray. Summary of product characteristics. GW Pharma Ltd; August 2020. [cited 2021 Jan 28]. Available from: https://www.medicines.org.uk/emc/product/602/smpc#gref
  • Collin C, Davies P, Mutiboko IK, et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007;14(3):290–296.
  • Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451–459.
  • Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011;18(9):1122–1131.
  • Sativex® oromucosal spray. Summary of product characteristics. Neopharm Scientific Ltd; September 2012. [cited 2021 Jan 28]. Available from: http://www.pharmaline.co.il/images/newsletterregistration/neopharm/2012/03092012/sativex_dr.pdf
  • Häuser W, Finn DP, Kalso E, et al. 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(9):1547–1564. .
  • Prieto González JM, Vila Silván C. Safety and tolerability of nabiximols oromucosal spray: a review of real-world experience in observational studies, registries and case reports. Exp Rev Neurother. 2021;21(5):547–558. .
  • Fallon MT, Lux EA, McQuade R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo- phase 3 studies. Br J Pain. 2017;11(3):119–133.
  • Vachová M, Novotná A, Mares J, et al. A multicentre, double-blind, randomised, parallel-group, placebo-controlled study of effect of long-term Sativex® treatment on cognition and mood of patients with spasticity due to multiple sclerosis. J Mult Scler. 2014;1:2. .
  • Fairhurst C, Kumar R, Checketts D, et al. Efficacy and safety of nabiximols cannabinoid medicine for paediatric spasticity in cerebral palsy or traumatic brain injury: a randomized controlled trial. Dev Med Child Neurol. 2020;62(9):1031–1039.
  • Trojano M, Celius EG, Donzé C, et al. Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights. Eur Neurol. 2014;72(Suppl 1):15–19.
  • Coghe G, Pau M, Corona F, et al. Walking improvements with nabiximols in patients with multiple sclerosis. J Neurol. 2015;262(11):2472–2477.
  • Illomei G, Spinicci G, Locci E, et al. Muscle elastography: a new imaging technique for multiple sclerosis spasticity measurement. Neurol Sci. 2017;38(3):433–439.
  • Mallada Frechín J. Effect of tetrahydrocannabinol:cannabidiol oromucosal spray on activities of daily living in multiple sclerosis patients with resistant spasticity: a retrospective, observational study. Neurodegener Dis Manag. 2018;8(3):151–159.
  • Sorosina M, Clarelli F, Ferrè L, et al. Clinical response to nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018;25(7):934–e70.
  • Meyer T, Funke A, Münch C, et al. Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD). BMC Neurol. 2019;19(1):222.
  • Selvarajah D, Gandhi R, Emery CJ, et al. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care. 2010;33(1):128–130.
  • Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21–29.
  • Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–441.
  • Aragona M, Onesti E, Tomassini V, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharmacol. 2009;32(1):41–47.
  • Notcutt W, Langford R, Davies P, et al. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012;18(2):219–228.
  • Tomassini V, Onesti E, Tinelli E, et al. Assessing the neurophysiological effects of cannabinoids on spasticity in multiple sclerosis. J Neurosci Rehabil. 2014;1(2):1–13.
  • Leocani L, Nuara A, Houdayer E, et al. Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol. 2015;262(11):2520–2527.
  • Markovà J, Essner U, Akmaz B, et al. Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. Int J Neurosci. 2019;129:119–128.
  • EU Clinical Trials Register. Sativex® as add-on therapy vs. further optimised first-line ANTispastics the SAVANT trial; 2015. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-004451-40
  • Wade DT, Makela PM, House H, et al. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler. 2006;12(5):639–645.
  • Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013;260(1):285–295.
  • Lus G, Cantello R, Danni MC, et al. Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study. Neurodegener Dis Manage. 2018;8(2):105–113.
  • Haupts M, Vila C, Jonas A, et al. Influence of previous failed antispasticity therapy on the efficacy and tolerability of THC:CBD oromucosal spray for multiple sclerosis spasticity. Eur Neurol. 2016;75(5–6):236–243.
  • Riva N, Mora G, Sorarù G, et al. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019;18(2):155–164.
  • Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299–306.
  • Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–819.
  • Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133(1):210–220.
  • ClinicalTrials.gov. A double blind, randomized, placebo controlled, parallel group study of Sativex in the treatment of subjects with pain due to diabetic neuropathy; 2012. [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT00710424
  • ClinicalTrials.gov. A study to evaluate the effects of cannabis-based medicine in patients with pain of neurological origin; 2012. Available from: http://ClinicalTrials.gov/show/NCT01606176
  • ClinicalTrials.gov. A study of cannabis based medicine extracts and placebo in patients with pain due to spinal cord injury; 2012; [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT01606202
  • Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol. 2013;260(4):984–997.
  • Lynch ME, Cesar-Rittenberg P, Hohmann AG. 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. 2014;47(1):166–173.
  • Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18(7):999–1012.
  • ClinicalTrials.gov. A study to determine the maintenance of effect after long-term treatment of Sativex® in subjects with neuropathic pain. [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT00713817
  • Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007;29(9):2068–2079.
  • ClinicalTrials.gov. A study to compare the safety and tolerability of Sativex® in patients with neuropathic pain; 2012. Available from: https://clinicaltrials.gov/ct2/show/NCT00713323
  • Hoggart B, Ratcliffe S, Ehler E, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. J Neurol. 2015;262(1):2740.
  • Russo M, Naro A, Leo A, et al. Evaluating Sativex® in neuropathic pain management: a clinical and neurophysiological assessment in multiple sclerosis. Pain Med. 2016;17(6):1145–1154.
  • Turri M, Teatini F, Donato F, et al. Pain modulation after oromucosal cannabinoid spray (SATIVEX®) in patients with multiple sclerosis: a study with quantitative sensory testing and laser-evoked potentials. Medicines (Basel). 2018;5(3):59.
  • Johnson JR, Burnell-Nugent M, Lossignol D, et al. 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. 2010;39(2):167–179.
  • Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–449.
  • ClinicalTrials.gov. Sativex® for relieving persistent pain in patients with advanced cancer (SPRAY III). [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT01361607
  • ClinicalTrials.gov. A two-part study of Sativex® oromucosal spray for relieving uncontrolled persistent pain in patients with advanced cancer. [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT01424566
  • Lichtman AH, Lux EA, McQuade R, et al. 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. 2018;55(2):179–188.e1.
  • Johnson JR, Lossignol D, Burnell-Nugent M, et al. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207–218.
  • ClinicalTrials.gov. Long term safety of Sativex oromucosal spray (Sativex®; nabiximols) as adjunctive therapy in patients with uncontrolled persistent chronic cancer related pain. 2018; [cited 2021 Jan 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT01337089
  • Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):50–52.
  • Überall MA. A review of scientific evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain. J Pain Res. 2020;13:399–410.
  • Wade D. Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough? Expert Rev Neurother. 2012;12(4 Suppl):9–14.
  • Honarmand K, Tierney MC, O’Connor P, et al. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology. 2011;76(13):1153–1160.
  • Torres-Moreno MC, Papaseit E, Torrens M, et al. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: a systematic review and meta-analysis. JAMA Network Open. 2018;1(6):e183485.
  • Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–2473.
  • Valeant Pharmaceuticals International Inc. Nabilone (Cesamet®) capsules: US prescribing information; 2015. [cited 2021 Jan 28]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018677s011lbl.pdf
  • Insys Therapeutics Inc. Dronabinol (Syndros®) oral solution: US prescribing information; 2018. [cited 2021 Jan 28]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c2bc83c1-f9fe-11e2-b778-0800200c9a66
  • Greenwich Biosciences Inc. Cannabidiol (Epidiolex®) oral solution: US prescribing information; 2018. [cited 2021 Jan 28]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bf27097-4870-43fb-94f0-f3d0871d1eec

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.