Effectiveness and safety of cannabinoids as an add-on therapy in the treatment of resistant spasticity in multiple sclerosis: a systematic review

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ Esta es la versión aceptada del artículo publicado en: This is a accepted manuscript of a paper published in: Cannabis and Cannabinoid Research DOI: https://doi.org/10.1089/can.2022.0254 El acceso a la versión publicada del artículo puede requerir la suscripción de la revista. Access to the published version may require subscription. “This is the original submission version (pre-peer review) of the following article: Effectiveness and safety of cannabinoids as an add-on therapy in the treatment of resistant spasticity in multiple sclerosis: a systematic review https://doi.org/10.1089/can.2022.0254 . This original submission version of the article may be used for non-commercial”. For Peer Review Cannabis and Cannabinoid Research EFFECTIVENES AND SAFETY OF CANNABINOIDS AS AN ADDON THERAPY IN THE TREATMENT OF RESISTANT SPASTICITY IN MULTIPLE SCLEROSIS: A Systematic Review Journal: Cannabis and Cannabinoid Research Manuscript ID CAN-2022-0254.R2 Manuscript Type: Review Date Submitted by the Author: n/a Complete List of Authors: Martínez-Paz, Carmen; University of Seville Faculty of Medicine, Preventive Medicine and Public Health García-Cabrera, Emilio; University of Seville Faculty of Medicine, Preventive Medicine and Public Health Vilches-Arenas, Angel; University of Seville Faculty of Medicine, Preventive Medicine and Public Health Keywords: Multiple sclerosis, Cannabidiol, Tetrahydrocannabinol Manuscript Keywords (Search Terms): Central nervous system, multiple sclerosis, spasticity, cannabinoids Abstract: Background: Spasticity continues to be a very prevalent, highly invalidating, and difficult-to-manage symptom in multiple sclerosis patients. The aim of this systematic review is to evaluate the effectiveness of the use of cannabis and cannabinoids in these patients, evaluating the use as an additional therapy. Methods: We performed a systematic review of the literature searching in the major scientific databases (PubMed, Scopus, EMBASE, WOS and Cochrane Library) for articles from January 2017 to May 2022 containing information about the effectiveness of using cannabis and cannabinoids in patients with insufficient response to first-line oral antispastic treatment. Results: A total of five medium-high quality articles were selected to be part of the study and all evaluated the effectiveness of the Tetrahydronnabinol (THC) and Cannabidiol (CBD) spray. The effectiveness of this drug, significant improvements are produced on the patient-related spasticity assessment scales, obtaining improvement up to 45%; and on quality of life, producing a decrease in the appearance of symptoms related to spasticity, as well as an increase in the development of basic activities of daily living (BADL). The average dose is 5-7 sprays/day. The discontinuation rate for these treatments is around 40% due to lack of effectiveness and adverse events. All reported adverse effects (AE) are mild to moderate in severity and their incidence is approximately 17%, although this figure tends to decrease with drug use. Conclusions Adding the THC: CBD sprays have been shown to be more effective in treating MS spasticity than optimizing the dose of first-line antispastic drugs in selected responders patients. The safety and tolerability profiles remain in line with those obtained in other trials. More patients would benefit from treatment if the initial response search period was extended ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. For Peer Review Page 1 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENES AND SAFETY OF CANNABINOIDS AS AN ADD-ON THERAPY IN THE TREATMENT OF RESISTANT SPASTICITY IN MULTIPLE SCLEROSIS: A systematic review Martinez-Paz Carmen MD1, García-Cabrera Emilio1 Pharm D Ph D, Vilches-Arenas Ángel1 MD PhD 1 Department of Preventive Medicine and Public Health. University of Seville Corresponding Author Emilio García Cabrera Pharm D, Ph D Department of Preventive Medicine and Public Health Faculty of Medicine Faculty University of Seville Av. Sanchez Pizjuan s/n 41009 Seville [email protected] RUNING TITLE: Systematic review THC:CBD spasticity in MS KEY WORDS: Central nervous system, multiple sclerosis, spasticity, cannabinoids. Page 2 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review ABSTRACT Background : Spasticity continues to be a very prevalent, highly invalidating, and difficult-to- manage symptom in patients with multiple sclerosis. The aim of this systematic review is to evaluate the effectiveness of the use of cannabis and cannabinoids in these patients, evaluating its use as an additional therapy. Methods: We performed a systematic review of the literature searching in the major scientific databases (PubMed, Scopus, EMBASE, WOS, and Cochrane Library) for articles from January 2017 to May 2022 containing information about the effectiveness of cannabis and cannabinoids in patients with insufficient response to first-line oral antispastic treatment. Results: A total of five medium-high quality articles were selected to be part of the study and all evaluated the effectiveness of the Tetrahydronnabinol (THC) and Cannabidiol (CBD) spray. The effectiveness of this drug, significant improvements are produced on the patient-related spasticity assessment scales, obtaining improvement up to 45%; and on quality of life, producing a decrease in the appearance of symptoms related to spasticity, as well as an increase in the development of basic activities of daily living (BADL). The average dose is 5-7 sprays/day. The discontinuation rate for these treatments is around 40% due to lack of effectiveness and adverse events. All reported adverse effects (AE) are mild to moderate in severity and their incidence is approximately 17%, although this figure tends to decrease with drug use. Conclusions Adding the THC: CBD sprays have been shown to be more effective in treating MS spasticity than optimizing the dose of first-line antispastic drugs in selected responders patients. The safety and tolerability profiles remain in line with those obtained in other trials. More patients would benefit from treatment if the initial response search period was extended. Page 3 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENES AND SAFETY OF CANNABINOIDS AS AN ADD-ON THERAPY IN THE TREATMENT OF RESISTANT SPASTICITY IN MULTIPLE SCLEROSIS: A systematic review Introduction Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system, the leading cause of non-traumatic neurological disability in young adults1 , with a prevalence of 2.8 million people worldwide2 . Spasticity is one of the most disabling and difficult to control symptoms of MS3. Intensive muscle stiffness, muscle weakness, muscle hypertonia, painful spasms, and insomnia that accompany it severely reduced patient quality of life4. Around 60% of MS patients have spasticity, which increases to 75% after 15 years of disease progression5. Treatment currently used is a combination of antispastic drugs such as baclofen, tizanidine, or dantrolene together with physiotherapy, with an ineffectiveness of around 40%5,6. The lack of response is mainly due to the appearance of adverse effects (AE) such as the risk of falls, sedation, cognitive difficulties, withdrawal syndrome, and dizziness at tolerable doses 7. Alternative routes such as intrathecal administration of baclofen or the use of botulinum toxin have been used, but require a high degree of specialisation in administration and high cost, which means its use is not widespread8. The low effectiveness and adherence to standard treatments encouraged the use of alternative therapies by patients to alleviate their symptoms. At least half of MS patients admit to having used cannabis for medicinal purposes9 , most of them with positive experiences and reporting a subjective improvement in spasticity and its accompanying symptoms. There are more than 100 types of cannabinoids, but the most important are tetrahydrocannabinol (THC) and cannabidiol (CBD)10. THC has psychoactive activity, and the ability to reduce muscle stiffness. On the other hand, CBD has almost no psychotomimetic activity and has a potent analgesic and anti-inflammatory effect11–13. THC: CBD combination, it avoids psychotropic stimulation without reducing its ability to decrease muscle tone10. In 2005, a 1:1 ratio of THC and CBD oral spray was approved for the first time in Canada, specifically for the treatment of spasticity in MS, after demonstrating good tolerance and Page 4 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review efficacy in clinical trials14. This medicine has been progressively approved since 2010 in most of Europe, as well as other countries such as New Zealand15. However, certain factors, such as legislation and high prescription costs, currently limit its use and, therefore, the experience of neurologists around the world8. Therefore, the objective of our study is to evaluate the effectiveness and safety of cannabis and its derivatives as an additional therapy in patients with multiple sclerosis who have inadequate control of spasticity with standard antispasticity treatment. Page 5 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Methods This systematic review adheres to the statement Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)16. The protocol was registered in the database of the International Prospective Register of Systematic Reviews (PROSPERO) after meeting their inclusion criteria17, registration number CRD42022351472. Data Sources and Searchers The literature review was conducted between November 2021 and August 2022. Five electronic databases (MEDLINE through PubMed, Cochrane, Embase, Web of Science, and Scopus) were searched to identify relevant articles. The search strategy was developed during a panel meeting after an initial article search. It was based on the use of key phrases and/or their abbreviations based on a Metadata System (MeSH) and various combinations of these phrases to increase search efficiency. The search strategy is included in the Supplementary Material S1. An extensive list of terms to describe the target population was formulated based on the PICO acronym. P (population): Resistant spasticity in multiple sclerosis I (intervention): Cannabinoids; C (comparator): control group, placebo group, and antispastic therapy; O (outcomes): Numeric Rating Scale (NRS scale). The Ashworth scale is a tool used to assess the severity of spasticity, or abnormal muscle tone, in people with neurological conditions such as multiple sclerosis, spinal cord injury, or cerebral palsy. It is a simple and easy-to-use scale that consists of five levels of muscle tone that range from 0 (normal) to 4 (severe spasticity). NRS, it is a type of assessment tool that is commonly used to measure subjective pain intensity and other subjective experiences, such as the severity of symptoms or the level of disability. The NRS is a simple, easy-to-use tool that consists of a scale ranging from 0 to 10, with 0 representing "no pain" or "no symptoms" and 10 representing "the worst pain imaginable" or "the worst symptoms imaginable. Page 6 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review The titles and abstracts of scientific articles retrieved from the databases were analysed for inclusion criteria. The inclusion criteria were: 1) articles published between January 2017 and May 2022; 2) articles written in English, Spanish, and French; 3) articles corresponding to experimental, observational and systematic review studies; 4) articles that include our key descriptors in their writing: "Multiple sclerosis," "spasticity," and "cannabis/cannabinoid," with literal terms as well as related scientific terms and synonyms appearing in the thesaurus of each database being accepted in the search, a process that is explained in more detail in Supplemental Material;4) articles that address the research PICO question: "Is cannabis a good treatment option for uncontrolled spasticity caused by multiple sclerosis?"; 5) articles that evaluate the effectiveness of the new treatment (cannabis and derivatives) as an adjunctive therapy: Only articles in which patients maintain first-line antispastic treatment are accepted. Articles evaluating the effectiveness of synthetic modified cannabinoids (different structure from extracted from the natural plant) or articles evaluating the use of "Hemp" products (cannabis sativa strain) that contained no more than 0.3% THC were excluded. Reference lists in the publications included in the review were also analysed to ensure that other articles that may meet the inclusion and exclusion criteria were not missed. Study Selection The review of the retrieved papers was carried out in five stages. The first step was to search for articles, second remove duplicates, third check the title, and fourth check the abstracts of papers identified as potentially relevant to the research questions. In the next step, the full texts of the articles identified during initial selection were reviewed and the quality assessment evaluated. In all stages, the review was performed by two independent reviewers (C.M.P., E.G.C), and by a third independent reviewer (A.V.A.) in contentious cases. Data Extraction Two reviewers independently extracted and documented data from each included study according to the recommendations of the Centre for Reviews and Dissemination18. We extracted data including the year of publication, country, study design, quality assessment, sample size, target population, description of interventions, outcome measures, and study results. Page 7 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review for responders from 4 to 8 weeks, it may cover more patients who could potentially benefit from the therapy. Quality of life was measured using various tools, such as the VAS EQ 100 scale, Barthel index, PGIC, and GIC, in most studies. In general, significant improvements were observed in all these measures21,25,26,32. On note, health related quality of life measured by VAS EQ 100 scale improved by an average of 20% in the study by D'hooghe et al. 24. Furthermore, the decrease in accompanying spasticity symptoms, such as pain, insomnia, spasms, and bladder dysfunction, resulted in improvements in quality of life, particularly in terms of a reduction in the frequency of spasms and insomnia25. However, the SAVANT study found that patients, caregivers, and physicians reported a decrease in the perception of improvement over time21. The THB:CBD dose is mean of 5-7 puffs/day in all studies. In the SAVANT study, figures of up to 8.5 sprays were reached on average21, but these were only in the placebo group. In the study by Etges et al.26 included in the systematic review, a small group of patients reported misused or abuse exceeded more than 24 puffs/day (the upper allowed limit being 12) without serious adverse effects or the development of dependence. The study of D’hooghe et al found in a cohort of patients followed for 6 and 12 months that doses were maintained over time, without increasing the number or frequency of puffs24. Regarding the limitations of this study, it is important to emphasise that the selected articles were obtained only from the main scientific databases. PubMed, Scopus, Cochrane Library, EMBASE, and WoS; leaving aside other types of publications such as presentations at conferences and theses, therefore, a publication bias may have been committed. It is worth noting that all the articles reviewed focused on the use of the THC: CBD drug Nabiximols (Sativex®), and articles that examined the use of cannabis as a natural plant (rather than its derivatives) were not included in the study because they did not meet the selection criteria. Furthermore, during the course of this review, we found in the search carried out in the Cochrane Library that numerous clinical trials that have not yet published their results were obtained because they were in progress at the time of the selection process. As strengths, we can highlight the following PRISMA guidelines to establish the structure of our study, as well as the use of the STROBE, PRISMA, and CONSORT lists to assess the quality of the articles included in the review. These strict quality criteria, together with the selection of Page 14 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review articles written in English, Spanish, and French, published between January 2017 and May 2022, may have caused selection bias. We have chosen to focus on articles published in the last five years for several reasons. Firstly, previous reviews of the literature on this topic have already been conducted and it is important to update our understanding of the current state of the field. By limiting our search to the most recent literature, we can ensure that we are considering the most current and relevant research. Additionally, limiting the search to the last five years helps minimise the risk of including studies that may be outdated or no longer applicable, as the field of research can change rapidly over time. By focussing on the most recent studies, we can draw new conclusions that are more reflective of the current state of knowledge on the topic. In summary, this systematic review shows that the use of cannabinoids as an adjuvant for resistant spasticity in multiple sclerosis is safe, well tolerated, and effective in selected responders at a dose of 5-7 sprays per day. Page 15 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review ACKNOWLEDGMENTS To my family, for never letting me lose sight of my goals. Thank you for giving me everything; this achievement is more yours than mine. AUTHOR DISCLOSURE STATEMENT No competing financial interests exist. FUNDING INFORMATION No funding was received for this article. SUPPLEMENTARY MATERIAL Search strategy REFERENCES 1. Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review. Vol. 133, American Journal of Medicine. Elsevier Inc.; 2020. p. 1380-1390.e2. 2. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler J. 2020 Dec 1;26(14):1816–21. 3. Oreja-Guevara C. Clinical efficacy and effectiveness of Sativex ®, a combined cannabinoid medicine, in multiple sclerosis-related spasticity. In: Expert Review of Neurotherapeutics. Expert Rev Neurother; 2012. p. 3–8. 4. Patti F, Chisari CG, Solaro C, Benedetti MD, Berra E, Bianco A, et al. Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study. Neurol Sci. 2020 Oct 1;41(10):2905–13. 5. Izquierdo G. Multiple sclerosis symptoms and spasticity management: new data. Vol. 7, Neurodegenerative disease management. Neurodegener Dis Manag; 2017. p. 7–11. 6. Otero-Romero S, Sastre-Garriga J, Comi G, Hartung HP, Soelberg Sørensen P, Thompson AJ, et al. Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Vol. 22, Multiple Sclerosis. SAGE Publications Page 16 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Ltd; 2016. p. 1386–96. 7. Zettl UK, Rommer P, Hipp P, Patejdl R. 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Vandenbroucke JP, Von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med. 2007 Oct;4(10):1628–54. 21. Markovà J, Essner U, Akmaz B, Marinelli M, Trompke C, Lentschat A, 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 Feb 1;129(2):119–28. 22. Meuth SG, Henze T, Essner U, Trompke C, Vila Silván C. Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial. Int J Neurosci. 2020 Dec 1;130(12):1199–205. 23. Akgün K, Essner U, Seydel C, Ziemssen T. Daily Practice Managing Resistant Multiple Sclerosis Spasticity With Delta-9-Tetrahydrocannabinol: Cannabidiol Oromucosal Spray: A Systematic Review of Observational Studies. J Cent Nerv Syst Dis. 2019 Jan;11:117957351983199. 24. D’hooghe M, Willekens B, Delvaux V, D’haeseleer M, Guillaume D, Laureys G, et al. Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience. BMC Neurol. 2021 Dec 1;21(1). Page 18 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 25. 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. 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Eur Neurol. 2014;72(1–2):95–102. 30. Ferrè L, Nuara A, Pavan G, Radaelli M, Moiola L, Rodegher M, et al. Efficacy and safety of nabiximols (Sativex®) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurol Sci. 2016 Feb 1;37(2):235–42. 31. Lorente Fernández L, Monte Boquet E, Pérez-Miralles F, Gil Gómez I, Escutia Roig M, Boscá Blasco I, et al. Experiencia clínica con los cannabinoides en la terapia de la espasticidad en la esclerosis múltiple. Neurologia. 2014;29(5):257–60. 32. Flachenecker P, Henze T, Zettl UK. Nabiximols (THC/CBD Oromucosal Spray, Sativex®) in clinical practice - results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur Neurol. 2014;71(5–6):271–9. Page 19 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review … artículos First screening: Search in the different databases: PubMed, Scopus, EMBASE, WoS and Cochrane Library. 348 papers 57 papers 11 papers 5 papers 889 papers Second screening: It was excluded 541 duplicate articles. Third screening: It was excluded 291 articles by title. Fourth screening: It was excluded 46 articles by abstract. Fifth screening: It was excluded 6 articles after reading and quality assessment application Figure 1. Flowchart of the scientific article selection process Page 20 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Table 1. Clinical trials included in the systematic review Article, author. Year and (country). Study and quality assessment Sample size and patient characteristics Intervention Outcome Measure Study results Sativex (®) as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a doubleblind, placebo-controlled randomised clinical trial, Markovà et al. 2019 (Czech Rep.) 21, Randomized clinical trial controlled by placebo. CONSORT GUIDELINE 20/25 191 patients phase A 85 (44.5%) non-responders excluded 106 patients phase B 53 THC:CBD spray vs 53 placebo Secondary progressive MS (48.2%) Relapsing remitting MS (40.8%) NSR score mean (SD) 6.4 (1.2) Efficacy NRS scale patient who achieved ≥ 30% improvement in the MS spasticity 0-10 NRS score from baseline Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs Efficacy (41/53; 77,4%) THC:CBD vs (17/53; 32,1%) placebo; OR 7,0 (IC 95%: 2,95 – 16,74) . Safety AES N=46 (24.1%) SAE N=2 (1.0%) Interruption N=29 (15.2%) Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial, Meuth SG et al. 2020. (Germany)16 Randomised Clinical trial, subgroup analysis. CONSORT GUIDELINE 20/25 N=106 EDSS score at baseline EDSS score < 6 N= 48 (45.3%) EDSS score ≥ 6 N= 58 (54.7%) NRS score NRS score < 6 N= 30 (28.3%) EDSS score ≥ 6 N= 76 (71.7%) MS spasticity MS spasticity ≤ 5 years N=53 12 weeks THC:CBD spray vs placebo. The patients adjusted the dose until symptom optimization or a maximum of 12 sprays per day was achieved. NRS spasticity and pain reduction vs baseline and relative reduction (%) vs baseline. THC:CBD 41.21%-50.66% NRC spasticity reduction vs 19.83-31.5% reduction in placebo THC:CBD 34.33-59.38% NRS pain reduction vs 21.71-46.10% reduction in placebo Page 21 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review MS spasticity > 5 years N= 53 AES, Adverse Events; EDSS, Expanded Disability Status Scale; ; MS, Multiple sclerosis; NRS, Numerical Rating Scale; ;SAE, Serious adverse events; THC:CBD: Tetrahydrocannabinol:cannabidiol; OR: Odds Ratio. Table 2. Observational studies and systematic review of observational studies included Article, author. Year and, (country). Study and quality assessment Sample size and patient characteristics Intervention Outcome Measure Study results Daily Practice Managing Resistant Multiple Sclerosis Spasticity with Delta-9- Tetrahydrocannabinol:Cannabidiol Oromucosal Spray: A systematic review of observational studies Akgün K et al. 2019 (Germany) 23 Systematic review of observational studies PRISMA GUIDELINE 20/27 14 publications of observational studies with 3989 MS patients included in the review 56% female. Mean duration of MS disease 16 years. EDSS mean 6.2 Median Length of follow-up 30 days to 4.5 years. Mean dose (spray/day) 4-7 Effectiveness MS spasticity was assessed using the 0-10 MS spasticity NRS change and additionally in some studies by the MAS. Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs The proportion of patients achieving >20% improvement in the NRS scale in the first 4 weeks ranged from 41.9% to 82.9% and was maintained for 6-12 months. AEs reported 13.1% to 80.5% 18.5-39.0% of discontinuation rate due to lack of effectiveness or AEs. Page 22 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience, D’hooghe et al. 2021.(Belgium). 24 Retrospective analysis observational study STROBE LIST. 16/22 276 patients with THC:CBD prescriptions in 8 canters. 12 weeks during THC:CBD spray, evaluating effectiveness at 4 and 8 weeks. Median spray doses per day 6. Effectiveness The NRS spasticity scale is used. MCID: >20% response on the NRS scale CID: >30% NRS response. Quality of life VAS, EQ 5D and EQ VAS scales are used. Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs Mean NRS scores improved from 8.1 at baseline to 5.2 (week 4), 4.6 (week 8) and 4.1 (week 12). A total of the 33.7% of patients dropped out due to lack of effectiveness before week 8. 171 (74%) of 230 evaluable patients met the response criteria at the end of the study (week 12). AEs reported 39 in 23 patients (9.7%) Effect of tetrahydrocannabinol:cannabidiol oromucosal spray on activities of daily living in multiple sclerosis patients with resistant spasticity: a retrospective, observational study, Mallada J. 2018, (Spain) 25 Cross-sectional study. STROBE LIST 17/22 42 patients 32 THC:CBD spray and 10 controls. 50% female mean age 51 years EDSS mean 5.9 12 weeks evaluation of real use of THC:CBD spray. The mean dose was 5.6 ± 2.5 sprays/day and the mean treatment time was 31.9 ± 25.8 months. Effectiveness Survey of 16 items of ADL. NRS spasticity scale Tolerability GIC. ADL surveys completed by the THC:CBD spray group compared with control (36.2 vs 20.2; p = 0.022)- General tolerability of THC:CBD spray from the start of treatment to the present moment was positive in 78.2%. ADL, activities of daily living; AES, adverse events; CID, clinically important difference ; EDSS, Expanded Disability Status Scale; GIC, Global impression of change; MAS, modified Ashworth scale; MCID , minimally clinically important difference ;MS, multiple sclerosis; NRS, numerical Rating Scale; ;SAE, serious adverse events; THC:CBD: Tetrahydrocannabinol:cannabidiol Page 23 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review ABSTRACT Background : Spasticity continues to be a very prevalent, highly invalidating, and difficult-to- manage symptom in patients with multiple sclerosis patients. The aim of this systematic review is to evaluate the effectiveness of the use of cannabis and cannabinoids in these patients, evaluating theits use as an additional therapy. Methods: We performed a systematic review of the literature searching in the major scientific databases (PubMed, Scopus, EMBASE, WOS, and Cochrane Library) for articles from January 2017 to May 2022 containing information about the effectiveness of using cannabis and cannabinoids in patients with insufficient response to first-line oral antispastic treatment. Results: A total of five medium-high quality articles were selected to be part of the study and all evaluated the effectiveness of the Tetrahydronnabinol (THC) and Cannabidiol (CBD) spray. The effectiveness of this drug, significant improvements are produced on the patient-related spasticity assessment scales, obtaining improvement up to 45%; and on quality of life, producing a decrease in the appearance of symptoms related to spasticity, as well as an increase in the development of basic activities of daily living (BADL). The average dose is 5-7 sprays/day. The discontinuation rate for these treatments is around 40% due to lack of effectiveness and adverse events. All reported adverse effects (AE) are mild to moderate in severity and their incidence is approximately 17%, although this figure tends to decrease with drug use. Conclusions Adding the THC: CBD sprays have been shown to be more effective in treating MS spasticity than optimizing the dose of first-line antispastic drugs in selected responders patients. The safety and tolerability profiles remain in line with those obtained in other trials. More patients would benefit from treatment if the initial response search period was extended. Page 30 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENES AND SAFETY OF CANNABINOIDS AS AN ADD-ON THERAPY IN THE TREATMENT OF RESISTANT SPASTICITY IN MULTIPLE SCLEROSIS: A Systematic Reviewsystematic review Introduction Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system, the leading cause of nontraumaticnon-traumatic neurological disability in young adults1 , with a prevalence of 2.8 million people worldwide2 . Spasticity is one of the most disabling and difficult to control symptoms of MS3. Intensive muscle stiffness, muscle weakness, muscle hypertonia, painful spasms, and insomnia that accompany it severely reduced the patient'spatient quality of life4. Around 60% of MS patients have spasticity, increasingwhich increases to 75% after 15 years of disease progression5. The treatmentTreatment currently used is a combination of antispastic drugs such as baclofen, tizanidine, or dantrolene together with physiotherapy, with an ineffectiveness of around 40%5,6. The lack of response is mainly due to the appearance of adverse effects (AE) likesuch as the risk of falls, sedation, cognitive difficulties, withdrawal syndrome, and dizziness at tolerable doses 7. Alternative routes such as intrathecal administration of baclofen or the use of botulinum toxin have been used, but require a high degree of specializationspecialisation in administration and high cost, which means its use is not widespread8. The low effectiveness and adherence to standard treatments encouraged the use of alternative therapies by patients to alleviate their symptoms. At least half of MS patients admit to having used cannabis for medicinal purposes9 , most of them with positive experiences and reporting a subjective improvement in spasticity and its accompanying symptoms. There are more than 100 types of cannabinoids, but the most important are tetrahydrocannabinol (THC) and cannabidiol (CBD)10. THC has psychoactive activity, and the ability to reduce muscle stiffness. On the other hand, CBD has almost no psychomimeticpsychotomimetic activity and has a potent analgesic and anti-inflammatory effect11–13. THC: CBD combination, it avoids psychotropic stimulation without reducing its ability to decrease muscle tone10. Page 31 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review In 2005, a 1:1 ratio of THC and CBD oral spray was approved for the first time in Canada, specifically for the treatment of spasticity in MS, after demonstrating good tolerance and efficacy in clinical trials14. This medicine has been progressively approved since 2010 in most of Europe, as well as in other countries such as New Zealand15. However, certain factors, such as legislation and high prescription costs, currently limit its use and, therefore, the experience of neurologists around the world8. Therefore, the objective of our study is to evaluate the effectiveness and safety of cannabis and its derivatives as an additional therapy in patients with multiple sclerosis who have inadequate control of spasticity with standard antispasticity treatment. Page 32 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Methods This systematic review adheres to the statement Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)16. The protocol was registered in the database of the International Prospective Register of Systematic Reviews (PROSPERO) after meets withmeeting their inclusion criteria17, registration number CRD42022351472. Data Sources and Searchers The literature review was conducted between November 2021 and August 2022. Five electronic databases (MEDLINE viathrough PubMed, Cochrane, Embase, Web of Science, and Scopus) were searched to identify relevant articles. The search strategy was developed during a panel meeting after an initial article search. It was based on the use of key phrases and/or their abbreviations based on a Metadata System (MeSH) and various combinations of these phrases to increase search efficiency. The search strategy is included in the Supplementary Material S1. An extensive list of terms to describe the target population was formulated based on the PICO acronym. P (population): Resistant spasticity in multiple sclerosis I (intervention): Cannabinoids; C (comparator): control group, placebo group, and antispastic therapy; O (outcomes): Ashworth scale, Multiple Sclerosis Spasticity scale (MSSS), or Numeric Rating Scale (NRS scale). The Ashworth scale is a tool used to assess the severity of spasticity, or abnormal muscle tone, in people with neurological conditions such as multiple sclerosis, spinal cord injury, or cerebral palsy. It is a simple, and easy-to-use scale that consists of five levels of muscle tone rangingthat range from 0 (normal) to 4 (severe spasticity). MSSS it is a standardized assessment tool that consists of a series of questions or tasks designed to evaluate the presence and severity of spasticity in different parts of the body. It may include questions about the frequency, intensity, and duration of spasms, as well as the impact of spasticity on daily activities and mobility. NRS, it is a type of assessment tool that is commonly used to measure subjective pain intensity orand other subjective experiences, such as the severity of symptoms or the level of disability. The NRS is a simple, easy-to-use tool that Page 33 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review consists of a scale ranging from 0 to 10, with 0 representing "no pain" or "no symptoms" and 10 representing "the worst pain imaginable" or "the worst symptoms imaginable. The titles and abstracts of scientific articles retrieved from the databases were analysed for inclusion criteria. The inclusion criteria were: 1) articles published between January 2017 and May 2022; 2) articles written in English, Spanish, and French; 3) articles corresponding to experimental, observational and systematic review studies; 4) articles that include our key descriptors in their writing: "Multiple sclerosis," "spasticity," and "cannabis/cannabinoid," with literal terms as well as related scientific terms and synonyms appearing in the thesaurus of each database being accepted in the search, a process that is explained in more detail in Supplemental Material;4) articles that address the research PICO question: "Is cannabis a good treatment option for uncontrolled spasticity caused by multiple sclerosis?"; 5) articles that evaluate the effectiveness of the new treatment (cannabis and derivatives) as an adjunctive therapy: Only articles in which patients maintain first-line antispastic treatment are accepted. Articles evaluating the effectiveness of synthetic modified cannabinoids (different structure from extracted from the natural plant) or articles evaluating the use of "Hemp" products (cannabis sativa strain) that contained no more than 0.3% THC were excluded. Reference lists in the publications included in the review were also analysed to ensure that other articles that may meet the inclusion and exclusion criteria were not missed. Study Selection The review of the retrieved papers was carried out in five stages. The first step was to search thefor articles, second eliminate duplicateremove duplicates, third check the title, and fourth check the abstracts of papers identified as potentially relevant to the research questions. In the next step, the full texts of the articles identified during initial selection were reviewed and the quality assessment evaluated. In all stages, the review was performed by two independent reviewers (C.M.P., E.G.C), and by a third independent reviewer (A.V.A.) in contentious cases. Data Extraction Two reviewers independently extracted and documented data from each included study according to the recommendations of the Centre for Reviews and Dissemination18. We extracted data including the year of publication, country, study design, quality assessment, Page 34 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review sample size, target population, description of interventions, outcome measures, and study results. Methodological Quality Assessment The methodological quality of randomised clinical trials was assessed using the CONSORT guideline19, for systematic review, the PRISMA statement16 and for observational studies STROBE20. All studies with 50% or less checked items were excluded for review. In all cases, the evaluation was conducted by two independent reviewers. Data Synthesis and Analysis Data extracted from all included studies were tabulated, including study authors and sample characteristics, measurement of outcome variables, and key results. All identified studies were included in a qualitative synthesis and are presented in the tables. Initially, it was intended to synthesise the data quantitatively by performing a meta-analysis. However, due to the low number of clinical trials found and the lack of a control group in observational studies, we were unable to perform a meta-analysis. Page 35 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Results Study selection After conducting an initial search, we identified 889 papersarticles. After eliminating duplicates, this number was reduced to 341. Of these papersarticles, 11 met the eligibility criteria for our study based on the PICO question and inclusion and exclusion criteria (Figure 1). Of these 11 papers, we exclude six articles: three references did not meet our quality assessment criteria; two articles presented at conferences and were not accessible, and one reference, after deep revision, did not answer the research question. Finally, five articles were included in the final review comprisingconsisting of two RCT-type studies21,22 (Table 1), two observational studies, and a systematic review of observational studies23–25 (Table 2). RCT Participants The two clinical trial publications belong to the same study, the SAVANT study. One of them is the publication of the total results 21, with two phases (Phase A and B), and the other, the analysis of subgroups 22 A total of 191 patients diagnosed with relapsing MS or secondary progressive MS (89%), predominantly women (70.2%) median age 53 years, were included in phase A, 85 patients (44.5%) were excluded for a response rate lower than 20% of the MS spasticity 0-10 NRS score compared to baseline, the remaining 106 patients continued in phase B and were randomly included in two arms 1:1, and 88% completed treatment21. In the second trial, is a subgroup analysis performed according to: Expanded disability status scale [EDSS] score (< 6 and 6); Spasticity severity 0-10 NRS score (4 to 6 and > 6), and spasticity duration (< 5 and <5 years) 22. Intervention All patients previousprior to startstarting the study had previously been treated with one or two optimizedoptimised oral antispasticity therapies (oral baclofen and/or oral tizanidine) for at least 3 months and continued during the trial. Dose of THC: CBD during the 12 weeks was individualizedindividualised and adjusted by each patient according to their needs, until the symptoms stabilization with a maximum of twelve sprays per day. Page 36 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Outcome Measure The efficacy results in the main results of the SAVANT clinical trial are expressed as an improvement of at least 30% onin the MS spasticity NRS score compared to baseline. Other secondary efficacy variables such as change from baseline in MS spasticity NRS score, NRS pain, modified Ashworth scale (MAS) and Expanded Disability Status Scale (EDSS) were included. In subgroups analysis, only change from baseline was included. Safety outcomes were measured like the number of adverse events (AEs), the number of serious adverse events (SAEs), and the number of treatment interruption related to AEs. Synthesis of Results Two RCTs reported significant improvements in MS spasticity measure by NRS score and pain NRS score of the subjects, independently of the baseline characteristics. Differences in the MS spasticity score of THC: CBD versus placebo was reached from the second week of treatment, reaching the maximum difference at 10 weeks and remaining stable until the end of the trial at 12 weeks21. In the subgroup analysis, the results showed that while the treatment had a significant effect on reducing pain in those with more severe spasticity (as indicated by a 0-10 NRS score greater than 6), it did not significantly affect the level of spasticity in these patients. However, treatment did lead tocaused a numerical decrease in both spasticity and pain in those with moderate spasticity (0-10 NRS score greater than 6) at the start of the study, compared to placebo22. A total of 75 adverse events (AE) were recorded in 46 (24.1%) patients, most of them related (64/75) to moderate to mild intensity. The most frequent AEAEs were vertigo (23.4%), somnolence (9.5%), dizziness (6.2%),%) diarrhoea (6.2%), and nausea (6.2%). A total of 29 patients (15.2%) discontinued treatment due to adverse events; one was a serious adverse event (tubulointerstitial nephritis of severe intensity) not related to THC:CBD 21. The mean daily use of THC:CBD spray was 7.3-7.7 sprays/day. Observational Studies Participants In the systematic review, 14 articles of observational studies23 summarizing 3989 patients, 56% female mean age 50 years, 16 years of duration of MS disease, and mean of EDSS at baseline Page 37 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review were 6.2. PatientsThe patients included in the cross-sectional study by Mallada et al . had similar characteristics25 , and the patient included in the observational study published by Marie D’hooghe et al. was not described24. Intervention THC:CBD spray used in a heterogenicity period of time ranging from 30 days to 4.5 years, with a number of sprays per day ranging from 4 to 7 per day. The study by D’hooghe et al. 24 assessed the efficacy of the treatment each 4 weeks. Etges et al. 26 was an international registry focus on safety data, and collect also the data of abuse and misuse of THC: CBD. Outcome Measure All articles included assessed spasticity with the MS spasticity NRS score, in addition, the D’hooghe et al. study used relative improvement compared to baseline, the minimal clinical important difference (MCID; ≥ 20% improvement in baseline NRS score) and clinicalclinically important different (CID; ≥ 20% improvement in baseline NRS score) to the patient’s global impression of change in severity of spasticity severity. Other measures such as the frequency of spams, pain, and other associated symptoms, patient global impression of change (PGIC)27 or global impression of change (GIC)25, were recorded. The qualityQuality of life, on different scales EuroQol 5-Dimension (EQ-5D), Visual Analogue Scale of Emotional Quotation Visual Analog Scale, (EQ 0-100 VAS) was also recorded in the studies included in the systematic review and observational study23,24 and the assessment of activities of daily life (ADL) in the cross-sectional study measured by Barthel Index25. The number of AEs and SAEs, and the number of treatment discontinuation were the safety measures in all studies. Synthesis of Results The MCID ranged from 41.9% to 82.9%, being the study with a higher patient evaluation 28 a proportion of 70.5%. The CID at 12 weeks was 28% in the systematic review 23 and 74% in the D´hooghe et al study 24 and 35-40% during the first year of treatment 23. The GIC was positive in 97% of the patients 25. A total of 33% of the patients improved VAS EQ 100 after 4 weeks of treatment, maintained after 12 weeks 24. Furthermore, the impairment of daily activities measured by Barthel index improves by 9% compared to baseline 29. The AE reported in most Page 38 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review studies ranged from 10 to 20%, but in monocentric observational studies included in the review, it showed higher rates of AE (40.2-80.5%) 27,30,31. Higher rates of AE occur during the first 4 weeks of treatment and decreased with prolonged use. The reported serious adverse events (SAE) related to drug are less than 1% 4,14,26,28, being the most common disorders of the nervous system. The withdrawal of adverse event rate was from 6.3% to 25%26,32 The study ofby Etges et al.26 is the only study in which misuse data was registered; it is reported that 66 patients (7%) have reported exceeding the maximum of 12 daily sprays; despite this, no studies have reported cases of abuse or dependence on treatment. Page 39 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 25. 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 Jun 1;8(3):151–9. 26. Etges T, Karolia K, Grint T, Taylor A, Lauder H, Daka B, et al. An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex® (THC: CBD, nabiximols) oromucosal spray. Ther Clin Risk Manag. 2016 Nov 11;12:1667–75. 27. Paolicelli D, Direnzo V, Manni A, D’Onghia M, Tortorella C, Zoccolella S, et al. Long- Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients. J Clin Pharmacol. 2016;56(7):845–51. 28. Patti F, Messina S, Solaro C, Amato MP, Bergamaschi R, Bonavita S, et al. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J Neurol Neurosurg Psychiatry. 2016 Sep 1;87(9):944–51. 29. Flachenecker P, Henze T, Zettl UK. Long-term effectiveness and safety of nabiximols (tetrahydrocannabinol/ cannabidiol oromucosal spray) in clinical practice. Eur Neurol. 2014;72(1–2):95–102. 30. Ferrè L, Nuara A, Pavan G, Radaelli M, Moiola L, Rodegher M, et al. Efficacy and safety of nabiximols (Sativex®) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurol Sci. 2016 Feb 1;37(2):235–42. 31. Lorente Fernández L, Monte Boquet E, Pérez-Miralles F, Gil Gómez I, Escutia Roig M, Boscá Blasco I, et al. Experiencia clínica con los cannabinoides en la terapia de la espasticidad en la esclerosis múltiple. Neurologia. 2014;29(5):257–60. 32. Flachenecker P, Henze T, Zettl UK. Nabiximols (THC/CBD Oromucosal Spray, Sativex®) in clinical practice - results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur Neurol. 2014;71(5–6):271–9. Page 46 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review … artículos First screening: Search in the different databases: PubMed, Scopus, EMBASE, WoS and Cochrane Library. 348 papers 57 papers 11 papers 5 papers 889 papers Second screening: It was excluded 541 duplicate articles. Third screening: It was excluded 291 articles by title. Fourth screening: It was excluded 46 articles by abstract. Fifth screening: It was excluded 6 articles after reading and quality assessment application Figure 1. Flowchart of the scientific article selection process Page 47 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Table 1. Clinical trials included in the systematic review Article, author. Year and (country). Study and quality assessment Sample size and patient characteristics Intervention Outcome Measure Study results Sativex (®) as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a doubleblind, placebo-controlled randomised clinical trial, Markovà et al. 2019 (Czech Rep.) 21, Randomized clinical trial controlled by placebo. CONSORT GUIDELINE 20/25 191 patients phase A 85 (44.5%) non-responders excluded 106 patients phase B 53 THC:CBD spray vs 53 placebo Secondary progressive MS (48.2%) Relapsing remitting MS (40.8%) NSR score mean (SD) 6.4 (1.2) Efficacy NRS scale patient who achieved ≥ 30% improvement in the MS spasticity 0-10 NRS score from baseline Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs Efficacy (41/53; 77,4%) THC:CBD vs (17/53; 32,1%) placebo; OR 7,0 (IC 95%: 2,95 – 16,74) . Safety AES N=46 (24.1%) SAE N=2 (1.0%) Interruption N=29 (15.2%) Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial, Meuth SG et al. 2020. (Germany)16 Randomised Clinical trial, subgroup analysis. CONSORT GUIDELINE 20/25 N=106 EDSS score at baseline EDSS score < 6 N= 48 (45.3%) EDSS score ≥ 6 N= 58 (54.7%) NRS score NRS score < 6 N= 30 (28.3%) EDSS score ≥ 6 N= 76 (71.7%) MS spasticity MS spasticity ≤ 5 years N=53 12 weeks THC:CBD spray vs placebo. The patients adjusted the dose until symptom optimization or a maximum of 12 sprays per day was achieved. NRS spasticity and pain reduction vs baseline and relative reduction (%) vs baseline. THC:CBD 41.21%-50.66% NRC spasticity reduction vs 19.83-31.5% reduction in placebo THC:CBD 34.33-59.38% NRS pain reduction vs 21.71-46.10% reduction in placebo Page 48 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review MS spasticity > 5 years N= 53 AES, Adverse Events; EDSS, Expanded Disability Status Scale; ; MS, Multiple sclerosis; NRS, Numerical Rating Scale; ;SAE, Serious adverse events; THC:CBD: Tetrahydrocannabinol:cannabidiol; OR: Odds Ratio. Table 2. Observational studies and systematic review of observational studies included Article, author. Year and, (country). Study and quality assessment Sample size and patient characteristics Intervention Outcome Measure Study results Daily Practice Managing Resistant Multiple Sclerosis Spasticity with Delta-9- Tetrahydrocannabinol:Cannabidiol Oromucosal Spray: A systematic review of observational studies Akgün K et al. 2019 (Germany) 23 Systematic review of observational studies PRISMA GUIDELINE 20/27 14 publications of observational studies with 3989 MS patients included in the review 56% female. Mean duration of MS disease 16 years. EDSS mean 6.2 Median Length of follow-up 30 days to 4.5 years. Mean dose (spray/day) 4-7 Effectiveness MS spasticity was assessed using the 0-10 MS spasticity NRS change and additionally in some studies by the MAS. Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs The proportion of patients achieving >20% improvement in the NRS scale in the first 4 weeks ranged from 41.9% to 82.9% and was maintained for 6-12 months. AEs reported 13.1% to 80.5% 18.5-39.0% of discontinuation rate due to lack of effectiveness or AEs. Page 49 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience, D’hooghe et al. 2021.(Belgium). 24 Retrospective analysis observational study STROBE LIST. 16/22 276 patients with THC:CBD prescriptions in 8 canters. 12 weeks during THC:CBD spray, evaluating effectiveness at 4 and 8 weeks. Median spray doses per day 6. Effectiveness The NRS spasticity scale is used. MCID: >20% response on the NRS scale CID: >30% NRS response. Quality of life VAS, EQ 5D and EQ VAS scales are used. Safety Numbers of AEs, SAEs, and treatment interruptions related to AEs Mean NRS scores improved from 8.1 at baseline to 5.2 (week 4), 4.6 (week 8) and 4.1 (week 12). A total of the 33.7% of patients dropped out due to lack of effectiveness before week 8. 171 (74%) of 230 evaluable patients met the response criteria at the end of the study (week 12). AEs reported 39 in 23 patients (9.7%) Effect of tetrahydrocannabinol:cannabidiol oromucosal spray on activities of daily living in multiple sclerosis patients with resistant spasticity: a retrospective, observational study, Mallada J. 2018, (Spain) 25 Cross-sectional study. STROBE LIST 17/22 42 patients 32 THC:CBD spray and 10 controls. 50% female mean age 51 years EDSS mean 5.9 12 weeks evaluation of real use of THC:CBD spray. The mean dose was 5.6 ± 2.5 sprays/day and the mean treatment time was 31.9 ± 25.8 months. Effectiveness Survey of 16 items of ADL. NRS spasticity scale Tolerability GIC. ADL surveys completed by the THC:CBD spray group compared with control (36.2 vs 20.2; p = 0.022)- General tolerability of THC:CBD spray from the start of treatment to the present moment was positive in 78.2%. ADL, activities of daily living; AES, adverse events; CID, clinically important difference ; EDSS, Expanded Disability Status Scale; GIC, Global impression of change; MAS, modified Ashworth scale; MCID , minimally clinically important difference ;MS, multiple sclerosis; NRS, numerical Rating Scale; ;SAE, serious adverse events; THC:CBD: Tetrahydrocannabinol:cannabidiol Page 50 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Page 51 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Supplemental Material S1 Search strategy SEARCH FILTERS N REFERENCES Free search: (Cannabinoid OR Nabiximols OR Sativex OR THC OR CBD OR cannabis) AND (spasticity OR spastic) AND ("Multiple Sclerosis" OR "Sclerosis, Multiple" OR "Disseminated Sclerosis" OR "Sclerosis, Disseminated" OR "MS (Multiple Sclerosis)") 145 PubMed MESH search: ((("Cannabis"[Mesh]) OR "Cannabinoids"[Mesh]) AND "Muscle Spasticity"[Mesh]) AND "Multiple Sclerosis"[Mesh] 42 Scopus TITLE-ABS-KEY ( ( ( ( ( "Cannabis" [mesh] ) OR "Cannabinoids" [mesh] ) AND "Muscle Spasticity" [mesh] ) AND "Multiple Sclerosis" [mesh] ) OR ( ( cannabinoid OR nabiximols OR sativex OR th c OR cbd OR cannabis ) AND ( spasticity OR spastic ) AND ( "Multiple Sclerosis" OR "Sclerosis, Multiple" OR "Disseminated Sclerosis" OR "Sclerosis, Disseminated" OR "MS (Multiple Sclerosis)" ) ) ) Language: English, Spanish and French 212 EMBASE (Cannabinoid OR Nabiximols OR Sativex OR THC OR CBD OR cannabis) AND (spasticity OR spastic) AND ("Multiple Sclerosis" OR "Sclerosis, Multiple" OR "Disseminated Sclerosis" OR "Sclerosis, Disseminated" OR "MS (Multiple Sclerosis)") Date: January 2017- May 2022 296 WOS (((("Cannabis"[Mesh]) OR "Cannabinoids"[Mesh]) AND "Muscle Spasticity"[Mesh]) AND "Multiple Sclerosis"[Mesh]) OR ((Cannabinoid OR Nabiximols OR Sativex OR THC OR CBD OR cannabis) AND (spasticity OR spastic) AND ("Multiple Sclerosis" OR "Sclerosis, Multiple" OR "Disseminated Sclerosis" OR "Sclerosis, Disseminated" OR "MS (Multiple Sclerosis)")) 202 Page 52 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Cochrane Library (Cannabinoid OR Nabiximols OR Sativex OR THC OR CBD OR cannabis) AND (spasticity OR spastic) AND ("Multiple Sclerosis" OR "Sclerosis, Multiple" OR "Disseminated Sclerosis" OR "Sclerosis, Disseminated" OR "MS (Multiple Sclerosis)") 34 Page 53 of 52 ScholarOne Support phone: 434-964-4100 email: [email protected] Mary Ann Liebert, Inc. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60