A systematic review of European regional and national guidelines: a focus on the recommended use of nabiximols in the management of spasticity in multiple sclerosis

Figures & data

Figure 1. Flow Chart.

*Manual search of websites of national specialist relevant medical associations identified from https://wfneurology.org/about-us/member-societies.

**Manual search of websites from national (governmental) HTA bodies that determine reimbursement for medical treatments; limited to European countries where nabiximols (Sativex oromucosal spray) is known to be reimbursed. Relevant HTAs identified from https://www.eunethta.eu/about-eunethta/eunethtanetwork/.

^Two relevant documents from UK's HTA body, NICE, were included.

DM, disease modification; HTA, Health Technology Assessment; NICE, National Institute for Health and Care Excellence; UK, United Kingdom.

Figure 2. Composite treatment algorithm showing points of similarity and difference between the recommended treatment of generalized MSS in published national guidelines.

The information in this composite algorithm is based on all of the identified guidelines that described treatment pathways or lines of treatment (as shown in Table 1 [16,19,20,25,26,27,28,29,30,31]), not only those that formally developed an algorithm. This algorithm is limited to generalized spasticity; elements from the published guidelines that related to focal spasticity have been excluded.

Table 1. Available national/regional guidelines describing clinical practice relating to treatment of MSS.

Country	Authority	Date	Scope	Formal recommen-dations?*	Overview of recommended patient pathway (pharmacological)
					First-line	Second-line	Third-line	Fourth-line
Austria	ÖMSB [16]	2020	MS in general	N	Baclofen or tizanidine or gabapentin	Change of substance to a different first-line option	Nabiximols add-on	Intrathecal baclofen
Belgium**	EAN/BVN-SBN [17]	2020	Palliative care for severe, progressive MS	Y	NS	NS	NS	NS
Czech Republic	Czech Neurological Society [18]	2012	MS	Y	NS	NS	NS	NS
Denmark	DNKS [19]	2015	MS in general	N	Baclofen, tizanidine, benzodiazepine, or gabapentin	Sativex add-on	Baclofen pump	NS
Germany	DGN [21]	2019	Spasticity in a wide variety of indications	Y	NS	NS	NS	NS
	HTA; G-BA [20]	2018	Sativex in MS	N	Baclofen or tizanidine or dantrolene	Change of substance to a different first-line option	Nabiximols add-on or other anti-spasticity agent	NS
	DGN/KKNMS [22]	2014	MS in general	N	NS	NS	NS	NS
Italy	SIN/AISM [23]	2019	MSS	Y	NS	NS	NS	NS
Netherlands	FMS [24]	2021	MS	?	NS	NS	NS	NS
Portugal	HTA; Infarmed [25]	2019	Sativex in MS	N	Baclofen or tizanidine	Baclofen + tizanidine	Nabiximols add-on	NS
Spain	SEN [26]	2013	MSS	Y	Baclofen or tizanidine	Nabiximols add-on or baclofen + tizanidine	Other combinations of oral drugs	Intrathecal baclofen
	HTA; AQuAS [27]	2012	MS	Y	Baclofen	Add or switch to tizanidine	Switch to diazepam	All others (inc. gabapentin or nabiximols add-on or intrathecal baclofen)
Sweden	SMSS [28]	2019	MSS	N	Baclofen, tizanidine, diazepam, dantrolene or gabapentin	Nabiximols add-on	Intrathecal baclofen	-
UK	HTA; NICE [29,30]	2019	MS in general; [29] Cannabis-based only [30]	Y	Baclofen and/or gabapentin [29]	Tizanidine or dantrolene [29]	Benzodiazepines [29]	Nabiximols add-on [30]
Europe	ECTRIMS/ EFNS/ENS [31]	2016	MSS	Y	Baclofen or tizanidine or gabapentin	Dantrolene or diazepam	Combination or add nabiximols to monotherapy	Intrathecal baclofen

AQuAS, Catalan Agency for Health Quality and Assessment; ASISM, Associazione Italiana Sclerosi Multipla; BVN-SBN, Belgian Neurological Society; DGN, Deutsche Gesellschaft für Neurologie; DNKS, Danish Neurological Society; EAN, European Academy of Neurology; ECTRIMS, European Committee for Treatment and Research in Multiple Sclerosis; EFNS, European Federation of Neurological Societies; ENS, European Neurological Society; FMS, Federation of Medical Specialists; G-BA, Gemeinsamer Bundesausschuss; HTA, Health Technology Assessment bodies; KKNMS, Kompetenznetz Multiple Sklerose; MS, multiple sclerosis; MSS, multiple sclerosis-associated spasticity; NICE, National Institute for Clinical and Healthcare Excellence; NS, not specified; ÖMSB, Austrian Society for Neurology; SEN, Sociedad Española de Neurología; SIN, Società Italiana di Neurologia; SMSS, Svenska MS-sällskape; SSN, Société Suisse de Neurologie.

*Formal guidelines were defined as those that are evidence-based and/or generated using a dedicated and formal methodology.

**That relevant Belgian associations support the use of published European guidelines was identified from BVN-SBN website; https://neuro.be/1475-2/

Table 2. Sativex-related recommendations in the context of Ms-associated spasticity, as provided in the national guidelines.

Guideline	Nabiximols-related recommendation
Europe, EAN [17]	Nabiximols [Sativex] is recommended to reduce spasticity in patients with severe MS. Drug availability, the presence of other symptoms and possible adverse events should be considered in treatment decision making. Strength of evidence: moderate Strength of recommendation: strong
Italy [23]	Evidence exists to recommend cannabinoids, and particularly oromucosal spray nabiximols, [Sativex], for the treatment of spasticity in MS patients. Strength of recommendation: strong
Europe [31]	Use in MS patients with spasticity and a suboptimal therapeutic response or poor tolerance to oral drugs (baclofen, tizanidine and gabapentin).
	The therapeutic response must be evaluated after four weeks, as only less than 50% of patients are responders, and discontinuation should be considered if no significant symptom improvement is seen.
Spain [26]	The combined treatment of Sativex (nabiximols) was shown to reduce significant spasticity due to MS and refractory to conventional treatments (baclofen, diazepam, tizanidine, gabapentin, or combinations thereof). Strength of evidence: 1+ [strong] Strength of recommendation: A [strong]
	The therapeutic response should be evaluated at four weeks; consider discontinuation if the reduction in spasticity does not reach 20% than that presented by the patient at the start of treatment. Strength of evidence: 1+ [strong] Strength of recommendation: B [moderate]
Catalonian HTA [27]	In patients with MS and spasticity in whom no improvement is observed clinical or have a poor tolerance to other treatments, treatment with nabiximols (Sativex) is recommended. Its discontinuation must be evaluated if no improvement in symptomatology is observed in the short-term time limit. Strength of recommendation: strong
UK (NG144) [30]	Offer a four-week trial of [Sativex] to treat moderate to severe spasticity in adults with multiple sclerosis, if other pharmacological treatments for spasticity are not effective.
	After the four-week trial, continue [Sativex] if the person has had at least a 20% reduction in spasticity-related symptoms on a 0–10 patient-reported NRS.
	Treatment with [Sativex] should be initiated and supervised by a physician with specialist expertise in treating spasticity due to multiple sclerosis.

Only formal recommendations (evidence-based and/or developed using a formal methodology) are shown. NICE guidelines CG186 [29] are not included here as aspects relevant to cannabinoid-based treatments are superseded by NICE guidelines NG144 (shown) [30].

EAN, European Academy of Neurology; HTA, Health Technology Assessment; MS, multiple sclerosis; NRS, numerical rating scale; RCT, randomized controlled trial.

Table 3. Recommendations relating to the measurement and monitoring of clinical response to nabiximols.

Guideline	Assessment tool(s) to measure spasticity?	Definition of clinical response	When to assess efficacy	When to discontinue treatment
UK [30]	NRS	>20% improvement in NRS vs. baseline	After four weeks	-
Portugal [25]	NRS	>20% improvement in NRS vs. baseline	After four weeks	-
Europe [31]	-	-	After four weeks	Stop if there is ‘no significant symptom improvement after four weeks’*
Spain [26]	MAS, NRS, Penn’s	>20% improvement in spasticity vs. baseline**	After four weeks	Stop if improvement in spasticity is <20% vs. baseline**

*Significant symptom improvement was not defined.

**The measurement tool that should be used to identify a 20% improvement (out of a range of options) was not specified.

MAS, modified Ashworth Scale; NRS, numerical rating scale.

Baumhackl U, Berger T, E C. ÖMSB (Österreichische Multiple Sklerose Bibliothek): evidenzbasierte Informationen zu Allen Aspekten der MS für Betroffene sowie Ärzte und Ärztinnen und Angehörige medizinischer Gesundheitsberufe [ÖMSB Austrian multiple sclerosis library: evidence-based information on all aspects of MS for those affected as well as doctors, relatives and medical health professionals]. 2020. cited2021 Sept 30]. Available from: https://www.oegn.at/wp-content/uploads/2020/05/OEMSB_2020.pdf

 Google Scholar

Rasmussen P, Jensen H. Generelt on behandling af MS-symptomatisk. 2015. [cited 2021 Sept 29]. Available from: https://neuro.dk/wordpress/nnbv/generelt-om-symptomatisk-ms-behandling/

 Google Scholar

Bundesausschuss G. [Decision of the Federal Joint Committee: an amendment to the medicines directive (AMRL): annex XII - resolutions on the benefit assessment of drugs with new ones active ingredients according to § 35a sgb v - extract from Cannabis sativa L., folium cum flore (Active ingredient combination from Delta-9-Tetrahydrocannabinol and cannabidiol) ( Reassessment after the deadline). BAnz AT 30112018 B6. 2018.

 Google Scholar

Infarmed. [Public report on the evaluation of the request for the submission of medicune for human use] Relatoria publico de avaliacao do perido de comparticipacao de medicamento para uso humano: DCI – delta-9-tetrahidrocanabinol (THC PFV) + Canabidiol (CBD PFV). Prep de Fármacos Vegetais, ext Cannabis sativa. 2021. [cited 2021 Sept 30]. Available from: https://www.infarmed.pt/documents/15786/1437513/Relat%C3%B3rio±p%C3%BAblico±de±avalia%C3%A7%C3%A3o±do±medicamento±Sativex±2019/c055642c-92fe-4e84-9da6-f72f3a9c0e06?version=1.0.

 Google Scholar

Oreja-Guevara C, Montalban X, de Andrés C, et al. Consensus document on spasticity in patients with multiple sclerosis. Grupo de Enfermedades Desmielinizantes de la Sociedad Española de Neurología. Rev Neurol. 2013 Oct 16;57(8):359–373. PubMed PMID: 24081891; spa.

 PubMedGoogle Scholar

(AQuAS) CAfHQaA. Practice guide care clinic to people with multiple sclerosis. 2012. [cited Nov 2021]. Available from: https://aquas.gencat.cat/web/.content/minisite/aquas/publicacions/2012/pdf/gpc_esclerosi_multiple_aiaqs2012ca_completa.pdf

 Google Scholar

Svenska MS Sällskapet JL. Spasticitet Metodboken [Spasticity methodbook] 2019. [cited 2021 Sept 30 2021]. Available from: http://www.mssallskapet.se/wp-content/uploads/2019/03/Spasticitet.pdf

 Google Scholar

NICE. Multiple sclerosis: management of multiple sclerosis in primary and secondary care. CG186. 2019. [cited 2021 Sept 29]. Available from: www.nice.org.uk/guidance/cg186

 Google Scholar

NICE. Cannabis-based medicinal products. NICE guideline NG144. HYPERLINK “C:\Users\User\Desktop\Clients\PH Medical Communica- tions Ltd\GWP042_Sativex guidelines_narrative review www.nice.org.uk\guidance\ng144” 2019. [cited 2021 Sept 30]. Available from: www.nice.org.uk/guidance/ng144

 Google Scholar

Otero-Romero S, Sastre-Garriga J, Comi G, et al. Pharmacological management of spasticity in multiple sclerosis: systematic review and consensus paper. Mult Scler. 2016Oct;2211:1386–1396. PubMed PMID: 27207462; eng

 PubMed Web of Science ®Google Scholar

Solari A, Giordano A, Sastre-Garriga J, et al. EAN guideline on palliative care of people with severe, progressive multiple sclerosis. Eur J Neurol. 2020Aug;278:1510–1529. PubMed PMID: 32469447; eng

 PubMedGoogle Scholar

Society CN. Clinical standard for diagnosis and treatment of multiple sclerosis and neurimyelitis optica 2021. [cited 2021 Nov]. Available from: https://www.czech-neuro.cz/archiv/data/M/w/u/0031-rs-doporuceni.pdf

 Google Scholar

Platz T, J. Wissel, E. Donauer. Therapie des spastischen Syndroms, S2k-Leitlinie, 2018, in: deutsche Gesellschaft für Neurologie (Hrsg.), Leitlinien für Diagnostik und Therapie in der Neurologie. 2021. [cited 2021 Sept 29]. Available from: www.dgn.org/leitlinien

 Google Scholar

DGN, KKNMS. Guidelines for diagnosis and therapy of MS. 2014. [cited Jan 2021]. Available from: http://www.kompetenznetz-multiplesklerose.de/wp-content/uploads/2016/02/dgn-kknms_ms-ll_20140813.pdf

 Google Scholar

Comi G, Solari A, Leocani L, et al. Italian consensus on treatment of spasticity in multiple sclerosis. Eur J Neurol. 2020Mar;273:445–453. PubMed PMID: 31652369; eng

 PubMedGoogle Scholar

Federation of Medical Specialists. [Multiple sclerosis]. 2021. [cited Nov 2021]. Available from: https://richtlijnendatabase.nl/richtlijn/multiple_sclerose_ms/startpagina_-_multiple_sclerose_ms.html

 Google Scholar

Data availability statement

Findings in this review were all drawn from publicly available information, as referenced within the text of the publication. No additional data repository is necessary.