Patient-reported benefits from nabiximols treatment in multiple sclerosis-related spasticity exceed conventional measures.

Aim: This prospective, multicenter, open-label, noninterventional 12-week study investigated the effectiveness and tolerability of add-on nabiximols oromucosal spray (Sativex®) in the real-world setting in Germany. Patients & methods: The main analysis set comprised 51 adult patients (49 nabiximols responders) with multiple sclerosis (MS) spasticity. Results: The mean overall goal attainment scale score (primary outcome measure) increased by 46% from baseline to week 12 (35.2 vs 51.4; p < 0.001). Mean gait speed was improved by 23% at 4 and 12 weeks. Clinically meaningful improvements in mean 0-10 numerical rating scale scores for spasticity, pain, sleep quality and urinary bladder dysfunction were recorded at 4 and 12 weeks. Conclusion: Nabiximols is a useful therapeutic option for patients with MS spasticity.

People with multiple sclerosis (MS) spasticity experience a variety of symptoms and have individual expectations about a new treatment. This study investigated patients' perceptions about the effectiveness and tolerability of nabiximols oromucosal spray (Sativex^®) when added to current medications for spasticity. Common treatment goals for patients (n = 51) were less pain, better walking and improved sleep. After 12 weeks of treatment, 62% of selected treatment goals were achieved 'as expected' or 'better than expected' and 65% of patients considered their spasticity to be 'much improved'. Meaningful improvements were recorded in spasticity-related symptoms of pain, sleep quality and bladder problems. Few side effects were reported. Nabiximols may be useful for MS patients with a poor response to usual spasticity medications.

Best Practice Guidelines for the Management of Patients with Post-Stroke Spasticity: A Modified Scoping Review.

This article aims to provide a concise overview of the best available evidence for managing post-stroke spasticity. A modified scoping review, conducted following the PRISMA guidelines and the PRISMA Extension for Scoping Reviews (PRISMA-ScR), involved an intensive search on Medline and PubMed from 1 January 2000 to 31 August 2023. The focus was placed on high-quality (GRADE A) medical, rehabilitation, and surgical interventions. In total, 32 treatments for post-stroke spasticity were identified. Two independent reviewers rigorously assessed studies, extracting data, and evaluating bias using GRADE criteria. Only interventions with GRADE A evidence were considered. The data included the study type, number of trials, participant characteristics, interventions, parameters, controls, outcomes, and limitations. The results revealed eleven treatments supported by GRADE A evidence, comprising 14 studies. Thirteen were systematic reviews and meta-analyses, and one was randomized control trial. The GRADE A treatments included stretching exercises, static stretching with positional orthosis, transcutaneous electrical nerve stimulation, extracorporeal shock wave therapy, peripheral magnetic stimulation, non-invasive brain stimulation, botulinum toxin A injection, dry needling, intrathecal baclofen, whole body vibration, and localized muscle vibration. In conclusion, this modified scoping review highlights the multimodal treatments supported by GRADE A evidence as being effective for improving functional recovery and quality of life in post-stroke spasticity. Further research and exploration of new therapeutic options are encouraged.

Therapeutic use of medical Cannabis in neurological diseases: a clinical update.

The use of medical Cannabis has increased in recent years due to changing legal circumstances in many countries. Approval exists only for a few neurological conditions such as rare forms of epilepsy or spasticity in multiple sclerosis. Beyond that, however, medical Cannabis is used for a wide range of neurological conditions and symptoms. In Germany, in parallel with new legislation that has simplified the prescription of medical Cannabis, an accompanying survey has been implemented for which initial data are now available. In this context, our review provides an overview of the evidence for the therapeutic use of medical Cannabis in neurology, the potential benefits, and side effects.

[Effect of "Tiaoshen Tongluo" acupuncture on nerve function injury, muscle tension and neurotransmitters through Nrf2/ROS pathway in spastic rats after stroke].

OBJECTIVE: To observe the effect of "Tiaoshen Tongluo" acupuncture (TTA) at "Dingzhongxian" (MS5) and right "Dingpangxian" (MS8) on neurological injury, muscle tension and neurotransmitters through nuclear transcription factor E2 related factor 2 (Nrf2)/reactive oxygen species (ROS) signaling pathway in spastic rats after stroke, so as to explore its mechanisms underlying relief of post-stroke spasm (PSS). METHODS: A total of 90 male SD rats were randomly divided into 6 groups, i.e. sham operation, PSS model, medication, non-acupoint acupuncture, TTA, TTA+ML385 groups, with 15 rats in each group. The PSS model was established by middle cerebral artery occlusion. After modeling, rats of the medication group were treated by gavage of baclofen (0.4 mg/kg), once daily for 7 days. For rats of the non-acupoint acupuncture group, the spot about 10 mm above the iliac crest and below the armpit of the affected side was needled, and for those of the TTA group and TTA+ML385 group, EA stimulation (1 mA, 2 Hz/15 Hz) was applied to MS5 and right MS8 for 10 min, once daily for 7 consecutive days. Intraperitoneal injection of ML385 ［ a specific nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, 30 mg/kg］ was given to rats of the TTA+ML385 group before TTA was performed. The rats' neurological deficit score (0-4 points) was evaluated by referring to Zea Longa's methods and the muscular spasm degree of the quadriceps femoris of the left hindlimb (0-4 points) assessed by using Ashworth scale (MAS). The muscular tension of the left quadriceps femoris was measured by using a tension sensor, and Hoffman (H)-reflex response and M and H waves of electromyogram of the muscle between the metatarsals of the left foot were measured using an electrophysiological recorder. The cerebral infarction volume was measured after 2,3,5-triphenyltetrazolium chloride (TTC) staining. The contents of γ-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu) and aspartic acid (Asp) of the right cortical infarct area were detected by using high performance capillary electrophoresis, and the contents of 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) were detected by fluorescence spectrophoto-metry, as well as the level of ROS in the right cerebral cortical infarction tissues was detected by dihydroethidium staining. The expression levels of Nrf2 and heme oxygenase-1 (HO-1) proteins in the infarcted cerebral area were detected using Western blot. RESULTS: Compared with the sham operation group, the neurological deficit score, MAS score, percentage of cerebral infarction volume, Hmax/Mmax ratio, contents of Glu and Asp and ROS level were significantly increased (P<0.001), whereas the muscle tone, stimulation threshold for inducing H-reflex, GABA, Gly, 5-HT, DA and NE contents, cerebral Nrf2 and HO-1 protein expression levels were apparently decreased (P<0.001) in the model group. In comparison with the model group, the neurological deficit score, MAS score, percentage of cerebral infarction volume, Hmax/Mmax ratio, contents of Glu, Asp and ROS levels were decreased (P<0.001), and the muscle tone, stimulation threshold for inducing H-reflex, GABA, Gly, 5-HT, DA and NE contents, Nrf2 and HO-1 protein expressions were increased (P<0.001, P<0.01) in both the medication and TTA groups. No significant differences were found between the non-acupoint group and model group, and between the medication and TTA groups in all the indexes mentioned above (P>0.05). After administration of ML385, the effects of TTA in reducing neurological deficit score, MAS score, Hmax/Mmax, percentage of cerebral infarct volume, Glu, Asp, ROS, and up-regulating H-reflex threshold, GABA, Gly, 5-HT, DA, NE, Nrf2 and HO-1 levels were eliminated (P<0.001，P<0.05,P<0.01). CONCLUSION: TTA can improve neurological behavior and muscle spasm in rats with PSS, which may be associated with its functions in regulating the levels of neurotransmitters in the cortical infarcted area by activating the Nrf2/ROS signaling pathway.

A Bayesian Network Meta-Analysis and Systematic Review of Guidance Techniques in Botulinum Toxin Injections and Their Hierarchy in the Treatment of Limb Spasticity.

Accurate targeting of overactive muscles is fundamental for successful botulinum neurotoxin (BoNT) injections in the treatment of spasticity. The necessity of instrumented guidance and the superiority of one or more guidance techniques are ambiguous. Here, we sought to investigate if guided BoNT injections lead to a better clinical outcome in adults with limb spasticity compared to non-guided injections. We also aimed to elucidate the hierarchy of common guidance techniques including electromyography, electrostimulation, manual needle placement and ultrasound. To this end, we conducted a Bayesian network meta-analysis and systematic review with 245 patients using the MetaInsight software, R and the Cochrane Review Manager. Our study provided, for the first time, quantitative evidence supporting the superiority of guided BoNT injections over the non-guided ones. The hierarchy comprised ultrasound on the first level, electrostimulation on the second, electromyography on the third and manual needle placement on the last level. The difference between ultrasound and electrostimulation was minor and, thus, appropriate contextualization is essential for decision making. Taken together, guided BoNT injections based on ultrasound and electrostimulation performed by experienced practitioners lead to a better clinical outcome within the first month post-injection in adults with limb spasticity. In the present study, ultrasound performed slightly better, but large-scale trials should shed more light on which modality is superior.

Effectiveness and Safety of Cannabinoids as an Add-On Therapy in the Treatment of Resistant Spasticity in Multiple Sclerosis: A Systematic Review.

Background: Spasticity continues to be a very prevalent, highly invalidating, and difficult-to-manage symptom in patients with multiple sclerosis (MS). 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 tetrahydrocannabinol (THC) and cannabidiol (CBD) spray. The effectiveness of this drug and the 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. 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 are mild to moderate in severity and their incidence is ∼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.

Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Effectiveness of physical therapy interventions on post-stroke spasticity: An umbrella review.

BACKGROUND: Post-stroke spasticity is often one of the primary impairments addressed in rehabilitation. However, limited guidance exists on the effectiveness of physical therapy (PT) interventions for post-stroke spasticity. OBJECTIVE: To evaluate the quality of evidence of PT interventions for post-stroke spasticity. METHODS: Ovid (Medline), Cochrane Library, CINAHL, Scopus, PEDro, and PROSPERO were searched to identify reviews based on the following criteria: 1) published between 2012 and 2021, 2) participants older than 18 years old, 3) post-stroke spasticity, 4) PT interventions, 5) clinical or neurophysiological measures of spasticity as primary outcomes. Assessment of Multiple Systematic Reviews 2 and the Grades of Recommendations Assessment, Development, and Evaluation assessed methodological quality. RESULTS: Eight articles were included in the analysis. No high-quality evidence was found. Moderate quality evidence exists for transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, resistance training, and lower extremity ergometer training with or without functional electrical stimulation. Low quality evidence exists for dynamic stretching, botulinum toxin with constraint-induced movement therapy, and static stretching using positional orthoses. CONCLUSION: Findings suggest that PT should prioritize a combination of active strategies over passive interventions, but further studies are needed prioritizing analyses of the movement system in managing post-stroke spasticity in conjunction with medical therapies.

Virtual Reality for Decreasing Procedural Pain during Botulinum Toxin Injection Related to Spasticity Treatment in Adults: A Pilot Study.

BACKGROUND AND OBJECTIVES: Botulinum toxin injections are commonly used for the treatment of spasticity. However, injection procedures are associated with pain and procedural anxiety. While pharmacological approaches are commonly used to reduce these, innovative technology might be considered as a potential non-pharmacological alternative. Given this context, immersive virtual reality (VR) has shown effectiveness in the management of procedural pain. Our retrospective pilot study aimed to assess the potential added value of virtual reality in the management of pain and anxiety during intramuscular injections of botulinum toxin. MATERIALS AND METHODS: Seventeen adult patients receiving botulinum toxin injections were included. A numerical rating scale was used to assess pain and anxiety during the injection procedure. The patients reported the pain experienced during previous injections without VR before injection and the pain experienced in the current procedure with VR after the end of the procedure. The level of satisfaction of VR experience, whether or not they agreed to reuse VR for the subsequent toxin botulinum injection, and whether or not they would recommend VR to other patients were assessed. RESULTS: The use of virtual reality led to a decrease of 1.8 pain-related points compared to the procedure without technology. No significant improvement in the level of anxiety was reported. Patients were very satisfied with their VR experiences (7.9 out of 10), and many would agree to reuse VR in their next injection procedure (88%) and to recommend the use of VR in other patients (100%). CONCLUSION: VR was useful for managing procedural pain related to botulinum toxin injection in adults, with a high level of satisfaction reported by the patients. VR should be considered as a valuable alternative to pharmacological approaches to manage procedural pain during botulinum toxin injection in adults.

Botulinum Toxin Use for Modulating Neuroimmune Cutaneous Activity in Psoriasis.

Psoriasis is a complex immune-mediated inflammatory disorder that generates enormous interest within the scientific communities worldwide, with new therapeutic targets being constantly identified and tested. Despite the numerous topical and systemic medications available for the treatment of psoriasis, alternative therapies are still needed for the optimal management of some patients who present with localized, resistant lesions. Novel insights into the contribution of cutaneous neurogenic inflammation in the pathogenesis of psoriasis have yielded exciting new potential roles of nerve-targeting treatments, namely botulinum toxin type A (BoNT-A), for the management of this disease. This paper aims to review the existing literature on knowledge regarding the potential role of BoNT-A in psoriasis treatment, with a focus on its ability to interfere with the immunopathogenetic aspects of psoriatic disease. Furthermore, in our paper, we are also including the first report of psoriatic lesions remission following local BoNT-A injections that were administered for treating upper limb spasticity, in a patient that concomitantly suffered from psoriasis and post-stroke spasticity.

Usability of an application device for nabiximols oromucosal spray in patients with upper limb impaired multiple sclerosis.

Aim: This study aimed to assess the usability of a specific EU-available application device for Sativex® (US adopted name: nabiximols) cannabinoid-based oromucosal spray in patients with multiple sclerosis (MS) and spasticity-related upper limb and hand impairment in routine daily practice. Methods: MS patients with upper limb and hand impairment evaluated the usability of the device using an ad hoc 18-item questionnaire. Results: 60 patients were included. The comprehensibility of the instructions for use, practical handling and ergonomics of the device were rated as optimal (mean scores ≥8.9/10 across questions). Assisting trained nurses also rated the device as easy to use and helpful for drug administration (mean scores 10/10). Conclusion: The application device may assist MS patients with upper limb impairment self-administer nabiximols oromucosal spray.

Many patients with multiple sclerosis lose some function in their upper limbs (arms) and hands because of spasticity, which can make it difficult to take their medication at the required times each day. Patients taking nabiximols oromucosal spray may not have the strength or coordination needed to press the spray nozzle into their mouth. To support delivery of the medicine in these patients, a specific application device has been developed that reduces the strength necessary to administer the spray. 60 patients with upper limb/hand impairment tested the device and completed an 18-item questionnaire. Patients rated the instructions for use, ease of use and ergonomic features of the device as optimal, with average scores of ≥8.9/10 across questions.

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.

INTRODUCTION: Spasticity is a common, debilitating symptom of multiple sclerosis (MS) with several treatment options including the cannabinoid-based treatment, nabiximols. The purpose of this review was to examine the existing clinical practice guidelines that direct the management of multiple-sclerosis-associated spasticity (MSS), to identify areas of similarity and divergence, and suggest where standardization and improvement may be obtained. AREAS COVERED: Published literature (PubMed), websites of relevant European Medical Associations and Health Technology Assessment bodies were systematically searched to identify guidelines describing the pharmacological management of MSS, focussing on European countries where nabiximols (Sativex® oromucosal spray) is approved. Sixteen publicly available guidelines were identified. Analysis was focused on, but not restricted to, the use of nabiximols in the wider context of the pharmacological treatment of MSS. EXPERT OPINION/COMMENTARY: We believe that currently MSS is insufficiently treated and this would be improved if a clear and detailed set of guidelines were available and implemented in daily practice. We would welcome the update and amalgamation of the existing guidelines by an international panel, using an evidence-based approach, into a single guideline that is more detailed and standardized in its approach to the initiation, monitoring and optimization of anti-spasticity drugs.

People with multiple sclerosis often experience tight or stiff muscles and an inability to control those muscles. This is known as spasticity, which can have a devastating impact on a person's ability to carry out their daily activities. In addition to physiotherapy, doctors can prescribe various medicines to improve spasticity; these are known as anti-spasticity treatments. Often, prescription choices are steered by guideline documents, written by medical experts. These documents contain important information such as when to prescribe, what to prescribe, how much to prescribe and how to measure how well the treatment is working. The purpose of this study was to examine whether the guidelines that guide the prescription of anti-spasticity treatments in people with multiple sclerosis in Europe, are fit for purpose for day-to-day medical practice. In particular, this article examines how the guidelines represent the newer cannabis-based treatment known as nabiximols, sold under the name Sativex oromucosal spray, which has become more widely available in many European countries over the last 10 years.

Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience.

BACKGROUND: This retrospective study evaluates patient-reported outcomes in patients with multiple sclerosis (MS) spasticity who were treated with a cannabinoid oromucosal spray (Sativex®, USAN name: nabiximols) after not sufficiently responding to previous anti-spasticity medications. METHODS: Of 276 patients from eight centers in Belgium who began treatment prior to 31 December 2017, effectiveness assessment data were available for 238 patients during the test period of 4 to 8/12 weeks, and for smaller patient cohorts with continued treatment for 6/12 months. RESULTS: Mean 0-10 spasticity Numerical Rating Scale (NRS) scores improved from 8.1 at baseline to 5.2 (week 4), 4.6 (week 8) and 4.1 (week 12). Mean EuroQoL Visual Analogue Scale (EQ VAS) scores increased from 39 at baseline to 52 (week 4), 57 (week 8) and 59 (week 12). Mean NRS and EQ VAS scores remained in the same 12 weeks' range in patients with longer-term data. The average dose of cannabinoid oromucosal spray was 6 sprays/day. Most of the 93 out of 276 patients, with initial prescription (33.7%), who discontinued treatment by week 12 did so within the first 8 weeks, mainly due to lack of effectiveness. By week 12, 171 (74%) of the 230 effectiveness evaluable patients reported a clinically meaningful response, corresponding to ≥30% NRS improvement. The tolerability of cannabinoid oromucosal spray was consistent with its known safety profile. CONCLUSIONS: More than 60% of the patients with MS who started add-on treatment with cannabinoid oromucosal spray reported a clinically relevant symptomatic effect and continued treatment after 12 weeks.

Electrical Stimulation of Injected Muscles to Boost Botulinum Toxin Effect on Spasticity: Rationale, Systematic Review and State of the Art.

Botulinum toxin type A (BoNT-A) represents a first-line treatment for spasticity, a common disabling consequence of many neurological diseases. Electrical stimulation of motor nerve endings has been reported to boost the effect of BoNT-A. To date, a wide range of stimulation protocols has been proposed in the literature. We conducted a systematic review of current literature on the protocols of electrical stimulation to boost the effect of BoNT-A injection in patients with spasticity. A systematic search using the MeSH terms "electric stimulation", "muscle spasticity" and "botulinum toxins" and strings "electric stimulation [mh] OR electrical stimulation AND muscle spasticity [mh] OR spasticity AND botulinum toxins [mh] OR botulinum toxin type A" was conducted on PubMed, Scopus, PEDro and Cochrane library electronic databases. Full-text articles written in English and published from database inception to March 2021 were included. Data on patient characteristics, electrical stimulation protocols and outcome measures were collected. This systematic review provides a complete overview of current literature on the role of electrical stimulation to boost the effect of BoNT-A injection for spasticity, together with a critical discussion on its rationale based on the neurobiology of BoNT-A uptake.

Effect of nabiximols on Goal Attainment Scale scores in patients with treatment-resistant multiple sclerosis spasticity.

Background: Nabiximols oromucosal spray (Sativex®) is an approved add-on treatment option for moderate-to-severe treatment-resistant multiple sclerosis (MS) spasticity. Materials & methods: This prospective, observational, noninterventional, 3-month follow-up pilot study assessed the evolution of patient-selected goal attainment scale (GAS) item scores and of MS spasticity and associated symptoms during nabiximols treatment. Results: In the full analysis set (n = 21), the mean (SD) overall unweighted GAS score increased from 32.1 (3.4) at baseline to 43.6 (14.6) at month 3 (p = 0.0060), constituting a clinically meaningful change. Slight improvements were observed in MS spasticity and most associated symptoms. Nabiximols improved walking ability and was well tolerated. Conclusion: The study provides proof-of-concept that GAS methodology can be applied to MS management in daily practice.

Lay abstract Many people with multiple sclerosis (MS) have muscle stiffness in their arms and legs that hinders their ability to perform usual daily activities such as walking or using a smartphone. This study followed 21 people with MS to see whether adding nabiximols (Sativex^®) spray to usual medications for muscle stiffness might help them to achieve goals (e.g., 'less fatigue', 'better walking') which had been selected individually as most important before starting treatment. After 3 months of treatment, the higher average score on the Goal Attainment Scale suggested that, overall, nabiximols can improve MS spasticity-related patient goals although outcomes varied considerably among patients. Patients also perceived improvements in muscle stiffness, other symptoms of MS and walking ability.

Interventions and lower-limb macroscopic muscle morphology in children with spastic cerebral palsy: a scoping review.

AIM: To identify and map studies that have assessed the effect of interventions on lower-limb macroscopic muscle-tendon morphology in children with spastic cerebral palsy (CP). METHOD: We conducted a literature search of studies that included pre- and post-treatment measurements of lower-limb macroscopic muscle-tendon morphology in children with spastic CP. Study quality was evaluated and significant intervention effects and effect sizes were extracted. RESULTS: Twenty-eight articles were identified. They covered seven different interventions including stretching, botulinum neurotoxin A (BoNT-A), strengthening, electrical stimulation, whole-body vibration, balance training, and orthopaedic surgery. Study quality ranged from poor (14 out of 28 studies) to good (2 out of 28). Study samples were small (n=4-32) and studies were variable regarding which muscles and macroscopic morphological parameters were assessed. Inconsistent effects after intervention (thickness and cross-sectional area for strengthening, volume for BoNT-A), no effect (belly length for stretching), and small effect sizes were reported. INTERPRETATION: Intervention studies reporting macroscopic muscle-tendon remodelling after interventions are limited and heterogeneous, making it difficult to generalize results. Studies that include control groups and standardized assessment protocols are needed to improve study quality and data synthesis. Lack or inconclusive effects at the macroscopic level could indicate that the effects of interventions should also be evaluated at the microscopic level. WHAT THIS PAPER ADDS: Muscle-targeted interventions to remodel muscle morphology are not well understood. Studies reporting macroscopic muscle remodelling following interventions are limited and heterogeneous. Passive stretching may preserve but does not increase muscle length. The effects of isolated botulinum neurotoxin A injections on muscle volume are inconsistent. Isolated strengthening shows no consistent increase in muscle volume or thickness.

Cannabis and multiple sclerosis.

INTRODUCTION: Patients with multiple sclerosis (MS) may suffer from spasticity and pain during their disease course. Baclofen, dantrolene, diazepam and gabapentin have been used as first-line options to treat these conditions, with modest results. Medical use of marijuana smoking has bypassed traditional clinical trials and has been legalized as a therapeutic option for MS-related spasticity and pain in some countries. Cannabis-derived drugs have been tested and approved for medical use. AREAS COVERED: With the development of nabiximols by the pharmaceutical industry, more countries have made it possible for patients with MS to have legal access to cannabis-related therapies. The evidence-based data on nabiximols and MS-related spasticity, pain, and urinary symptoms is consistent. There are over 7,500 patients reported in 33 studies (12 from the United Kingdom and 11 from Italy). EXPERT OPINION: Nabiximols is safe and effective for patients with MS whose spasticity could not be treated with the first-line oral drugs. At present, legislation, bureaucracy and costs involved in prescribing this drug limit the experience of neurologists from many countries. There is no scientific evidence that smoking marijuana can be beneficial to patients with MS.