gw-1000 and Muscle-Spasticity

Spasticity affects 54% of multiple sclerosis (MS) patients at disease onset, but this rate gradually increases with disease progression. Spasticity does not fully respond to standard treatment in one-third of the patients.. Our systematic review and meta-analysis assessed whether add-on nabiximols, can improve MS-associated refractory spasticity.. The systematic literature search was performed in Web of Science, MEDLINE, Scopus, CENTRAL, and Embase, on 15/10/2021, without restrictions. We included in the review blinded, randomized, placebo-controlled trials evaluating the efficacy of nabiximols in adult MS patients with refractory spasticity, by comparison with placebo. The primary outcome was responder rate by spasticity numerical rating scale (NRS). Secondary outcomes were spasticity-related parameters. We used random effect models to calculate odds ratios (OR) or mean differences and the corresponding 95% CI. Bias-factors were assessed with Cochrane risk of bias tool (RoB2). (PROSPERO ID: CRD42021282177).. We identified 9 eligible articles, of which 7 (1128 patients) were included in the meta-analysis. The spasticity numerical rating scale (NRS) was significantly higher in the nabiximols group than in the placebo group (OR 2.41 (95% CI 1.39; 4.18)). Secondary outcomes were in accordance with our primary results. At least some concerns were detected in the risk of bias analysis.. Our results indicate that nabiximols is efficient in MS associated spasticity, refractory to standard treatment and it may be considered as add-on symptomatic therapy. Nevertheless, further studies are needed to establish the optimal treatment protocol - dose, duration, moment of initiation, disease type.

Topics: Adult; Cannabidiol; Dronabinol; Humans; Multiple Sclerosis; Muscle Spasticity; Randomized Controlled Trials as Topic; Treatment Outcome

Effective symptomatic management of multiple sclerosis (MS) spasticity remains an unmet need for many patients. The second-line option nabiximols is the most widely investigated of the noninvasive antispasticity medications in this patient population. Clinical evidence accumulated with nabiximols since it was first approved in Europe in 2010 suggests that about 40% of initial responders (i.e., those with ≥20% improvement in their baseline 0-10 Numerical Rating Scale score) may expect to achieve clinically meaningful (≥30% Numerical Rating Scale response) and durable symptomatic improvement in MS spasticity. During 10 years' routine use of nabiximols, no new safety signals have emerged. Nabiximols-associated improvement in MS spasticity-related symptoms such as pain and sleep disruption suggests a need to track possible therapeutic effects beyond muscle tone control.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity

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.. 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.. 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.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

: Nabiximols oromucosal spray,a cannabis-based medicine containing a balanced ratio of Δ-9-tetrahydrocannabinol and cannabidiol, is approved widely as an add-on therapy for symptomatic relief of spasticity in people with multiple sclerosis (MS). Most safety data for nabiximols derive from use in MS spasticity, with some data available from the analgesia area.. : This review compiles safety and tolerability data from all published observational studies, registry analyses, and case reports identified in systematic searches in which nabiximols oromucosal spray was investigated for spasticity (n = 20) and/or chronic non-cancer pain (n = 4). Aligning with the known safety profile of nabiximols as demonstrated in randomized controlled trials, common adverse events reported consistently across studies conducted under clinical practice conditions were dizziness, fatigue and somnolence. The serious adverse event (SAE) rate with nabiximols in MS spasticityobservational studies was 3.1% (137/4351). A total of 39 treatment-related SAEs were reported in 32 patients with spasticity, all of which (where specified) were resolved. No treatment-related SAEs were recorded in nabiximols pain studies.. : Real-world experience with nabiximols oromucosal spray in treating spasticity and chronic pain indicates that, overall, it is well tolerated and has a good safety profile.

Topics: Analgesics, Opioid; Cannabidiol; Chronic Pain; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Registries

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.. 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).. 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.

Topics: Cannabidiol; Cannabinoid Receptor Modulators; Dronabinol; Drug Combinations; Humans; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Pain; Urologic Diseases

Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it. In this article, we review the evidence relating the antispasticity medicine, Δ. Articles were identified by searching PubMed from 1/1/2000 to 30/6/2017 using a specified list of search terms. The articles identified using these search terms were augmented with relevant references from these papers and other articles known to the authors.. The results from THC:CBD oromucosal spray driving studies and real-world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function. It should be noted that THC blood levels are significantly lower than the levels associated with recreational use of herbal cannabis.. THC:CBD oromucosal spray was shown not to impair driving performance. However, periodic assessment of patients with MS driving ability is recommended, especially after relapses and changes in treatment. Blood THC measurements might be above authorized thresholds for some countries following administration of THC:CBD oromucosal spray, thus specific knowledge of each country's driving regulations and a medical certificate are recommended.

Topics: Automobile Driving; Cannabidiol; Cognition; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents

Spasticity is a common symptom of multiple sclerosis (MS) affecting about 80% of MS patients. Numerous lines of evidence suggest that spasticity due to its complexity is not adequately managed with conventional anti-spastic therapies. Therefore, in order to improve the outcomes for the majority of MS patients, alternative approaches are needed to be discovered. Over the last years, the use of cannabinoid compounds as a potential treatment for MS-related symptoms has aroused great interest, owing to encouraging preclinical and clinical studies. To date, Sativex, an oromucosal spray containing tetrahydrocannabinol and cannabidiol in approximately 1:1 ratio, is the only commercially available formulation containing cannabinoids used as add-on therapy for treatment of spasticity in adult MS patients who are not responding to conventional antispastic therapies.. Here, by performing a literature search, we provided an overview of the last decade of clinical evaluations as well as post-marketing studies about effectiveness and safety of Sativex in the management of MS-related spasticity.. Sativex was proven effective in treating spasticity and also in improving the patient's quality of life. In addition, a low incidence of adverse reactions Sativex-related supports the good safety profile and its tolerability.. This review by recognizing the clinical effectiveness of Sativex in spasticity management, opened a new opportunity for many patients with spasticity resistant to common antispastic drugs.

Topics: Cannabidiol; Clinical Trials as Topic; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Treatment Outcome

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

From the time Sativex (THC:CBD) oromucosal spray first became available in European Union countries in 2010 for the management of treatment-resistant multiple sclerosis (MS) spasticity, data from daily practice have been collected through various projects.. A retrospective registry study and a prospective safety study of THC:CBD oromucosal spray are reported.. The most recent analysis of a retrospective registry established in the United Kingdom (UK), Germany and Switzerland, which collected safety data on more than 900 patients, has indicated a positive risk-benefit profile for THC:CBD oromucosal spray during long-term use. Long-term continuation rates were 68% (mean follow-up time 1 year) and the mean dose was 5.4 sprays/day. No new safety concerns were identified, and adverse events of special interest for a cannabis-based medicine were limited. The UK registry has since been closed but remains open in Germany and Switzerland. A prospective safety study undertaken in Spain involved 207 patients from 13 specialized MS centres who had been prescribed THC:CBD oromucosal spray. The findings aligned closely with the UK/German/Swiss registry data in terms of 1-year continuation rates (64.7%), mean daily dose (6.6 sprays/day) and safety profile, including no evidence of addiction, abuse or misuse.. The homogeneity between these observational studies supports the interest in THC:CBD oromucosal spray for management of MS spasticity in daily practice.

Topics: Accidental Falls; Cannabidiol; Depression; Dronabinol; Drug Combinations; Germany; Humans; Marijuana Abuse; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Plant Extracts; Prospective Studies; Registries; Retrospective Studies; Spain; Switzerland; Treatment Outcome; United Kingdom

Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients.. Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty.. The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs.. The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of antispasticity agents and to produce evidence-based treatment algorithms.

Topics: Amines; Analgesics; Baclofen; Cannabidiol; Clonidine; Cyclohexanecarboxylic Acids; Dantrolene; Diazepam; Dronabinol; Drug Combinations; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Humans; Injections, Spinal; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Phenol

In addition to muscle stiffness and increasing mobility restrictions, symptoms commonly associated with multiple sclerosis (MS) spasticity are spasms, sleep disturbances, pain, fatigue and bladder dysfunction. Treatment options include trigger factor avoidance, physiotherapy and antispasticity medication. Oral antispasticity agents commonly used in Germany are baclofen, tizanidine and gabapentin, but physician and patient satisfaction with their effectiveness is low. Over the past few years, randomized controlled trials, observational studies and registry data have demonstrated the positive risk:benefit profile of add-on 9-delta-tetra-hydrocannabinol:cannabidiol oromucosal spray for moderate-to-severe resistant MS spasticity. Herein, evidence for this novel therapeutic option is reviewed. A case study illustrates the level of improvement in daily functioning that is possible in treatment responders.

Topics: Administration, Oral; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle Relaxants, Central; Muscle Spasticity; Observational Studies as Topic; Plant Extracts; Randomized Controlled Trials as Topic

Individuals with multiple sclerosis (MS) spasticity may experience a range of symptoms, such as bladder dysfunction, pain, impaired sleep quality and mobility restrictions that worsen as spasticity severity increases. In this review, the effects of Sativex(®) oromucosal spray on symptoms and functional impairment associated with MS-related spasticity were examined. Across Sativex studies, there was a clear trend for improvement in spasticity-associated symptoms that was more pronounced and sustained over time in Sativex responders. Meaningful symptomatic improvement was achieved within the recommended dosage limit of ≤12 sprays per day. In appropriate patients, Sativex has the potential to minimize the consequences of spasticity-related symptoms on quality of life and reduce the economic burden on healthcare systems.

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Sleep; Visual Analog Scale

We identified 16 randomized placebo-controlled trials investigating cannabinoids as symptomatic treatment in multiple sclerosis (MS). There is evidence that nabiximols oromucosal spray may reduce subjective symptoms of spasticity and that dronabinol is effective against neuropathic pain in patients with MS. The existing treatment system in Denmark is in conformity with the existing data and there is not sufficient evidence to modify it.

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Evidence-Based Medicine; Humans; Multiple Sclerosis; Muscle Spasticity; Neuralgia; Treatment Outcome

Once the efficacy and tolerability of a new intervention have been demonstrated in clinical trials under ideal experimental conditions, observational studies within approved label conditions are performed to determine its effectiveness in real-world use and expand the safety/tolerability data. Several large observational studies have been conducted of Sativex(®) (THC:CBD) oromucosal spray as add-on therapy for moderate-to-severe treatment-resistant multiple sclerosis (MS) spasticity. Studies performed to date with a focus on tolerability have confirmed the absence of abuse, misuse, addiction and lack of impairment of cognition or driving ability. Open-label studies performed to date with a focus on effectiveness have indicated that about one-half to two-thirds of patients initiated on THC:CBD oromucosal spray continue to derive benefit after 3 months' treatment at a mean dosage of 5-7 sprays/day.

Topics: Activities of Daily Living; Cannabidiol; Disease Management; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Product Surveillance, Postmarketing

Guidelines from both the German and Spanish Neurology Societies for managing patients with multiple sclerosis (MS) spasticity emphasize the importance of setting clear objectives and use evidence levels and grades to support their recommendations. Swedish guidelines for MS spasticity also reflect the need to establish treatment aims and recommend use of validated scales to measure symptom changes. Treatment of generalized MS spasticity, beyond physiotherapy, tends to begin with baclofen, tizanidine and/or diazepam, adding Sativex (THC:CBD) oromucosal spray for moderate-to-severe cases. The European Federation of Neurological Societies/European Academy of Neurology Taskforce on Spasticity in Multiple Sclerosis is currently reviewing the literature supporting the pharmacological treatment of MS spasticity and aims to publish recommendations in the near future to guide clinicians in their treatment choices.

Topics: Algorithms; Cannabidiol; Clinical Trials as Topic; Disease Management; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

New clinical experience with 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex®) involving more than an additional 1,000 patients with MS spasticity (approximately 150 in clinical studies and 900 in post-marketing surveillance studies) have become available in 2013 and are reviewed. A randomized, placebo controlled long-term follow-up clinical trial with THC:CBD spray versus placebo demonstrated that it was not associated with cognitive decline, depression or significant mood changes after 12 months of treatment. Furthermore, in a prospective observational pilot study involving 33 patients (60% female) aged 33-68 years and a mean disease duration of 6.6 years, THC:CBD oromucosal spray did not adversely influence standard driving ability in patients with moderate to severe MS spasticity. Other new long term observational data about the use of THC:CBD oromucosal spray in clinical practice are available from patient registries in the UK, Germany and Spain. Findings to date reinforce the efficacy and safety observed in Phase III clinical trials. It is of interest that in practice average dosages used by patients tended to be lower than those reported in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained in the majority of patients. Importantly, no additional safety concerns were identified in the registry studies which included findings from patients who have been treated for prolonged periods (in the German/UK registry 45% of patients had >2 years exposure). Thus, these new data support a positive benefit-risk relationship for THC:CBD oromucosal spray during longer-term use.

Topics: Affect; Automobile Driving; Cannabidiol; Clinical Trials as Topic; Cognition; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Parasympatholytics; Plant Extracts; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.

Topics: Adult; Cannabidiol; Cannabinoid Receptor Agonists; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Severity of Illness Index

In individuals with multiple sclerosis (MS) spasticity, associated symptoms such as spasms, pain, mobility restrictions and sleep disturbances can interfere with the ability to perform activities of daily living and reduce quality of life (QoL). Recent cross-sectional studies from Europe have confirmed that advancing severity of MS spasticity correlates directly with worsening QoL. The treatment effect of Sativex(®) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) on QoL has been evaluated in randomized controlled trials, observational studies conducted under everyday clinical practice conditions and a survey in long-term users. Symptomatic relief of MS spasticity in responders to Sativex was associated with quantifiable improvements in QoL and activities of daily living that were maintained over time. Benefits were perceived by both patients and caregivers.

Topics: Activities of Daily Living; Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Outcome Assessment, Health Care; Plant Extracts; Quality of Life

Refractory spasticity, central neuropathic pain and bladder dysfunction are common clinical problems in patients with multiple sclerosis (MS). None of the currently available oral medications has proven to be reliably effective and can be limited by toxicity. Cannabinoids have shown therapeutic effects on those MS-associated symptoms. Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) Sativex (nabiximols) is an oromucosal spray formulation that contains THC and CBD in an approximate 1:1 ratio and is described as an endocannabinoid system modulator. The efficacy of THC/CBD on MS-associated spasticity, pain and bladder dysfunction has been studied in clinical trials as well as in clinical practice studies. Adverse effects are usually mild or moderate and the low rate of drug discontinuation provides good evidence of long-term tolerability. This article focuses on the pharmacological properties, clinical efficacy and tolerability of THC/CBD in MS patients.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Neuralgia; Plant Extracts

Spasticity is one of the main symptoms associated with multiple sclerosis (MS). Epidemiological studies indicate that approximately two-thirds of MS patients experience spasticity and, in a relevant proportion of this group, spasticity is moderate to severe. Yet, spasticity remains largely undertreated. The most commonly used oral antispasticity agents (e.g., baclofen, tizanidine, gabapentin) generally do not reduce spasticity adequately at dosages that are well tolerated by patients. This review of MS spasticity cases from around Europe presents current knowledge of considerations for administration of a new agent (tetrahydrocannabinol/cannabidiol-based nabiximols [Sativex®] oromucosal spray) for management of MS spasticity, with the aim of ensuring appropriate and optimal use for best outcomes. Assessment of the European clinical experience is intended to provide a better understanding of the prescribing regulations for MS spasticity treatments, facilitate identification of suitable candidate patients for Sativex and increase awareness of alternative management approaches for MS-related spasticity.

Topics: Adult; Aged; Cannabidiol; Dronabinol; Drug Combinations; Europe; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Treatment Outcome

Sativex® (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain), a cannabinoid oromucosal spray containing a 1:1 ratio of 9-δ-tetrahydrocannabinol and cannabidiol, has been licensed in Germany since July 2011 as add-on therapy for moderate-to-severe multiple sclerosis (MS) treatment-resistant spasticity symptoms. The 'MOVE 2' study evaluated clinical outcomes, treatment satisfaction, quality of life (QoL) and provision of care in MS patients with spasticity receiving Sativex in everyday clinical practice. Data from 300 patients were collected from 42 specialized MS centers across Germany and were available for this analysis. Assessments, including the MS spasticity 0-10 numerical rating scale, modified Ashworth scale, patients' and physicians' clinical impressions, and QoL scales were rated at baseline and at 1 and 3 months after starting treatment with Sativex. Sativex provided relief of MS-related spasticity in the majority of patients who were previously resistant to treatment. In addition, clear improvements were noted in MS spasticity-associated symptoms (e.g., sleep quality, bladder function and mobility), activities of daily living and QoL. Sativex was generally well tolerated. The majority of patients (84%) reported no adverse events, and there was only a limited risk of serious adverse reactions. Furthermore, based on data from Sativex clinical trials, a Markov model-based analysis has shown that Sativex is a cost-effective treatment option for patients with MS spasticity in Germany.

Topics: Anti-Dyskinesia Agents; Attitude of Health Personnel; Attitude to Health; Cannabidiol; Cannabinoid Receptor Agonists; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Drug Costs; Drug Resistance; Germany; Health Care Costs; Humans; Multiple Sclerosis; Muscle Spasticity; Physicians; Plant Extracts; Quality of Life

Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest. Sativex® (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression. Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events. Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.

Topics: Anti-Dyskinesia Agents; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Clinical Trials, Phase III as Topic; Cost of Illness; Dronabinol; Drug Combinations; Drug Resistance; Drugs, Investigational; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Practice Patterns, Physicians'; Quality of Life; Randomized Controlled Trials as Topic; Spain; United Kingdom

Biological activity of cannabinoids is caused by binding to two cannabinoid receptors CB1 and CB2. Psychoactive is not only tetrahydrocannabinol (THC) but also: cannabidiol, cannabigerol or cannabichromen. Formerly, the usefulness of hemp was assessed in the relation to temporary appeasement of the symptoms of some ailments as nausea or vomiting. Present discoveries indicates that cannabis-based drugs has shown ability to alleviate of autoimmunological disorders such as: Multiple sclerosis (MS), Rheumatoid arthritis (RA) or inflammatory bowel disease. Another studies indicates that cannabinoids play role in treatment of neurological disorders like Alzheimer disease or Amyotrophic lateral sclerosis (ALS) or even can reduce spreading of tumor cells. Cannabinoids stand out high safety profile considering acute toxicity, it is low possibility of deadly overdosing and side-effects are comprise in range of tolerated side-effects of other medications. In some countries marinol and nabilone are used as anti vomiting and nausea drug. First cannabis-based drug containg naturally occurring cannabinoids is Sativex. Sativex is delivered in an mucosal spray for patients suffering from spasticity in MS, pain relevant with cancer and neuropathic pain of various origin. Despite the relatively low acute toxicity of cannabinoids they should be avoid in patients with psychotic disorders, pregnant or breastfeeding woman. Cannabinoids prolong a time of reaction and decrease power of concentration that's why driving any vehicles is forbidden. Cannabis side-effects varies and depend from several factors like administrated dose, rout of administration and present state of mind. After sudden break from long-lasting use, withdrawal symptoms can appear, although they entirely disappear after a week or two.

Topics: Arthritis, Rheumatoid; Cannabidiol; Cannabinoids; Cannabis; Contraindications; Dronabinol; Drug Combinations; Humans; Inflammatory Bowel Diseases; Multiple Sclerosis; Muscle Spasticity; Nausea; Nervous System Diseases; Pain; Plant Extracts; Vomiting

Multiple sclerosis (MS) is associated with a wide range of disease symptoms and amongst these, spasticity is one of the most disabling and has the greatest impact on patient well-being and quality of life. Until now, available drug therapies for spasticity appear to have limited benefit and are often associated with poor tolerability. In a recent Spanish survey it was noted that multidrug therapy and a low control rate were common features for a large proportion of patients with MS-related spasticity, suggesting that currently available monotherapies lack significant activity. Sativex is a 1:1 mixture of δ-9-tetrahydrocannabinol and cannabidiol derived from Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with MS-related spasticity is steadily accumulating. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status. These are highly encouraging findings that provide some much needed optimism for the treatment of this disabling and often painful symptom of MS.

Topics: Cannabidiol; Cannabinoids; Clinical Trials as Topic; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Quality of Life; Spain

The adoption of new drug therapies involves an assessment of risk:benefit based upon the best clinical evidence, including clinical trials but also everyday clinical practice data collection. However, in the case of Sativex, a cannabinoid medicine containing the two main active ingredients of cannabis, δ-9-tetrahydrocannabinol and cannabidiol, the picture is somewhat clouded by preconceived views regarding the world's most widely used illicit drug, herbal cannabis. In this review, I aim to look beyond these preconceptions and evaluate the body of published data concerning this medicine currently approved in different countries for the management of one of the most frequent and disabling symptoms associated with multiple sclerosis, spasticity. In particular, data relevant to areas of concern such as tolerability, safety, psychoactivity, effects on withdrawal (including possible drug tolerance) and finally the potential for abuse/dependence are evaluated. Balancing these risk factors, the main positive clinical data published over the years by the Oxford Centre for Enablement, following on from the first pilot study in 2004, are presented. Based upon our experience, the benefits that are seen initially with Sativex when treating multiple sclerosis spasticity patients are generally maintained during long-term treatment. Furthermore, following withdrawal of Sativex, symptoms often return, but, beyond this, sudden cessation is generally safe with no evidence of physiological or psychological dependence. Dose escalation has not usually been observed in clinical trials or clinical practice after the first titration weeks. Adverse effects occur relatively frequently, but they are usually mild to moderate in intensity and rarely require drug discontinuation. Overall, Sativex appears to be well-tolerated and a useful addition for patients who have failed treatment with traditional antispastic agents.

Topics: Cannabidiol; Clinical Trials as Topic; Dronabinol; Drug Combinations; Drug Tolerance; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Psychotropic Drugs

Over the last two decades, experimental and clinical data suggest a therapeutic benefit of cannabis-based medicines for a variety of multiple sclerosis (MS) symptoms. Clinical trials, both with synthetic or plant-derived cannabinoids, have demonstrated clinical efficacy of cannabinoids for the treatment of spasticity, neuropathic pain and bladder dysfunction. Nabiximols, a 1:1 mix of delta-9-tetrahydrocanabinol and cannabidiol extract from cloned chemovars, was licensed in the UK in 2010 and has also been approved in other European countries and Canada. The European Federation of Neurological Societies recommends that cannabis should be used only as a second or third line treatment in central neuropathic pain.. After a brief discussion of the endocannabinoid system, this review focuses on the use of cannabis to improve MS symptoms. More specifically, the authors have analyzed clinical studies on cannabis-based medicine extract (CBME), in particular nabiximols, in spasticity, as well as pain, and bladder dysfunction in MS. The authors have considered the large randomized controlled trials examining the psychological effects associated with cannabinoids use as well as long-term follow-up studies.. Despite a number of trials with very promising results, there are still concerns related to relative paucity of data on long-term safety. Also, the long-term efficacy information in terms of the control of symptoms of a disease in which the natural history is progression is sparse. Therefore, further studies are required to improve the current knowledge of nabiximols.

Topics: Analgesics; Animals; Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Treatment Outcome; Urologic Diseases

Spasticity remains a prevalent symptom in multiple sclerosis, with a significant associated disability and quality of life impairment. A significant improvement in therapy aimed at reducing multiple sclerosis relapses and modifying its course has been achieved in recent years. Both general and specific traditional treatments have, however, major limitations. Thus, its use in real practice is lower than expected. Cannabinoids provide a new way for therapy. A delta-9-tetrahydrocannabinol plus cannabidiol (1:1) association, administered through an oromucosal route, has been approved in several countries including Spain; it causes a specific effect on CB(1) and CB(2) receptors, with traditional psychotropic cannabis actions being minimized. Randomized, placebo-controlled trials, as well as longer-term open-label extensions, have shown a clear-cut efficacy to reduce spasticity and their associated symptoms in those patients refractory to other therapies, with a good tolerability/safety profile. No tolerance, abuse or addictive issues have been found. New studies will be needed to find out potential new cannabinoid-related therapies.

Topics: Administration, Sublingual; Cannabidiol; Clinical Trials, Phase III as Topic; Double-Blind Method; Dronabinol; Drug Combinations; Humans; Legislation, Drug; Multicenter Studies as Topic; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts; Powders; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Retrospective Studies; Spain; Treatment Outcome

Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex®) in people with muscle spasticity due to multiple sclerosis.. All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from baseline in patient self-reported spasticity severity, and the various possible explanatory factors were regarded as fixed factors in the model.. There was no significant relationship between the effect of Sativex® on spasticity and the prior use of cannabis or the incidence of 'typical' adverse events. Nor was there any significant relationship between the prior use of cannabis and the incidence of 'typical' adverse events, nor between prior use of cannabis and dose of Sativex®.. There is no evidence to suggest that there was widespread unblinding to treatment allocation in these three studies. If any patients did become unblinded, then there is no evidence that this led to bias in the assessment of the treatment difference between Sativex® and Placebo for efficacy, adverse events or study drug dosing. This methodology may be suitable for assessment of the integrity of the blind in other randomized clinical trials.

Topics: Bias; Cannabidiol; Clinical Trials, Phase III as Topic; Double-Blind Method; Dronabinol; Drug Combinations; Humans; Linear Models; Marijuana Smoking; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Plant Extracts; Randomized Controlled Trials as Topic; Research Design; Self Report; Severity of Illness Index; Treatment Outcome

Multiple sclerosis (MS) is a neurological condition that is estimated to affect around 60,000 people in England and Wales, with a lifetime risk in the UK of 1 in 1,000.(1,2) Spasticity (an increase in muscle tone) is a common symptom of MS, resulting in muscle spasms, immobility, disturbed sleep and pain.(3,4) Complex drug combinations are sometimes necessary to manage symptoms of MS, but these are often only partially effective and associated with unacceptable side effects.(5) Cannabis extract containing delta9-tetrahydrocannabinol (dronabinol) and cannabidiol are the principal extracts from the cannabis plant present in a licensed preparation (▾Sativex - GW Pharma Ltd), the first cannabinoid preparation to be approved for medical use. Sativex has been licensed "for symptom improvement in adult patients with moderate to severe spasticity due to MS who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy".(6) Here we review the evidence for cannabis extract and its place in the treatment of the condition.

Topics: Adult; Cannabidiol; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Drug Costs; Drug Interactions; Humans; Meta-Analysis as Topic; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Spasticity is one of the most common and disabling symptoms associated with multiple sclerosis (MS). MS spasticity occurs through both myelin and nerve fiber (axonal) degradation, which commence in the early stages of the disease. More than 80% of MS patients experienced spasticity in a large UK survey, with more than 50% of patients reporting their spasticity to be `moderate' or `severe'. Data from a large US registry show that patients with moderate-to-severe MS spasticity experience levels of disability that correlate closely with being wheelchair-bound and/or bedridden. The Ashworth scale is the most commonly used scale for assessing the degree of MS spasticity. However, the validity, reliability and sensitivity of this scale have been challenged and it is not considered an ideal scale for assessing the severity of MS spasticity. The numerical rating scale, a well-established standard pain assessment tool, provides a reliable, valid and simplified scale for patient self-rated assessment of the mean level of spasticity over the previous 24 h (0 = no spasticity, 10 = worst possible spasticity). According to data from the German MS Register, almost a third of MS patients with spasticity were untreated. Despite the availability of oral agents for generalized spasticity (often used in conjunction with physical/rehabilitation management strategies), including baclofen, tizanidine, dantrolene and gabapentin, there is limited clinical evidence to support their use and there is a need for improved and better tolerated pharmacological therapies for MS spasticity. The endocannabinoid system modulator, Sativex(®) (nabiximols, USAN name), provides an alternative therapeutic approach in the management of MS spasticity.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Reproducibility of Results; Self Report; Severity of Illness Index

Endocannabinoids are endogenous agonists of the mammalian cannabinoid receptors CB(1) and CB(2), and they appear to be produced in tissues as an adaptive reaction to re-establish normal homeostasis when this is acutely altered. However, the production of endocannabinoids can be altered pathologically. The two most widely studied endocannabinoids are anandamide and 2-arachidonoyl glycerol. The levels of these endogenous modulators are regulated in different and sometimes opposing ways, and alterations in cerebrospinal fluid and/or spinal cord levels have been documented in animal models of neurodegenerative diseases and in samples from patients with multiple sclerosis (MS). Modulation of the endocannabinoid system has been shown to have therapeutic potential in a number of disease states. Sativex(®) (nabiximols, USAN name) contains the two main phytocannabinoids from Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 ratio, and it acts as an endocannabinoid system modulator. In an experimental mouse model of MS-related spasticity, Sativex dose-dependently improved hind limb flexion/stiffness and a dosage of 10 mg/kg was shown to be as effective as the most widely established anti-spasticity treatment baclofen (5 mg/kg). These findings with Sativex are very promising and offer encouragement for MS patients, the majority of whom will develop spasticity-related disabling and recalcitrant symptoms. Furthermore, research into the endocannabinoid system may offer potential in other neurodegenerative, inflammatory and pain disorders.

Topics: Animals; Cannabidiol; Disease Models, Animal; Dronabinol; Drug Combinations; Endocannabinoids; Mice; Multiple Sclerosis; Muscle Spasticity; Muscle, Skeletal; Plant Extracts

Sativex(®) (nabiximols, USAN name) oromucosal spray contains the two main active constituents of Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 molecular ratio, and acts as an endocannabinoid system modulator. Randomized, controlled clinical trials of Sativex as add-on therapy provide conclusive evidence of its efficacy in the treatment of more than 1500 patients with multiple sclerosis (MS)-related resistant spasticity. The primary end point in clinical trials was the mean change from baseline in the 0-10 numerical rating scale (NRS) spasticity score. The first pivotal clinical trial included 189 patients treated for 6 weeks with Sativex (n = 124) or placebo (n = 65). At study end, there was a significant reduction from baseline in patient-recorded NRS spasticity scores with Sativex compared with placebo (-1.18 vs -0.63; p = 0.048). In the second pivotal trial, 337 patients with MS-related resistant spasticity received Sativex (n = 167) or placebo (n = 170) over a 15-week period. In the per-protocol analysis (79% of the patient population), mean baseline NRS spasticity score was reduced significantly in patients receiving Sativex compared with placebo: -1.3 versus -0.8 points (p = 0.035). The third pivotal clinical trial, evaluating the sustained efficacy of Sativex, had a two-phase study design: in phase A (n = 572), 47% of patients were initial responders (improvement ≥ 20%) after 4 weeks of single-blind Sativex treatment who then entered phase B, a randomized, double-blind, 12-week placebo comparison. At the end of phase B, the change in NRS spasticity score improved by a further 0.04 units in initial responders treated with Sativex, but decreased by 0.81 units in placebo recipients (p = 0.0002). Significant improvements in quality-of-life measures from baseline to week 16 were also observed in patients receiving Sativex. The most common treatment-related adverse events with Sativex were mild-to moderate and transient episodes of dizziness, fatigue or somnolence. Sativex does not exhibit the side effects typically associated with recreational cannabis use and there are no signs of drug tolerance or withdrawal syndrome, or any evidence of drug misuse or abuse. Sativex oromucosal spray appears to be a useful and welcomed option for the management of resistant spasticity in MS patients. Although the management of MS has been improved by the availability of disease-modifying agents that target the underlying pathophysiological processes of

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Endocannabinoids; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Quality of Life; Treatment Outcome

People with multiple sclerosis may present with a wide range of disease symptoms during the evolution of the disease; among these, spasticity can have a marked impact on their well-being and quality of life. Symptom control, including spasticity, remains a key management strategy to improve the patient's well-being and functional status. However, available drug therapies for spasticity sometimes have limited benefit and they are often associated with poor tolerability. Sativex is a 1:1 mix of 9-delta-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with multiple sclerosis is accumulating steadily. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status when Sativex was added to the current treatment regimen. Adverse events such as dizziness, diarrhea, fatigue, nausea, headache and somnolence occur quite frequently with Sativex, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual 'uptitration'. In summary, initial well-controlled studies with Sativex oromucosal spray administered as an add-on to usual therapy have produced promising results and highlight encouraging avenues for future research.

Topics: Administration, Mucosal; Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Phytotherapy; Plant Extracts; Randomized Controlled Trials as Topic

To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis.. The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis.. 666 patients with multiple sclerosis and spasticity.. A 0-100 mm Visual Analogue Scale (VAS, transformed to a 0-10 scale) or a 0-10 Numerical Rating Scale (0-10 NRS) was used to measure spasticity. Patients achieving a > or =30% improvement from baseline in their spasticity score were defined as 'responders'. Global impression of change (GIC) at the end of treatment was also recorded.. The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was -1.30 compared with -0.97 for placebo. Using a linear model, the treatment difference was -0.32 (95% CI -0.61, -0.04, p = 0.026). A statistically significant greater proportion of treated patients were responders (odds ratio (OR) = 1.62, 95% CI 1.15, 2.28; p = 0.0073) and treated patients also reported greater improvement: odds ratio 1.67 (95% CI 1.05, 2.65; p = 0.030). High numbers of subjects experienced at least one adverse event, but most were mild to moderate in severity and all drug-related serious adverse events resolved.. The meta-analysis demonstrates that nabiximols is well tolerated and reduces spasticity.

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Pain Measurement; Plant Extracts; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Sativex is one of the first cannabis-based medicines to undergo conventional clinical development and to be approved as a prescription medicine. It is an oromucosal spray that allows flexible, individualised dosing. Patients self titrate their overall dose and pattern of dosing according to their response to and tolerance of the medicine. This usually results in the administration of approximately 8-12 sprays/day. Each spray delivers tetrahydrocannabinol 2.7 mg and cannabidiol 2.5 mg, giving an approximate average dose of tetrahydrocannabinol 22-32 mg/day and cannabidiol 20-30 mg/day. Development has concentrated on the treatment of symptoms of multiple sclerosis, notably spasticity and neuropathic pain, as well as the treatment of neuropathic pain of other aetiologies. Positive results in placebo-controlled trials of the use of Sativex as an add-on therapy in these indications demonstrate that Sativex is efficacious and well tolerated in the treatment of these symptoms. Sativex has been approved for use in neuropathic pain due to multiple sclerosis in Canada. If ongoing studies replicate the results already observed, further approvals for the treatment of spasticity in multiple sclerosis and for neuropathic pain are likely.

Topics: Analgesics; Cannabidiol; Cannabinoids; Dronabinol; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Phytotherapy; Plant Extracts; Randomized Controlled Trials as Topic; Self Administration; Sleep Wake Disorders

Nabiximols represents an increasingly employed add-on treatment option for spasticity in people with multiple sclerosis (PwMS) who either were unresponsive or reported excessive adverse reactions to other therapies. While several studies performed in the last decade demonstrated its effectiveness, safety, and tolerability, few quantitative data are available on the impact on motor dysfunctions. In this open-label, not concurrently controlled study, we aimed to assess the impact of a 4-week treatment with nabiximols on upper limb functionality.. Thirteen PwMS (9 female, 4 male) with moderate-severe spasticity underwent a combination of clinical tests (i.e., Box and Block, BBT and Nine-Hole Peg test, 9HPT) and instrumental kinematic analysis of the "hand to mouth" (HTM) movement by means of optical motion capture system.. After the treatment, improvements in gross and fine dexterity were found (BBT + 3 blocks/min, 9HPT - 2.9 s, p < 0.05 for both cases). The kinematic analysis indicated that HTM movement was faster (1.69 vs. 1.83 s, p = 0.05), smoother, and more stable. A significant reduction of the severity of spasticity, as indicated by the 0-10 numerical rating scale (4.2 vs. 6.3, p < 0.001), was also observed.. The findings from the present pilot study suggest that a 4-week treatment with nabiximols ameliorates the spasticity symptoms and the overall motor function of upper limb in PwMS with moderate-severe spasticity. The use of quantitative techniques for human movement analysis may provide valuable information about changes originated by the treatment in realistic upper limb motor tasks involved in activities of daily living.

Topics: Activities of Daily Living; Biomechanical Phenomena; Female; Humans; Male; Multiple Sclerosis; Muscle Spasticity; Pilot Projects; Upper Extremity

To provide a comprehensive assessment of the treatment effects of nabiximols oromucosal spray on multiple sclerosis spasticity in two clinical trials, GWSP0604 and SAVANT.. Both studies enriched for responders before randomization, defined by a ≥20% improvement in Spasticity 0-10 numeric rating scale (NRS) score. Additionally, SAVANT used randomized re-titration following washout. Spasticity NRS outcomes, spasm count, and modified Ashworth scale (MAS) scores were analyzed.. Mean change from baseline in average daily Spasticity NRS scores was significantly larger for nabiximols than placebo at all postbaseline timepoints, ranging from -0.36 to -0.89 in GWSP0604 and -0.52 to -1.96 in SAVANT. Percent reduction in geometric mean change from baseline in average daily spasm count for nabiximols ranged from 19-35% versus placebo. A treatment difference favoring nabiximols was observed in overall MAS scores during the randomized part of each study. Treatment effect was larger for combinations of lower limb muscle groups (ranging between -0.16 and -0.37).. Nabiximols leads to improvement in spasticity that was sustained over the 12-week treatment period as measured by average daily Spasticity NRS scores, daily spasm counts, and MAS scores for combinations of muscle groups, especially the combination of the 6 key muscle groups in the lower limbs in NRS responders to nabiximols treatment.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Muscle Tonus; Randomized Controlled Trials as Topic; Spasm

Spasticity in people with Multiple Sclerosis (pwMS) is one of the most disabling symptoms on walking ability and balance. Among the systemic antispastic drugs, Nabiximols showed a good tolerability, safety profile and relevant efficacy. A few studies assessed long-term effects of this drug through clinical scales and instrumental tools, but no study investigated short-term effects. The aim of our study is to quantitatively evaluate the immediate effects of Nabiximols on walking and balance and their maintenance after 4 weeks in pwMS and spasticity.. pwMS were enrolled and randomized in 2 treatment groups: Sativex (SG) and control (CG) group. All patients were assessed at T0 (before the first Sativex puff), T1(after 45 minutes) and T2 (after 4 weeks of treatment) using clinical scales and 3d-Gait Analysis . Then, the patients treated with Sativex, were divided into 5 subgroups according to Numeric Rating Scale for spasticity (NRSs) and Berg Balance Score (BBS) response: NRSs responder[1] and non-[2]; BBS responders[3] and non-[4]; NRSs-BBS responders[5].. 32 pwMS (22 SG, 10 CG) were recruited. Significant improvements were found between T0 and T1 in SG compared to CG in a few clinical and kinematic parameters. Larger significant differences were found for NRSs and BBS responders' groups versus CG. Eventually, no significant differences were found comparing the results between T1 and T2, suggesting the persistence of the improvements emerged at T1.. These results quantitatively demonstrated a short time effect of Nabiximols on balance and walking of pwMS, which is mantained after 4 weeks. Patients identified as responder by combination of NRSs and BBS showed the best efficacy. These findings may suggest how to early select the real responders in order to improve the adherence and cost-effectiveness of the therapy.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Gait Analysis; Humans; Multiple Sclerosis; Muscle Spasticity; Walking

Topics: Adult; Analgesics; Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Myalgia; Oral Sprays; Outcome Assessment, Health Care; Severity of Illness Index

To assess the efficacy, safety, and tolerability of oromucosal nabiximols cannabinoid medicine as adjunct therapy for children with spasticity due to cerebral palsy/traumatic central nervous system injury with inadequate response to existing treatment.. Overall, 72 patients (mean [SD] age 12y 4mo [3y 1mo], range 8-18y) were randomized at a ratio of 2:1 to receive nabiximols (n=47; 29 males, 18 females) or placebo (n=25; 15 males, 10 females) for 12 weeks (12 sprays/day max. based on clinical response/tolerability). The primary outcome was change from baseline in level of spasticity on a 0 to 10 Numerical Rating Scale (NRS), assessed by the primary caregiver at 12 weeks. Secondary outcomes included additional measures for spasticity, sleep quality, pain, health-related quality of life, comfort, depression, and safety.. There was no significant difference in the spasticity 0 to 10 NRS between nabiximols versus placebo groups after 12 weeks. No statistically significant differences were observed for any secondary endpoint. Adverse events were predominantly mild or moderate in severity; however, three cases of hallucinations were reported.. Nabiximols was generally well tolerated; however, neuropsychiatric adverse events were observed. No significant reduction in spasticity with nabiximols treatment versus placebo was observed.. Oromucosal nabiximols is generally well tolerated by paediatric patients. However, three cases of hallucinations were observed, one of which involved auditory hallucinations and a suicide attempt. Oromucosal nabiximols versus placebo did not reduce cerebral palsy/central nervous system injury-related spasticity.. Evaluar la eficacia, seguridad y tolerabilidad del cannabinoides nabiximol de aplicación en spray bucal como terapia complementaria para niños con espasticidad debido a parálisis cerebral o lesión traumática del sistema nervioso central que no responden al tratamiento convencional. MÉTODO: En total, 72 pacientes (media [DE] edad 12 años 4 meses [3 años 1 mes], rango 8-18 años) fueron aleatorizados en una proporción de 2: 1 para recibir nabiximol spray (n = 47; 29 masculinos, 18 femeninos) o placebo (n = 25; 15 masculinos, 10 femeninos) durante 12 semanas (12 aplicaciones de spray / día máx basados en la respuesta clínica / tolerabilidad). El resultado primario fue el cambio en el nivel basal de espasticidad en una Escala de Calificación Numérica (NRS) de 0 a 10, evaluada por el cuidador primario a las 12 semanas. Los resultados secundarios incluyeron medidas adicionales para la espasticidad, la calidad del sueño, el dolor, la calidad de vida relacionada con la salud, el confort, la depresión y la seguridad.. No hubo diferencias significativas en la espasticidad de 0 a 10 NRS entre los grupos de que recibieron nabiximol versus el grupo placebo después de 12 semanas. No se observaron diferencias estadísticamente significativas para ningún criterio de valoración secundario. Los eventos adversos fueron predominantemente leves o moderados en severidad; sin embargo, se informaron tres casos de alucinaciones. INTERPRETACIÓN: El nabiximol fue generalmente bien tolerado; sin embargo, se observaron eventos adversos neuropsiquiátricos. No se observó una reducción significativa en la espasticidad con el tratamiento con nabiximoles versus placebo.. Avaliar a eficácia, segurança e tolerabilidade do medicamento oromucosal nabiximols canabinóide como terapia adjunta para crianças com espasticidade devida a paralisia cerebral/lesão traumática do sistema nervoso central com resposta inadequada a tratamentos existentes. MÉTODO: Em geral, 72 pacientes (média [DP] idade 12a 4m [3a 1m], variação 8-18a) foram randomizados em uma taxa de 2:1 para receber nabiximols (n=47; 29 sexo masculino, 18 sexo feminino) ou placebo (n=25; 15 sexo masculino, 10 sexo feminino) por 12 semanas (12 sprays/dia máx. com base na resposta clínica/tolerabilidade). O resultado primário foi mudança com relação a linha de base no nível de espasticidade um uma Escala Numérica de Pontuação (ENP) de 0 a 10, avaliada pelo cuidador primário com 12 semanas. Resultados secundários incluíram medidas adicionais de espasticidade, qualidade do sono, dor, qualidade de vida relacionada à saúde, conforto, depressão, e segurança.. Não houve diferença significativa na espasticidade Segundo a ENP 0 a 10 entre os grupos nabiximols versus placebo após 12 semanas. Nenhuma diferença estatisticamente significativa foi observada para nenhum desfecho secundário. Eventos adversos foram predominantemente leves ou moderados em severidade; no entanto, três casos de alucinações foram reportados. INTERPRETAÇÃO: Nabiximols foi em geral bem tolerado; no entanto eventos adversos neuropsiquiátricos foram observados. Nenhuma redução significativa na espasticidade com o tratamento com nabiximols versus placebo foi observada.

Topics: Administration, Oral; Adolescent; Brain Injuries, Traumatic; Cannabidiol; Cerebral Palsy; Child; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Muscle Spasticity; Treatment Outcome

To investigate the action of cannabinoids on spasticity and pain in secondary progressive multiple sclerosis, by means of neurophysiological indexes.. We assessed 15 patients with progressive MS (11 females) using clinical scales for spasticity and pain, as well as neurophysiological variables (H/M ratio, cutaneous silent period or CSP). Testing occurred before (T0) and during (T1) a standard treatment with an oral spray containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Neurophysiological measures at T0 were compared with those of 14 healthy controls of similar age and sex (HC). We then compared the patient results at the two time points (T1 vs T0).. At T0, neurophysiological variables did not differ significantly between patients and controls. At T1, spasticity and pain scores improved, as detected by the Modified Ashworth Scale or MAS (P = .001), 9-Hole Peg Test or 9HPT (P = .018), numeric rating scale for spasticity or NRS (P = .001), and visual analogue scale for pain or VAS (P = .005). At the same time, the CSP was significantly prolonged (P = .001).. The THC-CBD spray improved spasticity and pain in secondary progressive MS patients. The spray prolonged CSP duration, which appears a promising tool for assessing and monitoring the analgesic effects of THC-CBD in MS.

Topics: Administration, Oral; Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Muscle Spasticity; Muscle, Skeletal; Pain; Pilot Projects; Treatment Outcome

Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex. Sativex. Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on THC:CBD spray (n = 53) or placebo (n = 53). The proportion of clinically relevant responders after 12 weeks (≥30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD spray than placebo (77.4 vs. 32.1%; p < 0.0001). Compared with placebo, THC:CBD spray also significantly improved key secondary endpoints: changes in mean spasticity NRS (p < 0.0001), mean pain NRS (p = 0.0013), and mean modified Ashworth's scale (p = 0.0007) scores from Phase B baseline to week 12. Adverse events, when present, were mild/moderate and without new safety concerns.. Add-on THC:CBD oromucosal spray provided better and clinically relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone.

Topics: Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Prospective Studies; Treatment Outcome

Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease.. We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18-80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 μL actuation contained 2·7 mg delta-9-tetrahydrocannabinol and 2·5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed.. Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0·11 (SD 0·48) in the nabiximols group and deteriorated by a mean of 0·16 (0·47) in the placebo group (adjusted effect estimate -0·32 [95% CI -0·57 to -0·069]; p=0·013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred.. In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials.. Italian Research Foundation for Amyotrophic Lateral Sclerosis.

Topics: Adult; Aged; Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Motor Neuron Disease; Muscle Spasticity; Quality of Life; Treatment Outcome

Patients with multiple sclerosis spasticity (n = 52) at six sites in Italy who were receiving THC:CBD oromucosal spray and had associated oral mucosal effects were randomized into Group A (chewing gum; n = 15); Group B (cold bottle; n = 20); and Group C (cold bottle + chewing gum; n = 17).. Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control.. Patient comfort, satisfaction and treatment adherence may benefit from these interventions.

Topics: Adult; Analgesics; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth; Multiple Sclerosis; Muscle Spasticity; Pilot Projects; Prospective Studies; Stomatitis; Taste; Taste Perception; Treatment Outcome

Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.. We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).. The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee 'Comitato Etico Regionale della Liguria'. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

Topics: Cannabidiol; Cross-Over Studies; Double-Blind Method; Dronabinol; Drug Combinations; Humans; Italy; Muscle Spasticity; Pilot Projects; Research Design; Stroke; Treatment Outcome

Currently, none of the available multiple sclerosis (MS) disease-modifying medications has been shown to stop or reverse gait disability. Recently, the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex) is an oromucosal spray formulation containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol and cannabidiol derived from cloned Cannabis sativa L. plant.. A single-center, prospective, parallel design, single-blind trial will be conducted at the IRCCS Neurolesi "Bonino-Pulejo" (Italy) involving MS patients affected by spasticity and undergoing a Robotic Rehabilitation training. The aim of the study is to clarify the role of Sativex coupled to a robotic neurehabilitation training in MS patients in improving motor outcomes, by means of clinical, kinematic, and neurophysiological measures. Patients will be randomly divided in 2 groups: one taking only an oral antispastic drug and the other with Sativex in add-on. After 1 month, we will evaluate the response to Sativex (responder patients' amelioration >20% at MRS score) enrolling into the study the first 20 patients with a good response to Sativex, whereas other 20 no-responder individuals will continue their antispastic drug. All the 40 subjects, were divided into 2 groups (A: Sativex + Lokomat Training, and B: other antispastic+Lokomat Training), will perform a neurorobotic-assisted gait training (each session will last at least 45 minutes, 3 times per week, for a total of 20 sessions). All the patients will undergo a complete physical and neurological examination at baseline, at the end of the robotic training (T1), and 30 days after the end of the neurorehabilitation training (T2).

Topics: Adolescent; Adult; Analgesics; Biomechanical Phenomena; Cannabidiol; Clinical Protocols; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neurological Rehabilitation; Oral Sprays; Robotics; Single-Blind Method; Treatment Outcome; Young Adult

Spasticity in multiple sclerosis (MS) results from an imbalance of inputs from descending pathways to the spinal motor circuits, as well as from a damage of the corticospinal tract (CST).. To assess CST impairment in MS patients with and without spasticity and to evaluate its evolution under Sativex. Ten MS patients with spasticity ("cases") underwent clinical (EDSS, 9-hole Peg, Ashworth scale, Timed 25-Foot Walk, and NRS for spasticity), MRI (CST fractional anisotropy [FA]), and electrophysiological (central motor conduction time [CMCT] and H/M ratio) evaluations at baseline and after 12 months. We selected 20 MS patients without spasticity as control group at baseline.. We confirm the presence of CST impairment in MS patients with spasticity. We did not identify structural/electrophysiological correlates that could explain Sativex

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Motor Neurons; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Pyramidal Tracts

Sativex® (THC:CBD oromucosal spray) is indicated as add-on treatment for patients with moderate to severe multiple sclerosis (MS) spasticity. We aimed to determine whether antispasticity treatment history influenced the efficacy and safety of add-on THC:CBD oromucosal spray in MS spasticity patients.. Post hoc analysis of an enriched-design clinical trial of THC:CBD oromucosal spray versus placebo, using records of patients under previous and current ineffective antispasticity therapies. Subgroups were patients with at least 1 failed therapy attempt with either baclofen or tizanidine (Group 1) or at least 2 failed therapy attempts with both baclofen and tizanidine (Group 2).. Of 241 patients in the intent-to-treat population, 162 and 57 patients met the criteria for Groups 1 and 2, respectively. In all groups, response on the spasticity 0-10 Numerical Rating Scale was significantly greater with THC:CBD oromucosal spray versus placebo, for minimal clinically important difference (MCID ≥18% improvement vs. baseline) and clinically important difference (CID, ≥30% improvement vs. baseline). THC:CBD oromucosal spray improved spasticity-related symptoms such as sleep quality and timed 10-meter walk independent of the number of prior failed therapy attempts. Tolerability was not influenced by pre-treatment history.. THC:CBD oromucosal spray provided consistent relief with good tolerability in MS spasticity patients irrespective of their antispasticity pre-treatment history.

Topics: Adult; Baclofen; Cannabidiol; Clonidine; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts

Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

Topics: Adult; Cannabidiol; Cerebral Cortex; Cross-Over Studies; Double-Blind Method; Dronabinol; Drug Combinations; Electric Stimulation; Electromyography; Evoked Potentials, Motor; Female; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Muscle Spasticity; Outcome Assessment, Health Care; Plant Extracts; Severity of Illness Index; Transcranial Magnetic Stimulation

Sativex is an endocannabinoid system modulator principally containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). During a 6-week randomised controlled trial, Sativex had a clinically relevant effect on spasticity associated with multiple sclerosis (MS). Patients self-titrated oromucosal Sativex to symptom relief or maximum tolerated dose (maximum of 130 mg THC and 120 mg CBD daily). The primary objective was to evaluate the safety and tolerability of long-term treatment by recording the incidence and severity of adverse events (AEs). Secondary outcomes were to determine evidence of developing tolerance and to assess the long-term dosing profile of Sativex. A validated 11-point Numerical Rating Scale of spasticity severity was used to assess efficacy. A total of 146 patients elected to enter this open-label follow-up safety trial. Mean treatment exposure was 334 days (standard deviation, SD = 209 days), and patients administered on average 7.3 (SD = 4.42) actuations per day. Fifty-two (36 %) patients withdrew from the study in the first year, 14 % due to AEs and 9 % due to lack of efficacy. Most AEs were mild/moderate in severity. Common (>10 %) treatment-related AEs were dizziness (24.7 %) and fatigue (12.3 %). Serious AEs occurred in five patients (3.4 %), with two psychiatric events reported by one patient. No psychoses, psychiatric AE trends, or withdrawal symptoms occurred following abrupt cessation of treatment. Baseline symptoms including spasticity did not deteriorate but were maintained to study completion in those patients who did not withdraw. No new safety concerns were identified with chronic Sativex treatment, and serious AEs were uncommon. There was no evidence of tolerance developing, and patients who remained in the study reported continued benefit.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Electrocardiography; Female; Humans; Longitudinal Studies; Male; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Pain Measurement; Phytotherapy; Plant Extracts; Sleep

Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical.. To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal.. An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects' previous effective and tolerated dose was continued.. A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject's Global Impression of Change scales in favour of Sativex.. Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.

Topics: Aged; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Muscle Spasticity; Placebos; Plant Extracts; Substance Withdrawal Syndrome

  Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design..   A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase..   Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols..   The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

Topics: Adult; Aged; Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients.. To compare Sativex with placebo in relieving symptoms of spasticity due to MS.. A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy.. The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (> or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved a > or =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity.. The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.

Topics: Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Mental Disorders; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Plant Extracts; Severity of Illness Index; Time Factors; Treatment Outcome

The endocannabinoid system (ECS) is involved in the pathophysiology of multiple sclerosis (MS), and relief from pain and spasticity has been reported in MS patients self-medicating with marijuana. A cannabis-based medication containing Delta(9)-tetrahydrocannabinol and cannabidiol (Sativex) has been approved in some countries for the treatment of MS-associated pain. The effects of this pharmaceutical preparation on other clinically relevant aspects of MS pathophysiology, however, are still unclear. In 20 MS patients, we measured the effects of Sativex on clinically measured spasticity and on neurophysiological and laboratory parameters that correlate with spasticity severity or with the modulation of the ECS. Sativex failed to affect spasticity and stretch reflex excitability. This compound also failed to affect the synthesis and the degradation of the endocannabinoid anandamide, as well as the expression of both CB1 and CB2 cannabinoid receptors in various subpopulations of peripheral lymphocytes.

Topics: Adult; Arachidonic Acids; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Endocannabinoids; Female; Humans; Lymphocytes; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Pain; Plant Extracts; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex, Stretch; Treatment Outcome; Young Adult

Randomized controlled trials and observational studies of nabiximols oromucosal spray in patients with multiple sclerosis (MS) spasticity have shown improvement in a range of associated symptoms (pain, spasms, fatigue, bladder dysfunction, and sleep disturbances). This study evaluated the effectiveness and tolerability of add-on nabiximols in the routine management of patients with MS spasticity in Austria, with a focus on spasticity-associated symptoms.. This was an open, prospective, multicenter, observational, non-interventional study of patients with MS spasticity receiving add-on treatment with nabiximols oromucosal spray. Main endpoints were patient-reported changes from baseline in the frequency (counts) or severity (mean Numerical Rating Scale [NRS] scores) of spasticity-associated symptoms, and patient-reported changes from baseline in impairment of daily activities due to spasticity, after 1 and 3 months of nabiximols treatment. No analyses were conducted for statistical significance.. There were 55 patients in the effectiveness population, and 62 in the safety population. Patients reported clinically relevant reductions from baseline to month 3 in the average number of spasms/day (-68.2%) and number of urinary incontinence episodes (-69.3%) in the week prior to the clinic visit, and reductions in mean 0-10 NRS scores for sleep impairment (-47.2%), fatigue (-26.4%), pain (40.4%), and spasticity severity (39.0%). There was no change from baseline in daily activity impairment due to spasticity. The majority of patients were at least partly satisfied with add-on nabiximols for spasticity-associated symptoms. There were 31 adverse events (27 treatment related) reported in 19 patients, with no new safety signals.. Add-on nabiximols improved the severity of MS spasticity and a range of spasticity-associated symptoms during real-world use in Austria. Nabiximols is an option for patients with MS spasticity who fail first-line oral antispasticity treatment.

Topics: Austria; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Prospective Studies; Spasm

Nabiximols (Sativex®) is a cannabinoid approved for multiple sclerosis (MS)-related spasticity. Its mechanism of action is partially understood, and efficacy is variable.. To conduct an exploratory analysis of brain networks connectivity changes on resting state (RS) functional MRI (fMRI) of MS patients treated with nabiximols.. We identified a group of MS patients treated with Sativex® at Verona University Hospital, who underwent RS brain fMRI in the 4 weeks before (T0) and 4-8 weeks after (T1) treatment start. Sativex® response was defined as ≥ 20% spasticity Numerical Rating Scale score reduction at T1 vs. T0. Connectivity changes on fMRI were compared between T0 and T1 in the whole group and according to response status. ROI-to-ROI and seed-to-voxel connectivity were evaluated.. Twelve MS patients (7 males) were eligible for the study. Seven patients (58.3%) resulted Sativex® responders at T1. On fMRI analysis, Sativex® exposure was associated with global brain connectivity increase (particularly in responders), decreased connectivity of motor areas, and bidirectional connectivity changes of the left cerebellum with a number of cortical areas.. Nabiximols administration is associated with brain connectivity increase of MS patients with spasticity. Modulation of sensorimotor cortical areas and cerebellum connectivity could play a role in nabiximols effect.

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Humans; Male; Multiple Sclerosis; Muscle Spasticity

Spasticity and urinary disturbances can profoundly impact the daily lives of persons with multiple sclerosis (pwMS). Cannabis has been associated with improvement in sphincteric disturbances. To our knowledge, few studies have evaluated the effect of nabiximols oromucosal spray (Sativex®) on urinary disturbances by instrumental methods.. This longitudinal study was conducted to assess the effect of nabiximols oromucosal spray on urinary disturbances by clinical and urodynamic evaluation in pwMS.. Neurological, spasticity, and quality of life (QoL) assessments were performed before (T0), and at one (T1) and six (T6) months after the start of nabiximols treatment. At these same time points, patients were assessed for urinary disturbances by the International Prostatic Symptoms Score (IPSS) and a urodynamic test evaluating maximum detrusor pressure (P. Our data suggest that nabiximols has an appreciable effect on ameliorating subjective perception of urinary disturbances and appears to have a positive effect on objective urodynamic parameters, particularly in patients with hyperactive bladder.

Topics: Humans; Longitudinal Studies; Multiple Sclerosis; Muscle Spasticity; Prospective Studies; Quality of Life; Urinary Bladder

Nabiximols is a therapeutic option for patients with multiple sclerosis (MS) spasticity whose symptoms are poorly controlled by conventional oral first-line medications. This study aimed to assess the relationship between changes in spasticity severity (measured on the 0-10 numeric rating scale [NRS]) and the presence of associated symptoms in patients treated with nabiximols, and to investigate the presence of the newly described 'spasticity-plus syndrome'.. We analyzed real-world data from the Italian Medicines Agency e-Registry on 1138 patients with MS spasticity who began treatment with nabiximols. Evaluation time points were baseline, 4 weeks, and 3, 6, 12 and 18 months after treatment start.. Common symptoms associated with MS spasticity in this cohort were pain (38.4% at baseline), sleep disturbances (32.7%), and spasms/cramps (28.5%). Pain was frequently clustered with sleep disturbances (57.2% of pain cases) and spasms/cramps (43.9%). Approximately one-third of patients with data at all evaluation time points maintained treatment at 18 months. Nabiximols reduced the baseline mean spasticity 0-10 NRS score by 24.6% at Week 4, and by 33.9% at 18 months in treatment continuers. Nabiximols resolved a range of MS spasticity-associated symptoms at Week 4, and after 18 months in treatment continuers.. This real-world analysis supports the concept of a spasticity-plus syndrome and suggests that nabiximols can favorably impact a range of spasticity-associated symptoms.

Topics: Cannabidiol; Central Nervous System Diseases; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Cramp; Muscle Spasticity; Pain; Spasm; Treatment Outcome

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

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Goals; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Pilot Projects; Plant Extracts; Proof of Concept Study; Prospective Studies; Quality of Life; Treatment Outcome

Spasticity is a common and disabling symptom in patients with multiple sclerosis (PwMS): as highlighted by many epidemiological studies, it is often a severe and not well treated. Despite the availability of evidence-based spasticity management guidelines, there is still great variability in everyday therapeutic approach, especially for the most complex cases.. In our single-centre study, we retrospectively evaluated PwMS-treated nabiximols and botulinum toxin injections (BTI) from July 2015 to April 2019. Clinical and demographic data were collected. The severity of spasticity and spasms was recorded by modified Ashworth Scale (mAS) and Penn Spasm Frequency Scale (PSFS) at baseline and after 1 month of treatment.. We evaluated 64 treatments for MS-related spasticity: 28 patients were treated with BTI and 36 patients with nabiximols. We found that both BTI and nabiximols are effective in reducing mAS (nabiximols, BTI: p < 0.001), PSFS frequency (nabiximols: p = 0.001, BTI: p = 0.008) and intensity (nabiximols: p = 0.001, BTI p = 0.016). No differences were found when directly comparing the efficacy of the two treatments, except for a statistical trend favouring BTI on spasms intensity (p = 0.091). Eleven patients were treated with both BTI and nabiximols, and only four patients continued both treatments. All dropouts were due to inefficacy of at least one of the two therapies.. Our single-centre experience highlights that both BTI and nabiximols are effective in treating multiple sclerosis-related spasticity; however, BTI treatment may be more effective on spasms intensity. Combined nabiximols and BTI treatment could represent a therapeutic option for severe spasticity.

Topics: Botulinum Toxins; Botulinum Toxins, Type A; Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Retrospective Studies; Spasm; Treatment Outcome

Uncertainty in model-based cost-utility analyses is commonly assessed in a probabilistic sensitivity analysis. Model parameters are implemented as distributions and values are sampled from these distributions in a Monte Carlo simulation. Bootstrapping is an alternative method that requires fewer assumptions and incorporates correlations between model parameters.. A Markov model-based cost-utility analysis comparing oromucosal spray containing delta-9-tetrahidrocannabinol + cannabidiol (Sativex®, nabiximols) plus standard care versus standard spasticity care alone in the management of multiple sclerosis spasticity was performed over a 5-year time horizon from the Belgian healthcare payer perspective. The probabilistic sensitivity analysis was implemented using a bootstrap approach to ensure that the correlations present in the source clinical trial data were incorporated in the uncertainty estimates.. Adding Sativex® spray to standard care was found to dominate standard spasticity care alone, with cost savings of €6,068 and a quality-adjusted life year gain of 0.145 per patient over the 5-year analysis. The probability of dominance increased from 29% in the first year to 94% in the fifth year, with the probability of QALY gains in excess of 99% for all years considered.. Adding Sativex® spray to spasticity care was found to dominate standard spasticity care alone in the Belgian healthcare setting. This study showed the use of bootstrapping techniques in a Markov model probabilistic sensitivity analysis instead of Monte Carlo simulations. Bootstrapping avoided the need to make distributional assumptions and allowed the incorporation of correlating structures present in the original clinical trial data in the uncertainty assessment.

Topics: Belgium; Cannabidiol; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Humans; Monte Carlo Method; Muscle Spasticity; Quality-Adjusted Life Years

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.. 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.. 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.. 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.

Topics: Belgium; Cannabidiol; Cannabinoids; Dronabinol; Drug Administration Schedule; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Patient Reported Outcome Measures; Plant Extracts; Quality of Life; Retrospective Studies; Severity of Illness Index

Nabiximols is an effective treatment for spasticity in MS. However, treatment discontinuation over-time might occur and predictors of sustained treatment persistence over long-term follow-up in real-world settings are highly needed. We aim at evaluating baseline predictors of treatment persistence on Nabiximols. This is a retrospective real-world study including MS patients treated with Nabiximols. At baseline (Nabiximols prescription), we evaluated disability using the EDSS, and cognitive function using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Nabiximols discontinuation was evaluated after 4 weeks of treatment ("titration phase''), and over the follow-up ("treatment phase"). We included 396 MS patients (228 females and 168 males). After 4 weeks (titration phase), 266 MS patients (67.2%) were considered persistent on treatment, while 130 patients dropped out. After 19 ± 21 months (treatment phase), 136 out of 266 MS patients (51.1%) were still on treatment, whereas 130 patients dropped at follow-up. Higher EDSS and cognitive impairment predicted treatment discontinuation at follow-up (p = 0.04 and p = 0.005, respectively). In conclusion, higher physical and cognitive disability predicted Nabiximols treatment discontinuation over 2 years in MS patients suffering from spasticity. Nabiximols should be started earlier to decrease the likelihood of treatment discontinuation over time.

Topics: Adult; Analgesics, Non-Narcotic; Cannabidiol; Cognitive Dysfunction; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Patient Compliance; Patient Dropouts; Retrospective Studies; Severity of Illness Index

Multiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients.. Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients.. A cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6 months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon.. Sativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1 month of treatment, 0.118 (0.073) after 3 months' treatment and 0.127 (0.080) after 6 months' treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve.. The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.

Topics: Adult; Cannabidiol; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Quality of Life; Quality-Adjusted Life Years

Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety.. An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS).. Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001).. These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility.

Topics: Adult; Aged; Cannabidiol; Cognition; Cognition Disorders; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neuropsychological Tests; Oral Sprays; Parasympatholytics; Pilot Projects; Prospective Studies; Single-Blind Method; Young Adult

Topics: Brain Injuries, Traumatic; Cannabidiol; Cannabinoids; Cerebral Palsy; Child; Dronabinol; Drug Combinations; Humans; Medicine; Muscle Spasticity; Safety

We performed a dual-task experiment to explore the effect of nabiximols on postural control in 22 patients with multiple sclerosis. They were assessed with static posturography and Stroop test in single- and dual-task conditions at treatment start and after 1, 3 and 12 months. At follow-up, we found more impaired postural control in single-task ( F = 3.07, p = 0.044) and dual-task ( F = 4.90, p = 0.005) conditions in patients who continued treatment (continuers, n = 11) compared with those who discontinued (quitters, n = 11). Continuers were more impaired at Stroop test only in dual-task condition ( F = 3.17, p = 0.038). Our findings suggest that nabiximols had a detrimental effect on postural control, especially in multi-tasking conditions.

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Executive Function; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Postural Balance; Psychomotor Performance; Stroop Test

Topics: Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Humans; Motor Neuron Disease; Muscle Spasticity

Proceedings of an Almirall-sponsored satellite symposium held at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Berlin, Germany, 10 October 2018.

Topics: Administration, Mucosal; Cannabidiol; Cannabinoid Receptor Modulators; Congresses as Topic; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Observational Studies as Topic; Oral Sprays; Randomized Controlled Trials as Topic; Societies, Medical

Subsequent to EMA approval of tetrahydrocannabinol (THC): cannabidiol (CBD) oromucosal spray based on results of various studies, including an enriched-design clinical trial, two newer postapproval randomized trials have confirmed its efficacy and safety for treating resistant multiple sclerosis spasticity, while simultaneously addressing specific authorities' concerns. A double-blind, placebo-controlled, Phase IV trial, conducted as part of the EMA's risk management plan, found no effect of THC:CBD spray on cognition and mood after 50 weeks of treatment. In the Sativex

Topics: Administration, Mucosal; Affect; Cannabidiol; Cannabinoid Receptor Modulators; Cognition; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Outcome and Process Assessment, Health Care; Randomized Controlled Trials as Topic

Postapproval studies have an essential role in demonstrating that an intervention is effective and well tolerated during use in daily clinical practice. Numerous large observational and registry studies of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray have been conducted subsequent to its approval in Europe in 2011. Collectively, these studies provide valuable insight into various aspects of THC:CBD spray during real-world use in patients with multiple sclerosis spasticity, including its long-term effectiveness and tolerability. The Italian Medicines Agency's web-based registry is the largest observational study of THC:CBD oromucosal spray conducted to date, reporting on more than 1600 patients prescribed THC:CBD spray since it was introduced in Italy in 2013, and further supporting its effectiveness and tolerability profile.

Topics: Administration, Mucosal; Cannabidiol; Cannabinoid Receptor Modulators; Dronabinol; Drug Approval; Drug Combinations; Humans; Italy; Multiple Sclerosis; Muscle Spasticity; Observational Studies as Topic; Oral Sprays; Pragmatic Clinical Trials as Topic; Registries

Nabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS).. To examine the impact of physiotherapy (PT) programs on effectiveness and persistence of nabiximols treatment in people with MS-related spasticity.. This is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0-10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment.. A total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3-5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23-0.69, p = 0.001).. Our real-life study confirms nabiximols' effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment.

Topics: Cannabidiol; Combined Modality Therapy; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Physical Therapy Modalities; Withholding Treatment

There is considerable public and political interest in the use of cannabis products for medical purposes.. The task force of the European Pain Federation (EFIC) conducted a survey with its national chapters representatives on the status of approval of all types of cannabis-based medicines, the covering of costs and the availability of a position paper of a national medical association on the use of medical cannabis for chronic pain and for symptom control in palliative/supportive care.. Thirty-one out of 37 contacted councillors responded. Plant-derived tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray is approved for spasticity in multiple sclerosis refractory to conventional treatment in 21 EFIC chapters. Plant-derived THC (dronabinol) is approved for some palliative care conditions in four EFIC chapters. Synthetic THC analogue (nabilone) is approved for chemotherapy-associated nausea and vomiting refractory to conventional treatment in four EFIC chapters'. Eight EFIC chapters' countries have an exceptional and six chapters an expanded access programme for medical cannabis. German and Israeli pain societies recommend the use of cannabis-based medicines as third-line drug therapies for chronic pain within a multicomponent approach. Conversely, the German medical association and a team of finish experts and officials do not recommend the prescription of medical cannabis due to the lack of high-quality evidence of efficacy and the potential harms.. There are marked differences between the countries represented in EFIC in the approval and availability of cannabis-based products for medical use. EFIC countries are encouraged to collaborate with the European Medicines Agency to publish a common document on cannabis-based medicines.. There are striking differences between European countries in the availability of plant-derived and synthetic cannabinoids and of medical cannabis for pain management and for symptom control in palliative care and in the covering of costs by health insurance companies or state social security systems.

Topics: Antiemetics; Antineoplastic Agents; Cannabidiol; Cannabinoid Receptor Agonists; Chronic Pain; Dronabinol; Drug Approval; Drug Combinations; Europe; Germany; Humans; Israel; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Nausea; Pain Management; Palliative Care; Societies, Medical; Surveys and Questionnaires; Vomiting

The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients.. We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis.. During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation.. These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.

Topics: Adult; Aged; Aged, 80 and over; Cannabidiol; Cost Sharing; Dronabinol; Drug Approval; Drug Combinations; Drug Costs; Drug Industry; Female; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Sclerosis; Multivariate Analysis; Muscle Spasticity; Parasympatholytics; Plant Extracts; Proportional Hazards Models; Registries; Regression Analysis; Severity of Illness Index; Young Adult

Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient's quality of life. Its treatment is complex and sometimes the outcome is insufficient. Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.. To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ®) as medication for use in special situations.. The research consists of a six-month observational study in patients with chronic spinal cord injuries with refractory spasticity. The variables collected were: modified Ashworth scale, Penn spasm frequency scale, Numeric Rating Scale, and Visual Analogue Scale for pain. Additionally, clinical variables and side effects of the treatment were also collected.. Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001). The use of the drug was withdrawn in two patients due to side effects.. Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.. Delta-9-tetrahidrocannabinol-cannabidiol en el tratamiento de la espasticidad en la lesion medular cronica: una experiencia clinica.. Introduccion. La espasticidad en la lesion medular cronica es una condicion que puede repercutir negativamente en la calidad de vida del paciente. Su tratamiento es complejo y, en ocasiones, el resultado es insuficiente. Recientemente, en la esclerosis multiple los cannabinoides se han empleado con exito en el tratamiento de la espasticidad refractaria a otras terapias. Objetivo. Cuantificar la respuesta clinica de un grupo de pacientes con lesion medular cronica espastica al farmaco delta-9-tetrahidrocannabinol-cannabidiol (Sativex ®), de administracion oral, como medicamento de uso en situaciones especiales. Pacientes y metodos. Estudio observacional durante seis meses en lesionados medulares cronicos con espasticidad refractaria. Las variables recogidas fueron: escala modificada de Ashworth, escala de frecuencia de espasmos de Penn, Numeric Rating Scale y escala visual analogica del dolor. De forma adicional se recogieron variables clinicas y efectos secundarios del tratamiento. Resultados. Quince pacientes tomaron parte en el estudio. Se observo mejoria significativa en tres de las escalas registradas: escala de Ashworth modificada (z = -2,97; p = 0,003), escala de frecuencia de espasmos de Penn (z = -2,76; p = 0,006) y Numeric Rating Scale (z = -3,21; p = 0,001). Se suspendio el uso del farmaco en dos pacientes por efectos secundarios. Conclusiones. Sativex se muestra como una alternativa en pacientes con espasticidad asociada a lesion medular cronica, en las que otras medidas terapeuticas resultan insuficientes. Son necesarios mas estudios para recomendar el uso de este farmaco y definir un perfil completo de sus efectos adversos a largo plazo.

Topics: Adult; Aged; Cannabidiol; Chronic Disease; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Muscle Spasticity; Spinal Cord Injuries; Treatment Outcome

Multiple sclerosis (MS) patients frequently suffer from limb spasticity and pain despite antispastic treatments. To investigate nabiximols efficacy and safety in a real-world monocentric Italian cohort, the following data were collected at baseline, week 4, 14 and 48: Ambulation Index (AI), 10-min walking test (10MWT), combined Modified Ashworth scale (cMAS), scores at numerical rating scale for spasticity (sNRS) and pain (pNRS). Responder status was defined as a ≥20 % reduction in sNRS after 4 weeks of treatment. 144 MS patients (123 progressive and 21 relapsing-remitting) complaining of moderate-to-severe spasticity (mean sNRS: 7.5) were included: 138 (95.8 %) completed the first month of therapy and were classified as follows-23.2 % were non-responders, 5.1 % were responders but discontinued treatment due to side effects, 71.7 % were responders with a mean 32 % reduction in sNRS (p < 0.001). In responders sNRS further decreased between 4 and 14 weeks (p = 0.03). Similarly, pNRS improvement was seen during the first month and between 4 and 14 weeks (p < 0.001 and p = 0.004, respectively). Moreover, at 4 weeks responders showed a significant (p < 0.05) improvement in cMAS, AI and 10MWT, which was maintained at 14 weeks. At 1-year follow-up, a benefit was still evident on spasticity and painful symptoms with a low drop-out rate. Confusion/ideomotor slowing, fatigue and dizziness were the most frequent side effects; no major adverse events were reported. Shorter disease duration at treatment start was associated with better response. This real-world study confirms nabiximols efficacy and safety in the treatment of MS-related spasticity and pain, which is maintained up to 48 weeks.

Topics: Adult; Cannabidiol; Cohort Studies; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Severity of Illness Index; Treatment Outcome

The prospective observational MObility ImproVEment (MOVE) 2 study is collecting real-life clinical outcomes data on patients with treatment-resistant multiple sclerosis (MS) spasticity treated with THC:CBD oromucosal spray in routine clinical practice. The MOVE 2 study has been ongoing in Italy, involving more than 30 MS centres across the country, since 2013.. Web-based real-time data collection techniques are combined with traditional patients' diaries to capture a wide spectrum of outcomes associated with this innovative cannabis-based medication. After surpassing the recruitment threshold of 300 patients, an interim analysis was performed to determine whether the data collected to date align with those from MOVE 2-Germany and the largest phase III randomized controlled trial (RCT) of THC:CBD oromucosal spray.. In the Italian cohort, THC:CBD oromucosal spray was added mainly to oral baclofen. Similar to MOVE 2-Germany, during 3 months' observation, treatment discontinuations were limited and patients recorded meaningful improvements on the patient-based 0-10 numerical rating scale and physician-rated modified Ashworth scale at mean daily doses that were about one-third lower than those used in the RCT. Also, similar to MOVE 2-Germany, the proportion of patients reporting adverse events was about one-third of the rate recorded in the RCT.. While MOVE 2-Italy continues, this interim analysis has enabled us to better define the place in therapy of THC:CBD oromucosal spray within the context of daily management of our patients with MS spasticity.

Topics: Adult; Amines; Baclofen; Calcium Channel Blockers; Cannabidiol; Cohort Studies; Cyclohexanecarboxylic Acids; Dronabinol; Drug Combinations; Drug Therapy, Combination; Female; Gabapentin; gamma-Aminobutyric Acid; Germany; Humans; Italy; Male; Medical Marijuana; Middle Aged; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Observational Studies as Topic; Oral Sprays; Plant Extracts; Pregabalin; Prospective Studies; Treatment Outcome

In Italy, all prescriptions for THC:CBD oromucosal spray for treatment of multiple sclerosis (MS) spasticity are linked to the official Agenzia Italiana del Farmaco (AIFA) web-based registry, which tracks the effectiveness and tolerability of medications in a prospective and observational manner.. AIFA e-registry data for THC:CBD oromucosal spray collected between January 2014 and February 2015 for 1,534 patients from 30 large Italian specialized MS centres were compiled. Patients had a long disease history (17.6 ± 8.6 years) and significant impairment (mean Expanded Disability Status Scale score 6.4 ± 1.2). MS spasticity was evaluated using the 0-10 numerical rating scale (NRS).. After the first month titration and trial period, 61.9% of patients achieved sufficient improvement in spasticity (≥20% NRS) to qualify for continued treatment. After 6 months, clinically meaningful ≥30% NRS improvement was recorded in 40.2% of patients continuing with treatment. Spasticity-associated symptoms such as cramps and nocturnal spasms improved in most responding patients. Mean reported doses of THC:CBD oromucosal spray (6.2-6.7 sprays/day) were lower than those reported in clinical trials. Adverse events (mainly mild to moderate) were reported by 15% of patients; no new safety concerns beyond the approved label were identified.. The results of the AIFA e-registry analysis align with those of other THC:CBD observational projects and reaffirm the characteristics of this therapeutic option in the management of treatment-resistant MS spasticity, a frequently overlooked symptom.

Topics: Adult; Cannabidiol; Data Collection; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Medical Marijuana; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Plant Extracts; Prospective Studies; Registries; Treatment Outcome

The aim of this observational study was to assess the efficacy of a tetrahydrocannabinol-cannabidiol (THC : CBD) oromucosal spray on spasticity using the stretch reflex in patients with multiple sclerosis (MS). Numeric rating scale (NRS) for spasticity, modified Ashworth scale (MAS), and the stretch reflex were assessed before and during treatment in 57 MS patients with spasticity eligible for THC : CBD treatment. A significant reduction in stretch reflex amplitude as well as significant reductions of NRS and MAS scores were observed. There was a low concordance between the three measures (stretch reflex, NRS, and MAS), likely related to the different aspects of muscle hypertonia assessed. Stretch reflex responders were taking a significantly higher number of puffs, whereas no differences were found in the responders by the other scales, suggesting that a higher dosage would add benefit if tolerated. The present study confirms the efficacy of cannabinoids in reducing spasticity in patients with MS, suggesting a higher sensitivity and specificity of the stretch reflex compared with other measures. As an objective and quantitative measure of spasticity, the stretch reflex is particularly useful to assess the effects of cannabinoids on spinal excitability and may play a role in future pharmacological studies.

Topics: Administration, Oral; Adult; Aged; Analgesics; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Mucosa; Multiple Sclerosis; Muscle Spasticity; Reflex, Stretch; Treatment Outcome

The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.. We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.. A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).. Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Topics: Administration, Oral; Cannabidiol; Dronabinol; Drug Combinations; Humans; Italy; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Safety

Nabiximols is a cannabinoid compound approved for the treatment of multiple sclerosis (MS)-related spasticity. However, additional symptoms, such as pain, urinary urgency and sleep disturbance, may benefit from treatment.. The present report describes a patient with secondary progressive MS and severe lower limbs spasticity who was started on treatment with nabiximols. The patient also suffered from trigeminal neuralgia, which he was not treating due to inefficacy or side effects of all previously tried medications. After nabiximols initiation the patient experienced a marked benefit on trigeminal neuralgia, which completely resolved, while spasticity responded only partially to treatment.. Nabiximols mechanism of action is based on the interaction with CB1 and CB2 receptors, which are expressed by central nervous system neurons and are known to modulate pain among other effects. The present case indicates that nabiximols and other cannabinoids need to be further tested for the treatment of trigeminal neuralgia.

Topics: Cannabidiol; Cannabinoid Receptor Modulators; Dronabinol; Drug Combinations; Humans; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Muscle Relaxants, Central; Muscle Spasticity; Trigeminal Neuralgia

Sativex® is an exclusive cannabinoid-based drug approved for the treatment of spasticity due to Multiple Sclerosis (MS). The most common side effects include dizziness, nausea, and somnolence. However, it is still under debate whether the drug could cause negative cognitive effects. The aim of our study was to investigate the effect of Sativex® on functional and psychological status in cannabis-naïve MS patients.. All the study participants (i.e. 40 patients affected by MS) underwent a specific clinical and neuropsychological assessment to investigate spasticity and associated symptoms, besides the cognitive and psychiatric domains commonly impaired in MS, before and after 1 and 6 months of Sativex® administration.. After the treatment, we did not observe any significant neurobehavioral impairment in all the patients, but one.. Our findings suggest that Sativex® treatment does not significantly affect the cognitive and neurobehavioral functions. However, the study supports the relevance of an extensive neuropsychological evaluation in MS patients selected for the drug administration, in an attempt to early detect the uncommon but important neurobehavioral side effects.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Follow-Up Studies; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Medical Marijuana; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Retrospective Studies; Treatment Outcome

Tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) is an add-on therapy for moderate-to-severe multiple sclerosis (MS)-related drug-resistant spasticity (MSS).. The MOVE-2 EU study collected data from everyday clinical practice concerning the effectiveness and tolerability of THC:CBD.. This was an observational, prospective, multicentre, non-interventional study. Patients with resistant MSS prescribed add-on THC:CBD oromucosal spray according to approved labelling, were followed for 3 months. After 1 month, only responders (≥20% improvement in spasticity) continued treatment. The main endpoints were the evolution of MSS and associated symptoms, quality of life (QoL) and tolerability.. Four hundred and thirty three patients (55% female) were recruited (98% in Italy). The mean duration of MSS was 7.4 years and baclofen was used by 78.1% of participants. Three hundred and forty nine participants continued with THC:CBD oromucosal spray after 1 month, and 281 after 3 months. THC:CBD mean dosage was 6 sprays/day. MSS scores and spasticity-related symptoms (spasms, fatigue, pain, sleep quality and bladder dysfunction) were significantly improved by THC:CBD at 3 months, as were activities of daily living, and QoL (EQ-5D VAS). Adverse events, none of which were severe or serious, were reported by 10.4% of patients.. In everyday clinical practice, THC:CBD oromucosal spray provided symptomatic relief of MSS and related troublesome symptoms.

Topics: Activities of Daily Living; Adult; Baclofen; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Plant Extracts; Prospective Studies; Quality of Life

Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS.. Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls.. A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth.. Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.

Topics: Adult; Aged; Cannabidiol; Cannabinoid Receptor Modulators; Disability Evaluation; Dronabinol; Drug Combinations; Evoked Potentials, Motor; Female; Follow-Up Studies; H-Reflex; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Nasal Sprays; Neuromuscular Agents; Oral Sprays; Plant Extracts; Severity of Illness Index; Treatment Outcome

At the 2016 MS Experts Summit, country-relevant aspects pertaining to the management of symptoms and disability in multiple sclerosis (MS), with emphasis on those associated with spasticity, were explored in interactive country breakout sessions chaired by selected MS experts. Attendees had the opportunity to review and discuss topics in their own native language. After feedback from each session leader, key messages were collated and presented in a Plenary Session by Summit chair, Professor Angelo Ghezzi. Topics at this year's Summit included: gait tracking (Germany/Switzerland); the Care Alliance against MS spasticity (Italy); MS spasticity and associated symptoms (France); improvement in MS symptoms and functionality and patients' independence (Spain); Swedish MS guidelines (Sweden/Rest of World).

Topics: Cannabidiol; Dronabinol; Drug Combinations; Europe; Gait Disorders, Neurologic; Humans; Multiple Sclerosis; Muscle Spasticity

Each year at the MS Experts Summit, relevant research in the field of multiple sclerosis spasticity is featured in poster sessions. In 2016, six new studies were presented.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity

The aim of the present observational study was to determine the effects of a delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex(®) spray), brand name Sativex(®), indicated for drug-resistant MS spasticity, on the driving ability of treated MS patients.. The study was conducted over a period of 4-6 weeks. Thirty-three MS patients with moderate to severe treatment-resistant spasticity and planned to begin add-on treatment with Sativex(®) were enrolled at three specialized MS centres in Germany. A set of five driving test procedures from a validated computerized test battery was used to evaluate the driving ability of eligible patients. Tests were performed by patients at baseline and repeated after 4-6 weeks of treatment with Sativex(®) oromucosal spray. According to German normative data, the test thresholds achieved by the general population served as a reference to allow for a fitness/unfitness to drive classification.. Patients showed comparable driving test results at baseline and at final visits. Only two patients changed classification shifting from 'unfit' to drive to 'fit' and vice versa. The mean severity of spasticity, as self-reported by the patients, improved with statistical significance. Sativex(®) was generally well tolerated.. Treatment of MS patients with Sativex(®) does not negatively impact on driving ability and may improve moderate to severe treatment-resistant MS spasticity.

Topics: Adult; Automobile Driving; Cannabidiol; Dronabinol; Drug Combinations; Female; Germany; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Pilot Projects; Plant Extracts

Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.

Topics: Cannabidiol; Cannabinoid Receptor Agonists; Cerebral Cortex; Dronabinol; Drug Combinations; Evoked Potentials, Motor; Humans; Multiple Sclerosis; Muscle Spasticity; Neural Inhibition; Plant Extracts; Pyramidal Tracts; Sensorimotor Cortex; Transcranial Magnetic Stimulation

Sativex® is a drug approved for use in the treatment of spasticity in multiple sclerosis. We sought to study the tolerability and effectiveness of this drug product in pathologies beyond the scope of the indications of the product data sheet, by means of its compassionate use.. To evaluate the effectiveness and safety of Sativex in pathologies that are not included on the product data sheet, using a compassionate use protocol.. A six-month observational study was conducted to evaluate the effectiveness and safety of Sativex in neuropathic pain and in spasticity from causes other than multiple sclerosis.. A total of 10 patients were included: six females and four males. Side effects appeared in only two of them and the drug product was withdrawn in one case. After starting treatment with Sativex by means of a compassionate use protocol, the consumption of concomitant drugs was reduced by 34.2% (p=0.004), and administration of botulinum toxin was suspended in seven patients (70%). The improvement on the Ashworth spasticity scale was 65.6% (p=0.004) and the score on the analogical visual scale dropped by 49.2% (p=0.026).. Sativex may be an interesting therapeutic alternative in patients with spasticity and pain when the treatments that are usually available have been employed but patients' quality of life continues to be significantly compromised.. Evaluacion de eficacia y tolerabilidad de Sativex ® en uso compasivo.. Introduccion. Sativex ® es un farmaco aprobado para el tratamiento de la espasticidad en la esclerosis multiple. Hemos querido estudiar la tolerabilidad y eficacia de este farmaco en patologias fuera de indicacion de ficha tecnica, mediante su uso compasivo. Objetivo. Valorar la eficacia y tolerabilidad de Sativex en patologias no incluidas en la ficha tecnica, mediante un protocolo de uso compasivo. Pacientes y metodos. Se realizo un estudio observacional, de seis meses de duracion, para evaluar la eficacia y tolerabilidad de Sativex en el dolor neuropatico y en la espasticidad de causa diferente a la esclerosis multiple. Resultados. Se incluyo un total de 10 pacientes, seis mujeres y cuatro hombres. Solo hubo efectos adversos en dos de ellos, y el farmaco se suspendio en un caso. Tras el inicio del tratamiento con Sativex mediante protocolo de uso compasivo, el consumo de farmacos concomitantes se redujo un 34,2% (p = 0,004), y se suspendio la administracion de toxina botulinica en siete pacientes (70%). La mejoria de la escala de espasticidad de Ashworth fue del 65,6% (p = 0,004) y la escala visual analogica disminuyo su puntuacion un 49,2% (p = 0,026). Conclusion. Sativex puede ser una alternativa terapeutica interesante en pacientes con espasticidad y dolor cuando se han utilizado los tratamientos habituales disponibles, pero los pacientes continuan con afectacion significativa de su calidad de vida.

Topics: Adult; Aged; Cannabidiol; Compassionate Use Trials; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Treatment Outcome

Multiple sclerosis (MS) is a chronic progressive disease that carries a high socioeconomic burden. Spasticity (rigidity and spasms) is common in MS and contributes to MS-related disability. This study aims to evaluate the cost-effectiveness of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol oromucosal spray) when used as add-on therapy for management of resistant MS-related spasticity in the context of the Italian healthcare system. A previously published Markov model-based analysis for the German and Spanish context was replicated, adapting it to the Italian setting. Model parameters were updated to reflect recent findings about MS-related spasticity and use of Sativex in daily clinical practice. The base case incremental cost-effectiveness ratio for Sativex use in Italy over a 5-year period was estimated to be €4968 per quality-adjusted life-year gained (year of costing: 2013). Sativex remained an efficient option in the Italian healthcare context - below the commonly accepted incremental threshold of €30,000 per quality-adjusted life-year gained - when deterministic and probabilistic sensitivity analyses were conducted. Sativex can be regarded as a cost-effective treatment option for patients with MS-related spasticity in Italy.

Topics: Cannabidiol; Cost of Illness; Cost-Benefit Analysis; Delivery of Health Care; Dronabinol; Drug Combinations; Humans; Italy; Markov Chains; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Quality-Adjusted Life Years

Topics: Cannabidiol; Cannabis; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts

The prospective, non-interventional Mobility Improvement (MOVE) 2 study was designed to provide real life data on clinical outcomes of patients with treatment-resistant multiple sclerosis (MS) spasticity receiving routine treatment with tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®), subsequent to its approval in European countries.. This interim analysis reports on MOVE 2 patients from Italy.. Interim data from 322 patients (58.3% female; mean age 51.1 ± 10.2 years) were analyzed. From baseline to month 3 of treatment (Visit 3), the mean 0-10 Numerical Rating Scale (NRS) score decreased by -19.1% (-1.6 points, p < 0.0001) and the mean modified Ashworth score decreased from 2.6 to 2.3 points (p < 0.0001). At Visit 3, 24.6% of 203 patients with available data were clinically relevant responders (≥30% improvement from baseline NRS score; p < 0.001 vs. baseline). The mean reported dose of THC:CBD oromucosal spray was 6.1 ± 2.5 sprays/day at Visit 1 (1 month) and 5.1 ± 2.6 sprays/day at Visit 3 (range 1-12 sprays/day at both timepoints). Forty-one (13.1%) patients reported at least one adverse event (AE), which included 3 serious AEs (1 unrelated). AEs with an incidence ≥1% were dizziness (5.6%), confusion (2.5%), nausea (1.25%) and somnolence (1.25%).. In everyday clinical practice in Italy, THC:CBD oromucosal spray provided symptomatic relief of MS spasticity with good tolerability in a relevant number of previously resistant patients.

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Italy; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Prospective Studies

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts; Practice Guidelines as Topic

Patients with multiple sclerosis (MS) represent a diverse and heterogeneous population varying in terms of disease type, its severity and variable progression/time-course, and with regard to the wide range of presenting symptoms. Consequently, detailed experience with individual patients is important to provide examples of therapy to specific patient types. In this article, real-life data from clinical practice showing specific aspects relating to use of 9-delta-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) in patients with moderate to severe spasticity resistant to usual therapy will be presented. Three common clinical scenarios will be considered: MS patients with resistance to usual spasticity therapies; patients with impairment in MS spasticity symptoms; MS patients with relevant impairment in quality of life/activities of daily living (QoL/ADL). These case reports highlight the diverse nature of the MS spasticity population and they show the possible usefulness of THC:CBD oromucosal spray in individual patients with moderate to severe spasticity resistant to existing therapies, within the frame of use approved after large clinical trial results. Perhaps the most important finding is the possibility of obtaining relevant improvements in QoL/ADL in some patients with resistant MS spasticity, allowing them to engage back in physical and social activities.

Topics: Activities of Daily Living; Adult; Aged; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Parasympatholytics; Plant Extracts; Quality of Life; Severity of Illness Index; Spinal Cord; Treatment Outcome

Nabiximols (Sativex®), a cannabinoid-based oromucosal spray, is an add-on therapy for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The primary objective was to provide real-life observational data of clinical experience of nabiximols in contrast to formal clinical trials of effectiveness.. This was an observational, prospective, multicenter, non-interventional study with a follow-up period of 3-4 months, conducted in routine care setting in Germany. Patients with moderate to severe MSS were included at nabiximols' initiation. Structured documentation forms, questionnaires and validated instruments were used for data collection at inclusion, 1 and 3 months after inclusion.. Overall, 335 patients were assessed of whom 276 fitted the criteria and were included in the effectiveness analysis. After 1 month, nabiximols provided relief of resistant MSS in 74.6% of patients according to specialist assessment; mean spasticity 0-10 numerical rating scale (NRS) score decreased from 6.1 ± 1.8 to 5.2 ± 2.0 points; in patients with NRS improvement ≥20% mean NRS score decreased by 40%. After 3 months, 55.3% of patients had continued to use nabiximols and the mean NRS score had decreased by 25% from baseline. 17% of patients reported adverse events.. Real-life data confirm nabiximols as an effective and well-tolerated treatment option for resistant MSS in clinical practice.

Topics: Adult; Aged; Cannabidiol; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Germany; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Plant Extracts; Prospective Studies; Severity of Illness Index; Sleep; Surveys and Questionnaires; Treatment Outcome; Young Adult

The therapeutic use of cannabis has generated a lot of interest in the past years, leading to a better understanding of its mechanisms of action. Countries like the United States and Canada have modified their laws in order to make cannabinoid use legal in the medical context. It's also the case in France now, where a recent decree was issued, authorizing the prescription of medication containing "therapeutic cannabis" (decree no. 2013-473, June 5, 2013). Cannabinoids such as dronabinol, Sativex and nabilone have been tested for the treatment of acute and chronic pain. These agents are most promising to relieve chronic pain associated with cancer, with human immunodeficiency virus infection and with multiple sclerosis. However, longer-term studies are required to determine potential long-term adverse effects and risks of misuse and addiction.

Topics: Antiemetics; Cannabidiol; Dronabinol; Drug Combinations; Fibromyalgia; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Plant Extracts

Nabiximols (Sativex®), in a cannabinoid-based oromucosal spray, is an add-on therapy option for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The study objective was to provide long-term data on clinical outcomes, tolerability, quality of life and treatment satisfaction for MSS patients receiving nabiximols in routine care.. This was the 12-month prolongation of the MOVE 2 study, an observational, prospective, multi-centre 3-month non-interventional study conducted in a routine care setting across Germany. Structured documentation forms, questionnaires and validated instruments were used for data collection.. In total, 52 patients were included in the effectiveness analysis after 12 months. The mean spasticity numerical rating scale (NRS, 0-10) score decreased significantly from 6.0 ± 1.8 points at MOVE 2 baseline to 4.8 ± 1.9 points after 1 month and remained on this level after 12 months (4.5 ± 2.0 points); in patients classified as 'initial responders' (≥20% NRS improvement after 1 month) similar results were found (baseline: 6.3 ± 1.4 points; after 1 month: 4.0 ± 1.0 points; after 12 months: 4.3 ± 1.9 points). The majority of patients (84%) did not report adverse events.. Real-life data confirm the long-term effectiveness and tolerability of nabiximols for the treatment of resistant MSS in everyday clinical practice.

Topics: Adult; Aged; Analgesics; Cannabidiol; Dronabinol; Drug Combinations; Female; Follow-Up Studies; Germany; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Patient Satisfaction; Prospective Studies; Quality of Life; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome

Spasticity arises from hyperexcitability of the neural stretch reflex arc secondary to injury of the corticospinal tract. In response to injury, the density of glutamatergic inputs from afferent 1A fibers to motor neurons increases dramatically and adaptive changes occur in the morphology of microglia cells in the spinal cord.. Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS. Stimulation of cannabinoid (CB)1 receptors reduces the hyperglutamatergic drive from sensory afferents to spinal cord motor neurons and blocks the synaptic effects of activated microglia and pro-inflammatory mediators (e.g. TNF-α) on glutamatergic transmission. Enhancing corticospinal tract excitability through intermittent theta burst stimulation inhibits the stretch reflex and spasticity by promoting long-term potentiation, a form of synaptic plasticity that requires stimulation of CB1 receptors. Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex®) are associated with enhanced cortical long-term potentiation. Key Messages: Glutamatergic and GABAergic pathways are involved in the regulation of muscle tone. CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways. THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits.

Topics: Animals; Cannabidiol; Dronabinol; Drug Combinations; Endocannabinoids; Humans; Motor Cortex; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Muscle, Skeletal; Neural Pathways; Plant Extracts; Spinal Cord

Most patients with multiple sclerosis (MS) experience spasticity as the clinical course evolves. Associated symptoms include (often painful) spasms, urinary dysfunction and sleep disturbances. THC:CBD oromucosal spray (Sativex®) is approved for symptom improvement in adult patients with moderate to severe MS-related spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.. In pivotal clinical trials of THC:CBD oromucosal spray, a meaningful proportion of patients with treatment-resistant MS spasticity achieved clinically relevant improvement with active treatment versus placebo. The utility of a 4-week trial of therapy to identify patients who respond to treatment was demonstrated in an enriched-design study. THC:CBD oromucosal spray was well tolerated in these studies, with no evidence of effects typically associated with recreational cannabis use. In a subsequent post approval clinical trial, THC:CBD oromucosal spray had no statistically significant effect on cognition and mood compared with placebo. Moreover, after 50 weeks' treatment, approximately two-thirds of patients, physicians and caregivers reported improvement from baseline in spasticity based on global impressions of change. Key Messages: In phase III clinical trials, approximately one-third of MS patients with treatment-resistant spasticity had a clinically relevant and statistically significant response to THC:CBD oromucosal spray. In addition to a reduction in spasticity, responders experienced meaningful relief from associated symptoms. THC:CBD oromucosal spray was generally well tolerated and efficacy was maintained over the longer term. A post-approval clinical trial indicated no effect of THC:CBD oromucosal spray on cognition or mood after 50 weeks of use.

Topics: Affect; Cannabidiol; Clinical Trials, Phase III as Topic; Cognition; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Plant Extracts; Randomized Controlled Trials as Topic

Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

Topics: Activities of Daily Living; Cannabidiol; Cost of Illness; Dronabinol; Drug Combinations; Europe; Humans; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Plant Extracts; Quality of Life

Clinical trials demonstrate the efficacy and tolerability of an intervention under experimental conditions, but information on use under daily practice conditions is required to confirm the effectiveness and safety of new management options.. Clinical outcomes for THC:CBD oromucosal spray (Sativex®) in patients with treatment-resistant MS spasticity have been collected in post-marketing safety registries from the UK and Germany, a safety study from Spain and two observational studies from Germany, including one investigating its effects on driving ability. Collectively, findings from daily practice support the long-term effectiveness and safety of THC:CBD oromucosal spray. The proportion of patients with a clinically relevant response (≥30% improvement from baseline on the spasticity 0-10 Numerical Rating Scale) at 3 months was similar to that reported in a large enriched-design pivotal clinical trial (41 vs. 36%). There was no evidence of abuse/misuse or other adverse events of special interest with a cannabis-based medicine and no impairment of driving ability. In actual clinical practice, average daily doses were ∼25% lower than those used in clinical trials. Key Messages: Observational data and real world experience reinforce the efficacy and safety of THC:CBD oromucosal spray as reported in phase III clinical trials. © 2014 S. Karger AG, Basel.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Germany; Humans; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Observational Studies as Topic; Plant Extracts; Registries; Spain; United Kingdom

To identify the areas of daily function most affected by the introduction of Sativex, a cannabis-based medicine, and the impact on caregivers and people with multiple sclerosis (MS).. Cannabinoid medicines have recently become available on prescription in several parts of the world, principally for the treatment of spasticity in people with MS. Their efficacy and safety have been demonstrated in the setting of randomised controlled clinical trials. Results of such studies may not always reflect the wider effectiveness that a medicine shows when used in clinical practice.. A short questionnaire survey consisting mostly of multiple-choice questions, along with some free-text questions aimed at the patient and primary caregiver (ie, partner, mother, nurse or outside carer). The questionnaire was developed in consultation with a patient representative organisation, field tested, ethics approval gained, then distributed to prescribers in the United Kingdom, with the request that they in turn forward it to any patients who had received repeat prescriptions for Sativex within the previous 16 weeks. Patients were seen in both a primary care (general practice) and a secondary care (hospital) setting. There was no control group in this study. Most patients had MS, and the primary reasons for using Sativex were spasticity and pain.. The response rate was 57%, with 124 questionnaires returned. The majority of respondents and their caregivers reported improvements across a range of daily functional activities, alongside a reduction in the use of concomitant anti-spasticity medication and in the use of other healthcare resources.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Cannabidiol; Caregivers; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Neuralgia; Off-Label Use; Phytotherapy; Plant Extracts; Practice Patterns, Physicians'; Sleep; Surveys and Questionnaires; United Kingdom

Topics: Anti-Dyskinesia Agents; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Dronabinol; Drug Combinations; Drugs, Investigational; Humans; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

Multiple sclerosis (MS) is a chronic, progressive disease that carries a high socioeconomic burden. Spasticity (rigidity and spasms) is common in MS and a key contributor to MS-related disability.. This study evaluated the cost-effectiveness of Sativex®, a 9-d-tetrahydrocannabinol/cannabidiol-based oromucosal spray that acts as an endocannabinoid system modulator. Sativex was recently approved for the management of resistant MS spasticity as add-on medication.. A Markov model-based analysis was performed over a 5-year horizon from a German and Spanish healthcare payer perspective. The incremental cost of Sativex was low compared with current spasticity treatments, and provided a quality-adjusted life-year gain over the current standard of care.. The base-case incremental cost-effectiveness ratio for Sativex was estimated at €11,214/quality-adjusted life-year in Germany, while the drug was the dominant option in Spain, providing savings of €3496/patient over a 5-year period (year of costing: 2010). This was seen because the lower severity of spasticity in patients who had improved led to reduced resource consumption (e.g., physiotherapy and medications).. Despite having a relatively high acquisition cost, Sativex was shown to be a cost-effective treatment option for patients with MS-related spasticity.

Topics: Cannabidiol; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Drug Costs; Drug Resistance; Germany; Humans; Markov Chains; Multiple Sclerosis; Muscle Spasticity; Plant Extracts; Quality-Adjusted Life Years; Severity of Illness Index; Spain

Spasticity is common in patients with multiple sclerosis (MS) and is a major contributor to disability. Sativex®, an oromucosal spray containing cannabis-based medicinal products, has been found to be effective in reducing spasticity symptoms.. Our objective was to estimate the cost effectiveness of Sativex® plus oral anti-spasticity medicines compared with the current standard treatment for moderate or severe spasticity in MS in the UK.. A Markov model was used to assess the costs and benefits of Sativex® plus oral anti-spasticity medicines or current standard treatment based on their effects on the quality of life of patients. The main outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per additional QALY gained over 5 years of treatment. One-way, multi-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the findings.. In the base case, Sativex® plus oral anti-spasticity medicines resulted in incremental costs of £7600 and a QALY gain of 0.15 per person over 5 years (ICER = £49 300 per QALY).[year 2009 data for costs]. Findings were sensitive to the costs of Sativex® (price and dose) and differences in utilities between responders and non-responders.. Using a willingness-to-pay threshold of £30 000 per QALY, Sativex® appears unlikely to be considered cost effective by UK funders of healthcare for spasticity in MS. This is unfortunate, since it appears that Sativex® use is likely to benefit some patients in the management of this common consequence of MS.

Topics: Administration, Mucosal; Administration, Oral; Cannabidiol; Cost-Benefit Analysis; Dronabinol; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Markov Chains; Middle Aged; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Plant Extracts; Quality-Adjusted Life Years; Severity of Illness Index; United Kingdom

Topics: Cannabidiol; Dronabinol; Drug Approval; Drug Combinations; Drug Therapy, Combination; Humans; Multiple Sclerosis; Muscle Spasticity; Norway; Oral Sprays; Plant Extracts

Topics: Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Multiple Sclerosis; Muscle Spasticity; Plant Extracts

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Approval; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Parasympatholytics; Plant Extracts

Topics: Cannabidiol; Cannabis; Dronabinol; Drug Approval; Drug Combinations; Germany; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Palliative Care; Phytotherapy; Plant Extracts; Psychoses, Substance-Induced