cannabidiol and Multiple-Sclerosis

Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC:CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies.. A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC:CBD oromucosal spray compared with a control condition.. Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD.. Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC:CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.

Topics: Cannabidiol; Cannabis; Cognition; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis

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

Cognitive impairment is a common manifestation of multiple sclerosis (MS).. To assess by systematic review and meta-analysis available evidence regarding the impact of nabiximols oromucosal spray on cognition in patients with MS.. A systematic literature search of clinical studies (all types, any comparator) that measured cognitive function in patients with MS spasticity treated with nabiximols. Meta-analysis for cognitive endpoints was not possible due to heterogenous measurement instruments and outcomes. Meta-analysis was performed for adverse events (AEs) of special interest (cognition disorders) reported in randomized controlled trials (RCTs) of nabiximols versus placebo in patients with MS (with or without spasticity). Certainty of evidence and risk of bias were assessed.. Seven clinical studies (three RCTs) directly assessing cognitive function were included in the qualitative analysis. There was no consistent evidence to suggest that nabiximols causes cognitive impairment as assessed by a range of specific psychometric instruments across cognitive domains. Thirteen double-blind, placebo-controlled RCTs (nabiximols, n = 964; placebo, n = 904) were included in the meta-analysis of cognitive AEs. Most cognitive AEs (30 of 32 events, 93.8%) reported with nabiximols in MS patients occurred with not in-label use, i.e., dosage >12 sprays per day and/or not administered primarily for treatment of spasticity.. Within the limitations of the review, we can conclude that no detrimental effects of nabiximols on cognitive function were observed in patients with MS spasticity during up to 12 months follow-up and that cognitive AEs were rare and occurred only when nabiximols was not used according to its approved label.

Topics: Cannabidiol; Cognition; Double-Blind Method; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Muscle Spasticity; Randomized Controlled Trials as Topic; Treatment Outcome

Sativex (USAN: nabiximols [NAB]) oromucosal spray is indicated for treatment of multiple sclerosis (MS) patients with moderate to severe spasticity and inadequate response to other antispasticity medications who demonstrate clinically significant improvement during an initial trial of therapy. This narrative review investigated the efficacy and effectiveness of NAB oromucosal spray for moderate to severe MS spasticity by examining spasticity 0-10 numerical rating scale (NRS) data from interventional and observational studies which featured a 4-week trial period as per the European Union-approved label.. Across both study types, clinically relevant and statistically significant reductions in mean MS spasticity 0-10 NRS scores were measured soon after treatment start and were maintained in the mid- to long term in treatment responders. Initial responder rates (≥20% NRS improvement from baseline at week 4) ranged from 47.6% to 81.4%, tending lower in the randomized clinical trials setting. Clinically relevant responder rates (≥30% NRS improvement from baseline at week 12) were similar between study types (range 30-41%) except for one outlier (74% in an observational study). Two open studies reported treatment continuation for ≥18 months in approximately half of patients who initiated treatment. In most longer term studies, symptomatic improvement in MS spasticity was maintained at mean daily dosages of about 6-7 sprays/day. Safety was consistent with the known profile of NAB.. Experimental and observational studies of NAB oromucosal spray recorded similar findings. About half to two-thirds of MS patients who begin treatment will perceive initial symptomatic relief of spasticity within the 4-week trial period. About 40% of patients who initiate treatment will reach the ≥30% NRS improvement threshold at 3 months, comprising the majority of patients who continue long-term treatment. A trial of therapy with NAB is useful to identify patients most likely to gain longer term improvement in spasticity symptoms and discontinue those with insufficient benefit.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Observational Studies as Topic; Plant Extracts

Multiple sclerosis (MS) is the most common chronic autoimmune disease of the central nervous system. Efficacy of treatments for MS is associated with risk of adverse effects, and effective and well-tolerated drugs remain a major unmet need. Cannabis (Cannabis sativa L., fam. Cannabaceae) and cannabinoids are popular among MS patients to treat spasticity and pain. Cannabinoids are endowed with remarkable immunomodulating properties, and in particular the non-psychotropic cannabinoid cannabidiol (CBD) is increasingly recognized as anti-inflammatory and immunosuppressive, nevertheless with excellent tolerability even at high doses. In this systematic review, we retrieved and critically evaluated available evidence regarding the immune and disease-modifying effects of CBD in experimental autoimmune encephalomyelitis (EAE) and in MS. Evidence in rodent models of EAE strongly supports CBD as effective, while clinical evidence is still limited and usually negative, due to paucity of studies and possibly to the use of suboptimal dosing regimens. Better characterization of targets acted upon by CBD in MS should be obtained in ex vivo/in vitro studies in human immune cells, and higher doses should be tested in well-designed clinical trials with clinically relevant efficacy endpoints. Graphical Abstract.

Topics: Animals; Cannabidiol; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Multiple Sclerosis

Topics: Aged; Anorexia; Antineoplastic Agents; Cancer Pain; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoids; Dizziness; Dose-Response Relationship, Drug; Dronabinol; Humans; Middle Aged; Multiple Sclerosis; Nausea; Neurodegenerative Diseases; Pain; Perceptual Disorders; Randomized Controlled Trials as Topic; Regression Analysis; Self Report; Vomiting

: 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

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.

Topics: Brain Injuries, Traumatic; Cannabidiol; Cannabinoids; Cannabis; Demyelinating Diseases; Humans; Multiple Sclerosis; Stroke

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Cannabidiol; Cannabinoids; Cannabis; Cartilage Diseases; Cytokines; Diabetes Mellitus, Type 1; Dronabinol; Humans; Immunomodulation; Lupus Erythematosus, Systemic; Mice; Multiple Sclerosis; Th17 Cells

To describe marijuana's clinical role for urologic symptoms.. Studies related to marijuana, voiding dysfunction, lower urinary tract symptoms (LUTS), and pain through January 2019 from PubMed were evaluated for relevance and quality.. Forty-eight studies were reviewed. Cannabinoids have mixed efficacy for neurogenic LUTS and little evidence for non-neurogenic LUTS, chronic non-cancer-related and perioperative pain. For cancer-related pain, high-level studies demonstrate cannabinoids are well-tolerated with unclear benefit.. Cannabinoids appear well-tolerated in the short-term, but their efficacy and long-term impact is unproven and unknown in urologic discomfort. Cannabinoids for urologic symptoms should be further explored with well-designed randomized controlled trials.

Topics: Cancer Pain; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoids; Cannabis; Chronic Pain; Cystitis, Interstitial; Dronabinol; Drug Combinations; Humans; Lower Urinary Tract Symptoms; Male; Medical Marijuana; Multiple Sclerosis; Pain, Procedural; Pelvic Pain; Urinary Incontinence

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

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Baclofen; Cannabidiol; Clinical Trials as Topic; Clonidine; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Drug Approval; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Multiple Sclerosis; Spinal Cord; Treatment Outcome; United States; United States Food and Drug Administration

Patients with multiple sclerosis have long turned to complementary therapies to manage symptoms that licensed products can only partially control. Around half of patients with multiple sclerosis admit to previous or current cannabis use for medicinal purposes and would endorse legalisation. Despite many governments worldwide relaxing regulations around medicinal cannabis, there remain many unanswered questions as to how clinicians should prescribe or recommend products, and access to pharmaceutical-grade products remains highly restricted. Here we address what adult neurologists need to know about cannabis and its use in multiple sclerosis.

Topics: Analgesics; Anti-Inflammatory Agents; Cannabidiol; Humans; Medical Marijuana; Multiple Sclerosis

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects.. We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

Topics: Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Humans; Multiple Sclerosis; Pain; Quality of Life; Randomized Controlled Trials as Topic; Systematic Reviews as Topic

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

Cannabis and cannabinoids have been used medically and recreationally for thousands of years and recently there has been a growing body of research in this area. With increased access now that medical marijuana is available in many jurisdictions, patients and providers want to know more about the evidence for benefits and risks of cannabinoid use. This paper provides an overview of the available cannabinoid-based formulations, a summary of the highest quality evidence for the use of cannabinoids for treating spasticity and pain associated with multiple sclerosis (MS), and a discussion of possible dosing regimens based on information from these studies.. Two recent high-quality systematic reviews concluded that the only strong evidence for medical marijuana in neurological disorders was for reducing the symptoms of patient-reported spasticity and central pain in MS and that the only complementary and alternative medicine (CAM) intervention in MS with strong supportive evidence was cannabinoids. Based on this review, they concluded that nabiximols (Sativex oral spray), oral cannabis extract (OCE), and synthetic tetrahydrocannabinol (THC) are probably effective at reducing patient-reported symptoms of spasticity in people with MS, but OCE and synthetic THC were not found to be effective for reducing physician-administered measures of spasticity. In addition, nabiximols, OCE, and synthetic THC are probably effective at reducing MS-related pain. Cannabinoids were generally well-tolerated. However, cannabis use has been associated with an increased risk of psychosis and schizophrenia in at-risk individuals, there is growing evidence that cannabis can increase the risk for cardiovascular diseases, including myocardial infarction (MI), hypertension, heart failure, and stroke, and a recently recognized adverse effect of cannabis is cannabinoid hyperemesis syndrome. The medical use of cannabinoids remains controversial. While cannabinoids have been studied for a variety of neurologic disorders, there is strongest evidence to indicate benefits in treatment of spasticity and neuropathic pain in multiple sclerosis. Although the best dose for an individual remains uncertain, most participants in the studies discussed in this paper used between 20 and 40 mg of THC a day in divided doses. Adverse events in studies were generally more common in the groups using cannabinoid products but serious adverse events were rare and cannabis products were generally well-tolerated. Cannabis use does appear to be associated with increased risk of certain adverse events, including psychosis, cardiovascular diseases, and cannabinoid hyperemesis syndrome.

Topics: Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Evidence-Based Medicine; Humans; Medical Marijuana; Multiple Sclerosis; Nervous System Diseases; Treatment Outcome

Multiple sclerosis (MS) is a complex disease with a heterogeneous and unpredictable clinical course. Mobility impairment after progressive paralyses and muscle tone spasticity is common. Areas covered: The prevalence, assessment, and pharmacological management of gait impairment and spasticity in MS and their effects on health-related quality of life (HRQoL) are discussed. The roles of oral and intrathecal baclofen and of delta-9-tetrahydrocannabinol/cannabidiol (THC:CBD) oromucosal spray in treating MS spasticity-related gait impairment are reviewed. Expert commentary: Mobility impairment and spasticity are experienced by approximately 90% and 80% of MS patients, respectively, during the disease course. Prevalence and severity of gait impairment and spasticity increase as disease progresses. The symptoms are related and both impact negatively on HRQoL. Oral baclofen and tizanidine are generally used for first-line treatment of MS spasticity but are ineffective in approximately 40% of cases. Second-line therapy includes add-on THC:CBD spray for patients with resistant MS spasticity. Results of studies evaluating baclofen for treating MS spasticity gait impairment are equivocal. In studies of patients with resistant MS spasticity, THC:CBD spray consistently improved the timed 10-meter walk test and significantly improved multiple spatial-temporal and kinematic gait parameters. THC:CBD oromucosal spray warrants further investigation as a treatment for MS spasticity-related gait impairment.

Topics: Baclofen; Cannabidiol; Disease Progression; Dronabinol; Drug Combinations; Gait Disorders, Neurologic; Humans; Multiple Sclerosis; Muscle Relaxants, Central; Muscle Spasticity; Nasal Sprays; Plant Extracts; Quality of Life

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

Spasticity, perceived by patients as muscle rigidity and spasms, is a common symptom in multiple sclerosis (MS). It is associated with functional impairment that can exacerbate other MS symptoms and reduce quality of life. Pharmacological treatment options are limited and frequently ineffective. Treatment adherence is a key issue to address in these patients. The efficacy and safety of 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray for treatment of MS spasticity were demonstrated in four Phase III trials. Observational studies and registry data subsequently confirmed the effectiveness and tolerability of THC:CBD oromucosal spray under everyday practice conditions. Among patients who respond to treatment, THC:CBD oromucosal spray has been shown to produce positive improvements in gait parameters and to normalize muscle fibers.

Topics: Cannabidiol; Disease Management; Dronabinol; Humans; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Oral Sprays

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

Sativex(®) is an oromucosal spray indicated for the treatment of moderate-to-severe spasticity in multiple sclerosis and is also an effective analgesic for advanced cancer patients. Sativex contains Δ(9)-tetrahydrocannabinol (THC) and cannabidiol in an approximately 1:1 ratio. The increasing prevalence of medicinal cannabis products highlights the importance of reliable bioanalysis and re-evaluation of the interpretation of positive test results for THC, as legal implications may arise in workplace, roadside and sports drug testing situations. This article summarizes published research on the bioanalysis of THC and cannabidiol, with particular focus on Sativex. Common screening and confirmatory testing of blood, urine, oral fluid and hair samples are outlined. Correlations between matrices and current analytical pitfalls are also addressed.

Topics: Analgesics; Cannabidiol; Doping in Sports; Dronabinol; Drug Combinations; Gas Chromatography-Mass Spectrometry; Hair; Humans; Multiple Sclerosis; Plant Extracts; Workplace

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

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated.

Topics: Cannabidiol; Clinical Trials as Topic; Dronabinol; Humans; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Oral Sprays; Placebo Effect

Answer questions and earn CME/CNE Marijuana has been used for centuries, and interest in its medicinal properties has been increasing in recent years. Investigations into these medicinal properties has led to the development of cannabinoid pharmaceuticals such as dronabinol, nabilone, and nabiximols. Dronabinol is best studied in the treatment of nausea secondary to cancer chemotherapy and anorexia associated with weight loss in patients with acquired immune deficiency syndrome, and is approved by the US Food and Drug Administration for those indications. Nabilone has been best studied for the treatment of nausea secondary to cancer chemotherapy. There are also limited studies of these drugs for other conditions. Nabiximols is only available in the United States through clinical trials, but is used in Canada and the United Kingdom for the treatment of spasticity secondary to multiple sclerosis and pain. Studies of marijuana have concentrated on nausea, appetite, and pain. This article will review the literature regarding the medical use of marijuana and these cannabinoid pharmaceuticals (with emphasis on indications relevant to oncology), as well as available information regarding adverse effects of marijuana use.

Topics: Analgesics, Non-Narcotic; Antiemetics; Canada; Cannabidiol; Clinical Trials as Topic; Dronabinol; Drug Combinations; Evidence-Based Medicine; Humans; Medical Marijuana; Multiple Sclerosis; Neoplasms; Pain; Treatment Outcome; United Kingdom; United States

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

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; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Neuralgia; Treatment Outcome

Pain associated with multiple sclerosis (MS) is frequent, and frequently not alleviated by currently available drugs. Nabiximols is a combination of two plant cannabinoids administered via an oromucosal pump spray and approved in Canada for the treatment of intractable central neuropathic pain due to MS and intractable cancer pain. Nabiximols exerts its analgesic effects through its interaction with the endocannabinoid system to modulate pain transmission via pain networks.. This review examines the characteristics of nabiximols, its pharmacokinetic properties and data on efficacy and tolerability in MS-related neuropathic pain. The authors, furthermore, provide information on the pharmacology and clinical data of nabiximols as neuropathic analgesic in MS.. Nabiximols is an appropriate therapy for pain patients who tend to be particularly resistant to pharmacological interventions. Its action depends on not only the local constellation of the endocannabinoid system signalling, but also the particular functional status of pain pathways and on the specific mechanism of neuropathic pain. It is therefore justifiable that further studies are initiated which aim to define the best responder profile and which explore the full potential of nabiximols in MS-related pain.

Topics: Analgesics; Canada; Cannabidiol; Cannabinoids; Clinical Trials as Topic; Dronabinol; Drug Combinations; Drug Evaluation, Preclinical; Humans; Multiple Sclerosis; Neuralgia; Plant Preparations; Randomized Controlled Trials as Topic

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

There is a growing consensus that cannabis dependence is a substantial and underappreciated problem. The key component responsible for the euphoric effects of cannabis and its dependence potential is δ-9-tetrahydrocannabinol (THC). THC-containing cannabinoid medicines theoretically pose a risk of abuse and dependence.. In order to evaluate the potential of Sativex to cause cannabis-like psychoactivity, abuse or dependence relevant data from all published papers have been reviewed along with the integrated safety analysis for Sativex use in multiple sclerosis (MS) patients on file at GW Pharmaceuticals.. In clinical trials, intoxication scores have been low and euphoria reported by only 2.2% of patients. Tolerance has not occurred, abrupt withdrawal has not resulted in a formal withdrawal syndrome, and no cases of abuse or diversion have been reported to date. A formal abuse liability study of Sativex in experienced cannabis smokers showed some abuse potential in comparison with placebo at higher doses, but scores were consistently lower than equivalent doses of THC. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients.

Topics: Cannabidiol; Cannabinoids; Clinical Trials as Topic; Dronabinol; Drug Combinations; Humans; Marijuana Abuse; Multiple Sclerosis; Plant Extracts; Psychotropic Drugs; Randomized Controlled Trials as Topic; Substance-Related Disorders

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

Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.

Topics: Alzheimer Disease; Animals; Cannabidiol; Cytoprotection; Disease Models, Animal; Humans; Huntington Disease; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Prion Diseases

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

Bayer AG has recently announced that it acquired exclusive rights for the marketing of GW Pharmaceuticals' new medicine Sativex in Europe and in other regions. Sativex is a sublingual spray on Cannabis extract basis, and is equipped with an electronic tool to facilitate accurate dosing and to prevent misuses. It is standardized for the THC and CBD. The new analgesic is proposed for the treatment of muscle spasticity and pains accompanying multiple sclerosis and as an efficient analgetic for neurogenic pain not responding well to opioids and to other therapies available. The entirely new mechanism of action through the recently discovered cannabinoid receptor system may offer a real therapeutic potential to the drug. Although the Government of Netherlands has authorized the sale of pharmaceutical grade Cannabis herb by pharmacies in the Netherlands, the availability on the pharmaceutical market of the registered preparation may render requests for the authorization of the smoking of Cannabis herb (marihuana) by individuals suffering of multiple sclerosis, neurogenic pain, AIDS wasting syndrome unnecessary. Nevertheless, the "old chameleon" plant Cannabis appears to gradually regain its previous status in mainstream therapy and pharmacy. As long as the plant Cannabis and its products continue to be classified as narcotic drugs, medical use of the new preparation will need close supervision.

Topics: Analgesics; Arachidonic Acids; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Drugs, Investigational; Endocannabinoids; Europe; Humans; Multiple Sclerosis; Pain; Plant Extracts; Polyunsaturated Alkamides

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

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

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

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

The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment.. Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments.. We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration.. One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength.. Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

Topics: Adult; Brain; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Laser-Evoked Potentials; Male; Middle Aged; Multiple Sclerosis; Neuralgia; Pain Management; Pain Measurement; Plant Extracts; Transcranial Magnetic Stimulation

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

Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex(®) treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex(®) use if both are taken concurrently.

Topics: Adult; Australia; Cannabidiol; Cannabinol; Chromatography, Liquid; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Multiple Sclerosis; Muscle Relaxants, Central; Oral Sprays; Pilot Projects; Plant Extracts; Saliva; Substance Abuse Detection; Tandem Mass Spectrometry

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

Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of -0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effe

Topics: Administration, Mucosal; Administration, Oral; Adult; Analgesics, Non-Narcotic; Analysis of Variance; Cannabidiol; Double-Blind Method; Dronabinol; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Sclerosis; Neuralgia; Pain Measurement; Treatment Outcome

  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

Bladder dysfunction is a common feature of multiple sclerosis (MS).. In this study we aimed to assess the efficacy, tolerability and safety of Sativex(®) (nabiximols) as an add-on therapy in alleviating bladder symptoms in patients with MS.. We undertook a 10-week, double-blind, randomized, placebo-controlled, parallel-group trial in 135 randomized subjects with MS and overactive bladder (OAB).. The primary endpoint was the reduction in daily number of urinary incontinence episodes from baseline to end of treatment (8 weeks). Other endpoints included incidence of nocturia and urgency, overall bladder condition (OBC), daytime frequency, Incontinence Quality of Life (I-QOL), Patient's Global Impression of Change (PGIC) and volume voided. The primary endpoint showed little difference between Sativex and placebo. Four out of seven secondary endpoints were significantly in favour of Sativex: number of episodes of nocturia (adjusted mean difference -0.28, p = 0.010), OBC (-1.16, p = 0.001), number of voids/day (-0.85, p = 0.001) and PGIC (p = 0.005). Of the other endpoints, number of daytime voids was statistically significantly in favour of Sativex (-0.57, p = 0.044). The improvement in I-QOL was in favour of Sativex but did not reach statistical significance.. Although the primary endpoint did not reach statistical significance, we conclude that Sativex did have some impact on the symptoms of overactive bladder in patients with MS, providing evidence of some improvement in symptoms associated with bladder dysfunction in these subjects.

Topics: Cannabidiol; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Plant Extracts; Urinary Bladder, Overactive

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

Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder analysis favoured active preparation, 40% of subjects achieved >30% benefit (P = 0.014). Eight withdrawals were attributed to adverse events (AEs); six were on active preparation and two on placebo. We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS.

Topics: Administration, Oral; Adult; Cannabidiol; Cannabinoids; Central Nervous System; Double-Blind Method; Dronabinol; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Placebos; Plant Extracts; Treatment Outcome

Central neuropathic pain (CNP), pain initiated or caused by a primary lesion or dysfunction of the central nervous system, occurs in ~28% of patients with multiple sclerosis (MS). Delta(9)-Tetrahydrocannabinol/cannabidiol (THC/CBD), an endocannabinoid system modulator, has demonstrated efficacy for up to 4 weeks in randomized controlled trials in the treatment of CNP in patients with MS.. The purpose of this extension was to establish long-term tolerability and effectiveness profiles for THC/CBD (Sativex (R), GW Pharmaceuticals plc, Salisbury, United Kingdom) oromucosal spray in CNP associated with MS.. This uncontrolled, open-label trial was an indefinite-duration extension of a previously reported 5-week randomized study in patients with MS and CNP. In the initial trial, patients were randomized to placebo or THC/CBD. Patients were only required to maintain their existing analgesia in the randomized study. In the open-label trial they could vary their other analgesia as required. All patients (placebo and THC/CBD) who completed the randomized trial commenced the open-label follow-up on THC/CBD (27 mg/mL: 25 mg/mL). Patients titrated their dosage, maintaining their existing analgesia. The primary end point of the trial was the number, frequency, and type of adverse events (AEs) reported by patients. Secondary end points included changes from baseline in 11-point numerical rating scale (NRS-11) neuropathic pain score, hematology and clinical chemistry test results, vital signs, trial drug usage, and intoxication visual analogue scale scores.. Sixty-six patients were enrolled in the randomized trial; 64 (97%) completed the randomized trial and 63 (95%) entered the open-label extension (race, white, 100%; sex, male, 14 [22%]; mean [SD] age, 49 [8.4] years [range, 27-71 years[). The mean (SD) duration of open-label treatment was 463 (378) days (median, 638 days; range, 3-917 days), with 34 (54%) patients completing >1 year of treatment with THC/CBD and 28 (44%) patients completing the open-label trial with a mean (SD) duration of treatment of 839 (42) days (median, 845 days; range, 701-917 days). Mean NRS-11 pain scores in the final week of the randomized trial were 3.8 in the treatment group and 5.0 in the placebo group. In the 28 (44%) patients who completed the 2-year follow up, the mean (SD) NRS-11 pain score in the final week of treatment was 2.9 (2.0) (range, 0-8.0). Fifty-eight (92%) patients experienced > or =1 treatment-related AE. These AEs were rated by the investigator as mild in 47 (75%) patients, moderate in 49 (78%), and severe in 32 (51%). The most commonly reported AEs were dizziness (27%), nausea (18 %), and feeling intoxicated (11%). Two treatment-related serious AEs (ventricular bigeminy and circulatory collapse) were judged to be treatment-related. Both serious AEs occurred in the same patient and resolved completely following a period of discontinuation. Eleven (17%) patients experienced oral discomfort, 4 persistently. Regular oral examinations revealed that 7 (11%) patients developed white buccal mucosal patches and 2 (3%) developed red buccal mucosal patches; all cases were deemed mild and resolved. Seventeen (25%) patients withdrew due to AEs. The mean number of sprays and patients experiencing intoxication remained stable throughout the follow-up trial.. THC/CBD was effective, with no evidence of tolerance, in these select patients with CNP and MS who completed approximately 2 years of treatment (n = 28). Ninety-two percent of patients experienced an AE, the most common of which were dizziness and nausea. The majority of AEs were deemed to be of mild to moderate severity by the investigators.

Topics: Administration, Oral; Administration, Sublingual; Adult; Aerosols; Analgesics, Opioid; Cannabidiol; Central Nervous System Diseases; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Mucosa; Multiple Sclerosis; Pain; Plant Extracts

To test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis. This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis (CAMS) study.. The CAMS study randomised 630 patients to receive oral administration of cannabis extract, Delta(9)-tetrahydrocannabinol (THC) or matched placebo. For this substudy subjects completed incontinence diaries.. All three groups showed a significant reduction, p<0.01, in adjusted episode rate (i.e. correcting for baseline imbalance) from baseline to the end of treatment: cannabis extract, 38%; THC, 33%; and placebo, 18%. Both active treatments showed significant effects over placebo (cannabis extract, p=0.005; THC, p=0.039).. The findings are suggestive of a clinical effect of cannabis on incontinence episodes in patients with MS. This is in contrast to the negative finding of the CAMS study, where no difference was seen in the primary outcome of spasticity.

Topics: Analgesics, Non-Narcotic; Cannabidiol; Cannabinoids; Comorbidity; Dronabinol; Female; Humans; Middle Aged; Multiple Sclerosis; Quality of Life; Urinary Incontinence, Urge; Urination; Urodynamics

Three Cannabis Based Medicinal Extracts (CBMEs) for sublingual use became available in 2000. A total of 34 'N of 1' studies were undertaken using this novel therapy for patients with chronic, mainly neuropathic, pain and associated symptoms to explore efficacy, tolerability, safety and dosages. Three CBMEs (Delta9 Tetrahydrocannabinol (THC), Cannabidiol (CBD) and a 1:1 mixture of them both) were given over a 12-week period. After an initial open-label period, the CBMEs were used in a randomised, double-blind, placebo controlled, crossover trial. Extracts which contained THC proved most effective in symptom control. Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed. Side-effects were common, reflecting a learning curve for both patient and study team. These were generally acceptable and little different to those seen when other psycho-active agents are used for chronic pain. These initial experiences with CBME open the way to more detailed and extensive studies.

Topics: Administration, Sublingual; Adult; Aged; Analgesics, Non-Narcotic; Cannabidiol; Chronic Disease; Cross-Over Studies; Depressive Disorder; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Pain; Pain Measurement; Patient Selection; Sleep; Treatment Outcome

Cannabis may alleviate some symptoms associated with multiple sclerosis (MS). This study investigated the effect of an orally administered standardized Cannabis sativa plant extract in MS patients with poorly controlled spasticity.. During their inpatient rehabilitation programme, 57 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled crossover study of cannabis-extract capsules standardized to 2.5 mg tetrahydrocannabinol (THC) and 0.9 mg cannabidiol (CBD) each. Patients in group A started with a drug escalation phase from 15 to maximally 30 mg THC by 5 mg per day if well tolerated, being on active medication for 14 days before starting placebo. Patients in group B started with placebo for seven days, crossed to the active period (14 days) and closed with a three-day placebo period (active drug dose escalation and placebo sham escalation as in group A). Measures used included daily self-report of spasm frequency and symptoms, Ashworth Scale, Rivermead Mobility Index, 10-m timed walk, nine-hole peg test, paced auditory serial addition test (PASAT), and the digit span test.. In the 50 patients included into the intention-to-treat analysis set, there were no statistically significant differences associated with active treatment compared to placebo, but trends in favour of active treatment were seen for spasm frequency, mobility and getting to sleep. In the 37 patients (per-protocol set) who received at least 90% of their prescribed dose, improvements in spasm frequency (P = 0.013) and mobility after excluding a patient who fell and stopped walking were seen (P = 0.01). Minor adverse events were slightly more frequent and severe during active treatment, and toxicity symptoms, which were generally mild, were more pronounced in the active phase.. A standardized Cannabis sativa plant extract might lower spasm frequency and increase mobility with tolerable side effects in MS patients with persistent spasticity not responding to other drugs.

Topics: Administration, Oral; Cannabidiol; Capsules; Cross-Over Studies; Double-Blind Method; Dronabinol; Humans; Movement; Multiple Sclerosis; Muscle Spasticity; Sleep

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.

Topics: Aerosols; Cannabidiol; Cannabis; Disability Evaluation; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Humans; Mouth Mucosa; Multiple Sclerosis; Muscle Spasticity; Pain; Pain Measurement; Plant Extracts; Tremor; Urinary Bladder Diseases

Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis.. We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Delta9-tetrahydrocannabinol (Delta9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat.. 611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0.40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 (95% CI -1.04 to 1.67), and for those taking Delta9-THC versus placebo it was 0.94 (-0.44 to 2.31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0.003), with improvement in spasticity reported in 61% (n=121, 95% CI 54.6-68.2), 60% (n=108, 52.5-66.8), and 46% (n=91, 39.0-52.9) of participants on cannabis extract, Delta9-THC, and placebo, respectively.. Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.

Topics: Cannabidiol; Cannabinoids; Dronabinol; Female; Humans; Locomotion; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Outcome Assessment, Health Care; Physical Examination; Placebos; Secondary Prevention; Treatment Outcome; United Kingdom; Walking

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

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

Cannabinoids are widely studied as therapeutic agents for the treatment of various diseases. Among them, THC and CBD are two important phytocannabinoids which have served as structural templates for the design of synthetic analogs. In this study, we designed and synthesized a variety of novel cannabinoids based on the structural backbones of THC and CBD using the carbon-silicon switch strategy. A dimethyl silyl group was introduced as the tail group and two series of novel compounds were designed and synthesized, which showed a wide range of binding affinity for CB1 and CB2 receptors. Among them, compound 15b was identified as a non-selective CB1 and CB2 agonist and 38b as a selective agonist for the CB2 receptor. Preliminary screening showed that both compounds have improved metabolic stability than their carbon analogs and good in vivo pharmacokinetic profiles. Furthermore, both 15b and 38b significantly alleviated the phenotype of experimental autoimmune encephalomyelitis (EAE) in mice.

Topics: Animals; Cannabinoids; Carbon; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Encephalomyelitis, Autoimmune, Experimental; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Multiple Sclerosis; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Silicon; Structure-Activity Relationship

The use of cannabis as medical therapy to treat chronic pain and spasticity in patients with multiple sclerosis (MS) is increasing. However, the evidence on safety when initiating treatment with medical cannabis oils is limited. The aim of this study was to investigate the safety of sublingual medical cannabis oils in patients with MS.. In this prospective observational safety study 28 patients with MS were treated with medical cannabis oils (THC-rich, CBD-rich and THC+CBD combined products) and were followed during a titration period of four weeks. Patients were evaluated at treatment start (Visit 1) and after four weeks treatment (Visit 2). At each visit neurological examination (Expanded Disability Status Scale - EDSS), ambulation (Timed 25-Foot Walk Test - T25FWT), routine blood tests, plasma cannabinoids, dexterity (9-Hole Peg Test - 9-HPT) and processing speed (Symbol Digit Modalities Test - SDMT) were tested. Adverse events (AEs) and tolerability were reported at Visit 2. Secondary, efficacy of medical cannabis on pain, spasticity and sleep disturbances were measured by numeric rating scale (NRS-11) each day during the 4-week treatment period.. During treatment with cannabis preparations containing 10-25 mg/mL THC, the most common AEs were dry mouth, drowsiness, dizziness and nausea of mild to moderate degree. Two patients experienced pronounced symptoms with excessive dreaming and drowsiness, respectively, which led to treatment stop during the titration. Three serious adverse events (SAE) were reported but were not associated with the treatment. Mean doses of THC and CBD were 4.0 mg and 7.0 mg, respectively, and primarily administered as a once-daily evening dose. Furthermore, pain decreased from a median NRS score of 7 to 4, (p = 0.01), spasticity decreased from a median NRS score of 6 to 2.5 (p = 0.01) and sleep disturbances decreased from a median NRS score of 7 to 3 (p < 0.001). No impairment in disability, ambulation, dexterity or processing speed was observed.. Treatment with medical cannabis oils was safe and well tolerated, and resulted in a reduction in pain intensity, spasticity and sleep disturbances in MS patients. This suggests that medical cannabis oils can be used safely, especially at relatively low doses and with slow titration, as an alternative to treat MS-related symptoms when conventional therapy is inadequate.

Topics: Cannabidiol; Cannabis; Dronabinol; Humans; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Oils

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

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

This exploratory pilot study investigated the effects of chronic Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on cerebral glucose metabolism in people with multiple sclerosis (PwMS). Compared with nonusers, THC users had hypermetabolism of 3 regions (

Topics: Adult; Aged; Cannabidiol; Cerebral Cortex; Dronabinol; Female; Glucose; Humans; Male; Middle Aged; Multiple Sclerosis; Pilot Projects

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

Topics: Antiemetics; Antineoplastic Agents; Cannabidiol; Cannabinoid Receptor Agonists; Chronic Pain; Decision Making, Shared; Dronabinol; Drug and Narcotic Control; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Nausea; Needs Assessment; Physicians, Primary Care; Practice Guidelines as Topic; Specialization; United Kingdom; Vomiting

The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice.. MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms.. Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group.. Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

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

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, affecting ambulation even in people with only mild neurological signs. Patients with MS frequently experience spasticity, which contributes significantly to impair their motor functions, including ambulation, owing to muscle stiffness, spasms, and pain.. To clarify the role of delta-9-tetrahydrocannabinol(THC):cannabidiol(CBD) oromucosal spray, coupled to robot-aided gait training (RAGT) using the Lokomat©Pro to improve functional ambulation in patients with MS.. We compared 20 patients with MS, who were treated with THC:CBD oromucosal spray in add-on to the ongoing oral antispastic therapy (OAT) (group A), with 20 individuals with MS (matched for clinical-demographic characteristics) who were treated only with OAT (group B). Both the groups underwent RAGT using the Lokomat-Pro (three 45-minute sessions per week). Our primary outcome measures were the Functional Independence Measure (FIM) and the 10 meters walking test (10MWT). As secondary outcome measures we evaluated the brain cortical excitability by using Transcranial Magnetic Stimulation. Both parameters were taken before and after the end of the RAGT.. FIM improved in group A more than in group B (p<0.001). Moreover, 10MWT decreased in group A more than in group B (p<0.001). These clinical findings were paralleled by a more evident reshape of intracortical excitability in both upper and lower limbs, as suggested by motor evoked potential amplitude increase (p<0.001), intracortical inhibition strengthening (p<0.001), and intracortical facilitation decrease (p=0.01) in group A as compared to group B.. Our results suggest that the combined THC:CBD-RAGT approach could be useful in improving gait performance in patients with MS.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Gait; Humans; Multiple Sclerosis; Robotic Surgical Procedures

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

Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.. This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.. A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months.. THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Topics: Adult; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Patient Compliance; Prospective Studies; Time Factors; Treatment Outcome; Withholding Treatment

Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination. Recently a combination of Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated. In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells. These effects were mediated through CB1 and CB2 receptors inasmuch as, THC+CBD failed to ameliorate EAE in mice deficient in CB1 and CB2. THC+CBD treatment also caused a decrease in the levels of brain infiltrating CD4+ T cells and pro-inflammatory molecules (IL-17, INF-γ, TNF-α, IL-1β, IL-6, and TBX21), while increasing anti-inflammatory phenotype such as FoxP3, STAT5b, IL-4, IL-10, and TGF-β. Also, the brain-derived cells showed increased apoptosis along with decreased percentage in G0/G1 phase with increased percentage in G2/M phase of cell cycle. miRNA microarray analysis of brain-derived CD4+ T cells revealed that THC+CBD treatment significantly down-regulated miR-21a-5p, miR-31-5p, miR-122-5p, miR-146a-5p, miR-150-5p, miR-155-5p, and miR-27b-5p while upregulating miR-706-5p and miR-7116. Pathway analysis showed that majority of the down-regulated miRs targeted molecules involved in cycle arrest and apoptosis such as CDKN2A, BCL2L11, and CCNG1, as well as anti-inflammatory molecules such as SOCS1 and FoxP3. Additionally, transfection studies involving miR-21 and use of

Topics: Animals; Anti-Inflammatory Agents; Brain; Cannabidiol; Cells, Cultured; Cytokines; Dronabinol; Encephalomyelitis, Autoimmune, Experimental; Female; Leukocytes, Mononuclear; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Multiple Sclerosis; Signal Transduction; Spinal Cord; Spleen

Cannabidiol (CBD) has been shown by our laboratory to attenuate experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we used microarray and next generation sequencing (NGS)-based approaches to determine whether CBD would alter genome-wide histone modification and gene expression in MOG sensitized lymphocytes. We compared H3K4me3 and H3K27me3 marks in CD4+ T cells from naïve, EAE and CBD treated EAE mice by ChIP-seq. Although the overall methylation level of these two histone marks did not change significantly, the signal intensity and coverage differed in individual genes, suggesting that CBD may modulate gene expression by altering histone methylation. Further analysis showed that these histone methylation signals were differentially enriched in the binding sites of certain transcription factors, such as ZNF143 and FoxA1, suggesting that these transcription factors may play important roles in CBD mediated immune modulation. Using microarray analysis, we found that the expression pattern of many EAE-induced genes was reversed by CBD treatment which was consistent with its effect on attenuating the clinical symptoms of EAE. A unique finding of this study was that the expression of many miRNAs and lncRNAs was dramatically affected by CBD. In summary, this study demonstrates that CBD suppresses inflammation through multiple mechanisms, from histone methylation to miRNA to lncRNA.

Topics: Animals; Cannabidiol; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Histones; Methylation; Mice; Multiple Sclerosis; Protein Processing, Post-Translational; RNA, Untranslated

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: Animals; Cannabidiol; Cannabis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Glatiramer Acetate; Immunosuppressive Agents; Mice; Multiple Sclerosis; Plant Extracts

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

Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS). Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act. In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids. THC + CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-β. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A. muc), which was significantly reduced after THC + CBD treatment. Fecal Material Transfer (FMT) experiments confirmed that THC + CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A. muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC + CBD reversed this trend. EAE mice treated with THC + CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls. Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabis; Cytokines; Disease Models, Animal; Dronabinol; Dysbiosis; Encephalomyelitis, Autoimmune, Experimental; Female; Gastrointestinal Microbiome; Inflammation; Interferon-gamma; Interleukin-17; Mice; Mice, Inbred C57BL; Multiple Sclerosis; RNA, Ribosomal, 16S

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

Lower urinary tract dysfunctions (LUTDs) are commonly reported in multiple sclerosis (MS) patients and are mainly related to neurogenic overactive bladder (OAB). The aim of this observational study was to assess the effect of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray on resistant OAB by means of clinical and instrumental tools. Twenty-one MS patients were screened, and 15 cases have been evaluated. They underwent a specific clinical assessment (overactive bladder symptom score, OABSS) and a urodynamic assessment evaluating the maximal cystometric capacity (CCmax), bladder compliance (Qmax), maximum detrusor pressure (Pdet max), detrusor pressure at the first desire (Pdet first), bladder volume at the first desire (BVFD), leakage volume (LV), and post-void residual volume (PVR), before and after 4 weeks of THC/CBD administration. A complete neurological evaluation, including the assessment of their spasticity using the Modified Ashworth Scale (MAS) and the spasticity 0-10 numerical rating scale (NRS), was performed at the same times. Mobility was evaluated through the 25-ft walking-time test (T25-WT). The THC/CBD treatment successfully reduced the OAB symptoms (p = 0.001). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016), while BVFD and CCmax were increased although the difference was not statistically significant. THC/CBD oromucosal spray has shown to be effective in improving overactive bladder symptoms in MS patients demonstrating a favorable impact on detrusor overactivity.

Topics: Administration, Mucosal; Administration, Oral; Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Pilot Projects; Prospective Studies; Treatment Outcome; Urinary Bladder, Overactive

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

Nabiximols (Sativex. Whole-genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non-responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro-inflammatory agents to support the immunomodulatory properties of the drug.. Individual effect size was modest; however, we observed a downregulation of several immune-related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS.. Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.

Topics: Adult; Cannabidiol; Down-Regulation; Dronabinol; Drug Combinations; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis

Topics: Cannabidiol; Cannabinoids; Down-Regulation; Dronabinol; Drug Combinations; Humans; Immunomodulation; Multiple Sclerosis

To examine evolution in activities of daily living (ADL) in patients with multiple sclerosis spasticity during long-term use of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray.. Functional impairment was assessed retrospectively (prior to start of treatment) and at the present moment using a 16-item ADL survey; results were compared. A control group without add-on THC:CBD oromucosal spray was included to investigate possible recall bias.. ADL was maintained or slightly improved with THC:CBD oromucosal spray across treatment time (mean 31.9 months) including significant improvement in 'standing up' (p < 0.05) and trends in other items. Significant improvements (p < 0.01) with THC:CBD oromucosal spray were observed in several multiple sclerosis spasticity-related symptoms. Overall, 96.9% of patients using THC:CBD oromucosal spray had a positive global impression of change during treatment.. In this pilot study, THC:CBD oromucosal spray maintained or improved aspects of daily functioning. Further study in a larger trial is warranted.

Topics: Activities of Daily Living; Adult; Cannabidiol; Dronabinol; Drug Combinations; Drug Delivery Systems; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Retrospective Studies; Statistics, Nonparametric; Treatment Outcome

Multiple sclerosis (MS) is a chronic debilitating autoimmune disease without a cure. While the use of marijuana cannabinoids for MS has recently been approved in some countries, the precise mechanism of action leading to attenuate neuroinflammation is not clear. We used experimental autoimmune encephalomyelitis (EAE), a murine model of MS, to explore the anti-inflammatory properties of cannabidiol (CBD), a non-psychoactive cannabinoid. Treatment with CBD caused attenuation of EAE disease paradigms as indicated by a significant reduction in clinical scores of paralysis, decreased T cell infiltration in the central nervous system, and reduced levels of IL-17 and IFNγ. Interestingly, CBD treatment led to a profound increase in myeloid-derived suppressor cells (MDSCs) in EAE mice when compared to the vehicle-treated EAE controls. These MDSCs caused robust inhibition of MOG-induced proliferation of T cells

Topics: Adoptive Transfer; Animals; Autoimmunity; Cannabidiol; Cytokines; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation Mediators; Lymphocyte Activation; Mice; Multiple Sclerosis; Myeloid-Derived Suppressor Cells; T-Lymphocyte Subsets; Transcription Factors; Treatment Outcome

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

Each year at the Multiple Sclerosis Experts Summit, relevant research in the field of multiple sclerosis spasticity is featured in poster sessions. The main studies presented at this year's meeting are summarized herein.

Topics: Cannabidiol; Dronabinol; Humans; Multiple Sclerosis; Muscle Spasticity; Neuromuscular Agents; Oral Sprays

A combination of molecular modeling and structure-activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.

Topics: Dose-Response Relationship, Drug; HEK293 Cells; Humans; Models, Molecular; Molecular Structure; Multiple Sclerosis; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

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

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40-week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 ± 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 ± 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms.

Topics: Adult; Aged; Cannabidiol; Cohort Studies; Dronabinol; Female; Follow-Up Studies; Humans; Italy; Male; Middle Aged; Mouth Mucosa; Multiple Sclerosis; Muscle Spasticity; Oral Sprays; Time Factors; Treatment Outcome; Young Adult

Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales.. A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone.. At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at £3,836/patient (ICER: £10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -£33,609/patient (ICER: -£95,423/QALY).. The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity.

Topics: Adult; Cannabidiol; Cost Savings; Cost-Benefit Analysis; Dronabinol; Hospitalization; Humans; Markov Chains; Models, Economic; Multiple Sclerosis; Muscle Spasticity; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Wales

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

Since 2013 in the Italian market has been introduced the Nabiximols, a drug containing two of the main active cannabinoids: Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and cannabidiol (CBD). This drug has been approved in Italy in the treatment of Multiple Sclerosis (MS). It is an oral spray formulation and each puff of 100μl contains 2.7mg of Δ(9)-THC and 2.5mg of CBD. In the present study we analyzed urine and blood samples collected from a group of 20 patients treated with Nabiximols in order to evaluate: blood Δ(9)-THC concentrations in relation to the dose administered and the duration of treatment and the potentiality of this medication to be used for drug habit.. The study was conducted on a sample group of patients affected by MS, of both sexes, age: 49-61 years, treated with Nabiximols for short (28 days) or long-term. The results of our study allow affirming that it is unlikely to use this medication for drug habit or to sale it in the black market because of the low blood concentrations available and of its high costs. These statements were confirmed by: (a) the low Δ(9)-THC concentrations in the pharmaceutical formulation; (b) the low blood concentrations produced by Nabiximols administration, more than 10 times smaller than the blood concentrations known to produce psychotropic effects; (c) the presence of CBD (Δ(9)-THC natural antagonist); (d) the route of administration (inhaled, not smoked).

Topics: Administration, Inhalation; Analgesics, Non-Narcotic; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Female; Forensic Toxicology; Humans; Male; Middle Aged; Multiple Sclerosis; Pain, Intractable

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

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

Sativex(®) is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS.. A Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures.. Sativex improved motor activity - reduced CNS infiltrates, microglial activity, axonal damage - and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ(9) -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors.. The data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.

Topics: Animals; Cannabidiol; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Dronabinol; Drug Combinations; Drug Therapy, Combination; Mice; Mice, Inbred Strains; Multiple Sclerosis; Plant Extracts; Theilovirus

Nabiximols (Sativex) is an oromucosal spray, containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), used as treatment for unresponsive spasticity in multiple sclerosis (MS) patients. Sativex is thought to not affect cognition or induce any psychiatric problem at the doses generally used. Nonetheless, it is known that the concomitant use of more than one muscle-relaxant drugs can result in additive neuropsychiatric effects. Herein we describe a case of a woman affected by MS and treated with baclofen and methylprednisolone, who developed important behavioral changes, including suicidal ideation, after 4 weeks of Sativex administration. We are not completely able to state if Sativex alone was responsible for our patient's psychiatric symptoms, in reason of the concomitant use of the other drugs.In conclusion, physicians should pay more attention when prescribing drugs to MS patients affected by spasticity, including Sativex, since neurobehavioral side effects may emerge especially in predisposed individuals.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Middle Aged; Multiple Sclerosis; Self-Injurious Behavior; Suicidal Ideation

The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown.. Using wire myography, the vascular effects of CBD were assessed in human mesenteric arteries, and the mechanisms of action probed pharmacologically. CBD-induced intracellular signalling was characterized using human aortic endothelial cells (HAECs). CBD caused acute, non-recoverable vasorelaxation of human mesenteric arteries with an Rmax of ∼ 40%. This was inhibited by cannabinoid receptor 1 (CB1) receptor antagonists, desensitization of transient receptor potential channels using capsaicin, removal of the endothelium, and inhibition of potassium efflux. There was no role for cannabinoid receptor-2 (CB2) receptor, peroxisome proliferator activated receptor (PPAR)γ, the novel endothelial cannabinoid receptor (CBe), or cyclooxygenase. CBD-induced vasorelaxation was blunted in males, and in patients with type 2 diabetes or hypercholesterolemia. In HAECs, CBD significantly reduced phosphorylated JNK, NFκB, p70s6 K and STAT5, and significantly increased phosphorylated CREB, ERK1/2, and Akt levels. CBD also increased phosphorylated eNOS (ser1177), which was correlated with increased levels of ERK1/2 and Akt levels. CB1 receptor antagonism prevented the increase in eNOS phosphorylation.. This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent.

Topics: Adult; Aged; Aged, 80 and over; Cannabidiol; Endothelium, Vascular; Female; Humans; Male; Mesenteric Arteries; Middle Aged; Multiple Sclerosis; Nitric Oxide; Receptor, Cannabinoid, CB1; Vasodilation; Vasodilator Agents

Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion-extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.

Topics: Adult; Biomechanical Phenomena; Cannabidiol; Dronabinol; Drug Combinations; Female; Gait Disorders, Neurologic; Humans; Male; Middle Aged; Multiple Sclerosis; Outcome Assessment, Health Care; Severity of Illness Index; Walking

Topics: Animals; Canada; Cannabidiol; Cannabinol; Cannabis; China; Dronabinol; Drug and Narcotic Control; Drug Approval; Drug Combinations; Endocannabinoids; Herbal Medicine; History, 16th Century; History, 17th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; History, Medieval; Humans; Medical Marijuana; Multiple Sclerosis; New Orleans; Phytotherapy; Plant Extracts; Plants, Medicinal; Receptors, Cannabinoid

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

Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated. The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis.. Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunization with myelin oligodendroglial glycoprotein (MOG)35-55 peptide in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Disease signs were evaluated using a standardized scoring system.. Immunohistochemical and Western blot assessments of key apoptotic markers reveal that CBD treatment is able to avoid Fas pathway activation, phospho-ERK p42/44 and cleaved caspase-3 triggering as well as alterations in mitochondrial permeability due to Bax/Bcl-2 unbalance. Moreover, CBD interferes with p53-p21 axis activation. As results, the absence of tissue apobody formation in spinal cord tissues of EAE-mice treated with CBD was established. Most of therapeutic properties of CS are currently ascribed to the psychotropic effects of phenylterpenoid delta-9 tetrahydrocannabinol.. We have demonstrated that, alone, purified CBD possesses an anti-apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS.

Topics: Animals; Apoptosis; Cannabidiol; Cannabis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Male; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Phytotherapy; Plant Extracts

Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS.. Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression.. Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1).. THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile.

Topics: Adult; Aged; Analgesics, Non-Narcotic; Cannabidiol; Dronabinol; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Pain; Retrospective Studies; Treatment Outcome

This detailed medical charts' data collection study conducted at a multiple sclerosis (MS) clinic in Germany evaluated the effectiveness of tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray in patients with resistant MS spasticity. Over a 15-month timeframe, THC:CBD spray was initiated in 166 patients. Mean follow-up was 9 months. In all, 120 patients remained on treatment for a response rate of 72%. THC:CBD spray was used as add-on therapy in 95 patients and as monotherapy in 25 patients to achieve best-possible therapeutic results. Among responders, the mean spasticity 0-10 numerical rating scale (NRS) score decreased by 57%, from 7.0 before treatment to 3.0 within 10 days of starting THC:CBD spray. The mean dosage was 4 sprays/day. Most patients who withdrew from treatment (40/46) had been receiving THC:CBD spray for less than 60 days. Main reasons for treatment discontinuation were: adverse drug reactions, mainly dizziness, fatigue and oral discomfort (23 patients; 13.9%); lack of efficacy (14 patients; 8.4%); or need for a baclofen pump (9 patients; 5.4%). No new safety signals were noted with THC:CBD spray during the evaluation period. In this routine clinical practice setting at an MS clinic in Germany, THC:CBD spray was effective and well tolerated as add-on therapy or as monotherapy in a relevant proportion of patients with resistant MS spasticity.

Topics: Adult; Cannabidiol; Disability Evaluation; Dronabinol; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Muscle Spasticity; Retrospective Studies; Treatment Outcome

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

Topics: Administration, Oral; Affect; Cannabidiol; Dose-Response Relationship, Drug; Dronabinol; Drug Combinations; Germany; Humans; Marijuana Abuse; Marijuana Smoking; Medical Marijuana; Multiple Sclerosis; Pain, Intractable; Phytotherapy; Plant Extracts; Randomized Controlled Trials as Topic; Receptors, Cannabinoid; Risk Factors; Wasting Syndrome

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

In The Netherlands, pharmaceutical-grade cultivated cannabis is distributed for medicinal purposes as commissioned by the Ministry of Health. Few studies have thus far described its therapeutic efficacy or subjective (adverse) effects in patients. The aims of this study are to assess the therapeutic satisfaction within a group of patients using prescribed pharmaceutical-grade cannabis and to compare the subjective effects among the available strains with special focus on their delta-9-tetrahydrocannabinol and cannabidiol content. In a cross-sectional and natural design, users of pharmaceutical-grade cannabis were investigated with questionnaires. Medical background of the patients was asked as well as experienced therapeutic effects and characteristics of cannabis use. Subjective effects were measured with psychometric scales and used to compare among the strains of cannabis used across this group of patients. One hundred two patients were included; their average age was 53 years and 76% used it for more than a year preceding this study. Chronic pain (53%; n = 54) was the most common medical indication for using cannabis followed by multiple sclerosis (23%; n = 23), and 86% (n = 88) of patients (almost) always experienced therapeutic satisfaction when using pharmaceutical cannabis. Dejection, anxiety, and appetite stimulation were found to differ among the 3 strains of cannabis. These results show that patients report therapeutic satisfaction with pharmaceutical cannabis, mainly pain alleviation. Some subjective effects were found to differ among the available strains of cannabis, which is discussed in relation to their different tetrahydrocannabinol/cannabidiol content. These results may aid in further research and critical appraisal for medicinally prescribed cannabis products.

Topics: Adult; Aged; Aged, 80 and over; Cannabidiol; Cannabis; Chronic Pain; Cross-Sectional Studies; Dronabinol; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Netherlands; Patient Satisfaction; Phytotherapy; Plant Preparations; Psychometrics; Surveys and Questionnaires; Treatment Outcome; Young Adult

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

Conventional drugs have only a limited impact on spasticity associated with multiple sclerosis and are rarely satisfactory. A solution for oral transmucosal delivery (spray) containing a mixture of cannabis extracts (2.7 mg of delta-9-tetrahydrocannabinol + 2.5 mg of cannabidiol per spray) has been granted marketing authorisation in France for patients who are inadequately relieved by standard treatments. Three double-blind, placebo-controlled trials in a total of about 300 patients tested this combination, in addition to ongoing treatment, for periods of 6 to 14 weeks. Individually, none of these trials showed any tangible anti-spastic efficacy, but two combined analyses showed "response rates" of about 35% with the mixture versus about 25% with placebo. In a trial with 572 patients, the 241 patients who "responded" after 4 weeks of treatment were randomised to either continue using the cannabis extract or receive placebo. Twelve weeks later, 75% of patients using the extract were still "responders", versus 51% of patients switched to placebo. The principal adverse effects of the cannabis extracts consist of neuropsychiatric disorders that resolve on treatment withdrawal. The potential for abuse increases with the dose and is tangible from 16 sprays per day. Pharmacokinetic interactions due to P-glycoprotein inhibition are likely. Treatment during pregnancy may lead to neonatal withdrawal symptoms. In practice, about 10% of patients in whom standard anti-spastic medications are unsatisfactory benefit from a specific effect of the cannabis extracts contained in this oral spray.

Topics: Administration, Mucosal; Aerosols; Cannabidiol; Dronabinol; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Packaging; Drug Storage; Evidence-Based Medicine; Humans; Multiple Sclerosis; Neuromuscular Agents; Treatment Outcome

Topics: Analgesics; Cannabidiol; Capital Financing; Charities; Dronabinol; Drug Combinations; Drug Industry; Humans; Multiple Sclerosis; Self-Help Groups; United Kingdom

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

Topics: Analgesics; Cannabidiol; Capital Financing; Charities; Dronabinol; Drug Industry; Humans; Multiple Sclerosis

Topics: Analgesics; Cannabidiol; Capital Financing; Charities; Dronabinol; Drug Industry; Humans; Multiple Sclerosis

We investigated the efficiency of nasal drug administration as a new non-invasive treatment strategy for MS. Glatiramer Acetate (GA) and GA-Cannabidiol (CBD) combination administered in nasal delivery system (NDS) resulted in a statistically significant decrease of clinical scores and inflammatory cytokine expression in experimental autoimmune encephalomyelitis (EAE) mice. Even a suboptimal dose of Prednisolone in NDS was effective in preventing the clinical signs of the disease. Neuron regeneration was observed in the hippocampus of EAE mice treated with GA-CBD in NDS. This work shows that nasal administration improved drug efficiency and stimulates further research for a non-invasive strategy for MS.

Topics: Administration, Intranasal; Animals; Cannabidiol; Encephalomyelitis, Autoimmune, Experimental; Female; Glatiramer Acetate; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Nerve Regeneration; Peptides

Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1β, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.

Topics: Animals; Brain; Cannabidiol; Cardiovirus Infections; Cell Adhesion; Cells, Cultured; Chemokine CCL2; Chemokine CCL5; Disease Models, Animal; Endothelial Cells; Inflammation; Interleukin-1beta; Mice; Motor Activity; Multiple Sclerosis; Receptor, Adenosine A2A; Triazines; Triazoles; Vascular Cell Adhesion Molecule-1

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

To evaluate the effect of a Cannabis sativa extract enriched in cannabidiol (CBD) botanic drug substance (BDS) and pure CBD, on bladder contractility in vitro. Cannabis based-medicines, including CBD-enriched extracts, have been shown to reduce urinary urgency, incontinence episodes, frequency, and nocturia in patients with multiple sclerosis.. Strips were cut from male Wistar rats and the human bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation, acetylcholine, KCl, and α,β-methylene adenosine triphosphate.. CBD BDS significantly reduced the contractions induced by acetylcholine, but not those induced with electrical field stimulation, KCl, or α,β-methylene adenosine triphosphate in the isolated rat bladder. The inhibitory effect of CBD BDS was not significantly modified by the cannabinoid or opioid receptor antagonists or by modulators of calcium levels, but it was increased by ruthenium red and capsazepine, 2 transient receptor potential vanilloid type-1 blockers. In humans, CBD BDS and pure CBD significantly reduced acetylcholine-induced contractions, an effect that was not changed by the transient receptor potential vanilloid type-1 blockers.. Our data have suggested that CBD BDS reduces cholinergic-mediated contractility and that this effect is modulated by transient receptor potential vanilloid type-1 in rats but not in humans. CBD is the chemical ingredient of CBD BDS responsible for such activity. If confirmed in vivo, such results could provide a pharmacologic basis to explain, at least in part, the efficacy of Cannabis medicines in reducing incontinence episodes in patients with multiple sclerosis.

Topics: Acetylcholine; Animals; Cannabidiol; Cannabis; Cholinergic Agonists; Humans; In Vitro Techniques; Male; Multiple Sclerosis; Muscle Contraction; Muscle, Smooth; Plant Extracts; Rats; Rats, Wistar; Urinary Bladder; Urinary Incontinence

Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration.. We used experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice, as a model of multiple sclerosis. Using immunocytochemistry and cell proliferation assays we evaluated the effects of CBD on microglial activation in MOG-immunized animals and on MOG-specific T-cell proliferation.. Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE. This effect of CBD was accompanied by diminished axonal damage and inflammation as well as microglial activation and T-cell recruitment in the spinal cord of MOG-injected mice. Moreover, CBD inhibited MOG-induced T-cell proliferation in vitro at both low and high concentrations of the myelin antigen. This effect was not mediated via the known cannabinoid CB(1) and CB(2) receptors.. CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.

Topics: Animals; Cannabidiol; Diffuse Axonal Injury; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; Nerve Degeneration; Spinal Cord; T-Lymphocytes

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

Multiple sclerosis (MS) is a chronic neurological disease that affects 240 per 100 000 Canadians. Of these patients, 10-80% (average 70%) experience pain. Sativex is a cannabis-based drug recently approved for neuropathic pain.. In this study, we determine individuals' preferences between two treatment options as well as the willingness to pay (WTP) for Sativex, expressed as the amount they would pay in insurance premiums to have access to that treatment.. The WTP instrument comprised a decision board as a visual aid, and a questionnaire. A decision board helps clinicians standardize the presentation of treatment information. In this study, the decision board described two treatment options: a three-drug combination (gabapentin, amytriptyline, acetaminophen [paracetamol] {i.e. pills}) and the three-drug combination plus Sativex (i.e. 'pills and oral spray'). Information on efficacy and adverse effects was taken from trial data; wording was guided by a panel of neurologists and tested for clarity on lay people. The instrument was administered to 500 participants from Canada's general population using the bidding game approach. Descriptive statistics were calculated.. Mean (SD) age of participants was 39 (13) years, with a female : male distribution of 56 : 44. The decision board was presented in both English (85%) and French (15%). Of 500 interviewees, 253 (50.6%) chose the 'pills and oral spray'. Mean monthly WTP for the insurance premium for those who chose the 'pills and oral spray' was Can dollars 8 (SD +/- 15, median 4, range 0-200).. Assuming that 51% of the general population are willing to pay additional premiums as reported in this study, the premiums collected would cover the cost of Sativex for all Canadian MS patients experiencing pain, with a surplus.

Topics: Administration, Oral; Administration, Sublingual; Adult; Aerosols; Aged; Aged, 80 and over; Analgesics, Opioid; Attitude to Health; Cannabidiol; Cost-Benefit Analysis; Decision Making; Dronabinol; Drug Combinations; Fees and Charges; Female; Humans; Insurance, Health; Interviews as Topic; Male; Middle Aged; Multiple Sclerosis; Pain; Patient Satisfaction; Plant Extracts; Surveys and Questionnaires

In animal models, the cannabinoid system has been convincingly implicated in the regulation of long-lasting synaptic plasticity. Both long-term potentiation (LTP) and depression (LTD) phenomena can be induced in the human motor cortex by transcranial magnetic theta burst stimulation (TBS).. Here, we explored the potential involvement of the cannabinoid system in TBS-induced synaptic plasticity in humans.. We tested the effects of a cannabis-based preparation (Sativex) on continuous TBS (cTBS) and intermittent TBS (iTBS) protocols in subjects with multiple sclerosis.. We observed a shift in the polarity of synaptic plasticity induced by cTBS. In these subjects, in fact, cTBS induced the expected inhibition of motor-evoked potentials (MEPs) before Sativex exposure, whereas it caused a persisting enhancement of MEP amplitude 4 weeks after. The LTP-like phenomenon induced by iTBS was conversely unaffected by Sativex.. Our results indicate that cannabis ingredients have metaplastic effects on the motor cortex, and strongly suggest that the cannabinoid system is involved in the modulation of synaptic plasticity not only in rodents but also in humans.

Topics: Adult; Animals; Cannabidiol; Cannabinoids; Dronabinol; Drug Combinations; Evoked Potentials, Motor; Female; Humans; Long-Term Potentiation; Long-Term Synaptic Depression; Male; Middle Aged; Motor Cortex; Multiple Sclerosis; Neuronal Plasticity; Plant Extracts; Theta Rhythm; Transcranial Magnetic Stimulation

An oromucosal spray has been developed from the major components of marijuana (cannabis), including tetrahydrocannabinol (THC) and cannabidiol (CBD), in alcohol with a peppermint flavouring, designed to be administered as a spray under the tongue or on the buccal mucosa to relieve pain in multiple sclerosis. Although the available evidence indicates its efficacy in this respect, some patients develop oral burning sensation, stinging or white lesions, probably burns.. To investigate the oral side-effects of oromucosal cannabis spray in multiple sclerosis (MS) patients.. A small open observational study.. A series of nine patients with MS who had been using a marijuana oromucosal spray for at least four weeks, were asked to attend for oral examination. Patients were asked whether they had ever experienced symptoms (dryness; bad taste; stinging) associated with use of the spray. A standard oral examination was carried out using a dental light, and the presence of any mucosal lesions recorded. Where mucosal lesions were present, patients were advised to discontinue the spray and re-attend after four weeks for re-examination. For ethical reasons, biopsies were not undertaken at the first visit.. Of nine patients invited to participate, eight attended. All admitted to a stinging sensation on using the oromucosal cannabis spray, and four had visible oral mucosal white lesions in the floor of the mouth.. Although the white lesions observed were almost certainly burns, resolving or improving on discontinuation of use of the medication, the high alcohol concentration of the oromucosal cannabis spray raises concern in relation to chronic oral use.

Topics: Administration, Oral; Adult; Aerosols; Aged; Burns, Chemical; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Mucosa; Multiple Sclerosis; Pain; Phytotherapy; Plant Extracts

Topics: Canada; Cannabidiol; Cannabis; Dronabinol; Drug Approval; Drug Combinations; Humans; Multiple Sclerosis; Neuralgia; Phytotherapy; Plant Extracts

Sativex (R) is a cannabis-based pharmaceutical product containing delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:1 ratio, delivered in an oromucosal (mouth) spray. It has been approved as adjunctive treatment for neuropathic pain in patients with multiple sclerosis (MS). It is being investigated for the management of other MS symptoms, such as spasticity. THC:CBD spray is regulated as a narcotic. Five randomized controlled trials (RCTs) compared the benefits and harms of THC:CBD spray with placebo. A total of 368 patients with various neurological conditions (including MS) were recruited. In some trials, THC:CBD spray significantly reduced neuropathic pain, spasticity, muscle spasms and sleep disturbances. The most common adverse events (AEs) reported in trials were dizziness, sleepiness, fatigue, feeling of intoxication and a bad taste. Long-term safety and the potential for dependence, abuse, misuse and diversion are unknown.

Topics: Administration, Oral; Administration, Sublingual; Aerosols; Analgesics; Canada; Cannabidiol; Dronabinol; Drug Approval; Humans; Multiple Sclerosis; Muscle Spasticity; Pain; Phytotherapy; Plant Extracts; Randomized Controlled Trials as Topic; Sleep Wake Disorders; Tremor; United Kingdom

GW Pharmaceuticals is developing GW-1000 (Sativex), a narrow ratio delta9-tetrahydrocannabinol:cannabidiol product for the potential treatment of multiple sclerosis, spinal cord injury, neurogenic pain and peripheral neuropathy. In March 2003, the company filed for approval for the treatment of MS with the UK Medicines Control Agency, and in May 2004, filed for new drug submission with Health Canada.

Topics: Administration, Oral; Analgesics; Animals; Biological Availability; Canada; Cannabidiol; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dronabinol; Drug Approval; Drug Combinations; Drug Evaluation, Preclinical; Drug Industry; Humans; Hyperalgesia; Investigational New Drug Application; Mice; Molecular Structure; Multiple Sclerosis; Patents as Topic; Peripheral Nervous System Diseases; Phytotherapy; Plant Extracts; Plant Preparations; Randomized Controlled Trials as Topic; Spinal Cord Injuries; Structure-Activity Relationship

The majority of patients with multiple sclerosis (MS) develop troublesome lower urinary tract symptoms (LUTS). Anecdotal reports suggest that cannabis may alleviate LUTS, and cannabinoid receptors in the bladder and nervous system are potential pharmacological targets. In an open trial we evaluated the safety, tolerability, dose range, and efficacy of two whole-plant extracts of Cannabis sativa in patients with advanced MS and refractory LUTS. Patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg of each per spray) for eight weeks followed by THC-only (2.5 mg THC per spray) for a further eight weeks, and then into a long-term extension. Assessments included urinary frequency and volume charts, incontinence pad weights, cystometry and visual analogue scales for secondary troublesome symptoms. Twenty-one patients were recruited and data from 15 were evaluated. Urinary urgency, the number and volume of incontinence episodes, frequency and nocturia all decreased significantly following treatment (P <0.05, Wilcoxon's signed rank test). However, daily total voided, catheterized and urinary incontinence pad weights also decreased significantly on both extracts. Patient self-assessment of pain, spasticity and quality of sleep improved significantly (P <0.05, Wilcoxon's signed rank test) with pain improvement continuing up to median of 35 weeks. There were few troublesome side effects, suggesting that cannabis-based medicinal extracts are a safe and effective treatment for urinary and other problems in patients with advanced MS.

Topics: Adult; Cannabidiol; Cannabis; Dose-Response Relationship, Drug; Dronabinol; Drug Administration Schedule; Follow-Up Studies; Humans; Medical Records; Middle Aged; Multiple Sclerosis; Pilot Projects; Plant Extracts; Sensation; Surveys and Questionnaires; Treatment Outcome; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Incontinence; Urination; Urodynamics

Topics: Administration, Oral; Affect; Appetite; Cannabidiol; Cannabinoids; Cannabis; Clinical Trials, Phase III as Topic; Double-Blind Method; Dronabinol; Humans; Multiple Sclerosis; Muscle Spasticity; Neuralgia; Plant Extracts; Reflex, Abnormal; Safety; Sleep; Switzerland; Treatment Outcome; United Kingdom

Topics: Administration, Oral; Cannabidiol; Cannabinoids; Double-Blind Method; Dronabinol; Drug and Narcotic Control; Humans; Multicenter Studies as Topic; Multiple Sclerosis; Muscle Spasticity; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome; United States