Daily Practice Managing Resistant Multiple Sclerosis Spasticity With Delta-9-Tetrahydrocannabinol: Cannabidiol Oromucosal Spray: A Systematic Review of Observational Studies.

 Image result for journal of central nervous system disease“Spasticity is one of the most common symptoms in people with multiple sclerosis (MS). Conventional anti-spasticity agents have limitations in their efficacy and tolerability.

Delta-9-tetrahydrocannabinol: cannabidiol (THC:CBD) spray, a cannabinoid-based medicine, is approved as an add-on therapy for MS spasticity not adequately controlled by other anti-spasticity medications. The results from randomized controlled trials (RCTs) have demonstrated a reduction in the severity of spasticity and associated symptoms. However, RCTs do not always reflect real-life outcomes. We systematically reviewed the complementary evidence from non-interventional real-world studies.

METHODS:

A systematic literature review was conducted to identify all non-RCT publications on THC:CBD spray between 2011 and 2017. Data on study design, patient characteristics, effectiveness, and safety outcomes were extracted from those publications meeting our inclusion criteria.

RESULTS:

In total, we reviewed 14 real-world publications including observational studies and treatment registries. The proportion of patients reaching the threshold of minimal clinical important difference (MCID), with at least a 20% reduction of the spasticity Numeric Rating Scale (NRS) score after 4 weeks ranged from 41.9% to 82.9%. The reduction in the mean NRS spasticity score after 4 weeks was maintained over 6-12 months. The average daily dose was five to six sprays. Delta-9-tetrahydrocannabinol: cannabidiol was well tolerated in the evaluated studies in the same way as in the RCTs. No new or unexpected adverse events or safety signals were reported in everyday clinical practice.

CONCLUSIONS:

The data evaluated in this systematic review provide evidence for the efficacy and safety of THC:CBD in clinical practice and confirm results obtained in RCTs.”

https://www.ncbi.nlm.nih.gov/pubmed/30886530

https://journals.sagepub.com/doi/10.1177/1179573519831997

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Special Considerations and Assessment in Patients with Multiple Sclerosis.

Physical Medicine and Rehabilitation Clinics of North America

“Multiple sclerosis is a progressive autoimmune neurologic disorder that may affect any region of the central nervous system. Spasticity in patients with multiple sclerosis can be debilitating and detrimental to the function and quality of life of patients. Treatment options include oral medications, chemodenervation, physical therapy, and modalities.

Cannabinoids in the form of a delta-9-tetrahydrocannabinol/cannabidiol oro-mucosal spray has been shown to be effective in addressing spasticity in multiple sclerosis.

Successful treatment of spasticity will be integrated, multimodal, and individualized.”

https://www.ncbi.nlm.nih.gov/pubmed/30626509

https://www.sciencedirect.com/science/article/pii/S1047965118307617?via%3Dihub

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Multiple sclerosis symptoms and spasticity management: new data.

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“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.”

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Sativex® effects on promoter methylation and on CNR1/CNR2 expression in peripheral blood mononuclear cells of progressive multiple sclerosis patients.

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“Multiple sclerosis (MS) is a chronic demyelinating central nervous system (CNS) disease that involve oligodendrocyte loss and failure to remyelinate damaged brain areas causing a progressive neurological disability.

Studies in MS mouse model suggest that cannabinoids ameliorate symptoms as spasticity, tremor and pain reducing inflammation via cannabinoid-mediated system.

The aim of our study is to investigate the changes in cannabinoid type 1 (CNR1) and 2 (CNR2) receptors mRNA expression levels and promoter methylation in peripheral blood mononuclear cells (PBMCs) of MS secondary progressive (MSS-SP) patients treated with Sativex®.

These results suggest that the different expression of cannabinoid receptors by Sativex® treatment in leukocytes might be regulated through a molecular mechanism that involve interferon modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/28716266

http://www.jns-journal.com/article/S0022-510X(17)30392-1/fulltext

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Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

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“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex®, nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients 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.

Twelve weeks’ therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial.

Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice.

Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD.

THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized.

THC/CBD has low abuse potential and a low risk of psychoactive effects.

In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.”

https://www.ncbi.nlm.nih.gov/pubmed/28293911

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Brain cannabinoid systems as targets for the therapy of neurological disorders.

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“Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.” https://www.ncbi.nlm.nih.gov/pubmed/9974182 

“Endocannabinoid System in Neurological Disorders.” https://www.ncbi.nlm.nih.gov/pubmed/27364363
“Cannabinoids in the Treatment of Neurological Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604187/
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Medical Marijuana: Just the Beginning of a Long, Strange Trip?

Physical Therapy Journal

“Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids.

Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties.

Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation where they ultimately reach the central and peripheral nervous systems.

Alternatively, products containing THC, CBD, or a combination of both compounds, can also be ingested as oral tablets, or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body.

Although there is still a need for randomized controlled clinical trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice.

Physical therapists should therefore be aware of the options that are available for patients considering medical marijuana, and be ready to provide information for these patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27660328

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Cost effectiveness of oromucosal cannabis-based medicine (sativex®) for spasticity in multiple sclerosis.

“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.

CONCLUSIONS:

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.”

http://www.ncbi.nlm.nih.gov/pubmed/23072659

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Medicinal use of cannabis: history and current status.

Abstract

“OBJECTIVE:

To provide an overview of the history and pharmacology of cannabis in relation to current scientific knowledge concerning actual and potential therapeutic uses of cannabis preparations and pure cannabinoids.

METHODS:

The literature on therapeutic uses of cannabis and cannabinoids was assessed with respect to type of study design, quality and variability of data, independent replications by the same or other investigators, magnitude of effects, comparison with other available treatments and reported adverse effects. The results of this review were also compared with those of major international reviews of this topic in the past five years.

CONCLUSIONS:

Pure tetrahydrocannabinol and several analogues have shown significant therapeutic benefits in the relief of nausea and vomiting, and stimulation of appetite in patients with wasting syndrome. Recent evidence clearly demonstrates analgesic and anti-spasticity effects that will probably prove to be clinically useful. Reduction of intraocular pressure in glaucoma and bronchodilation in asthma are not sufficiently strong, long lasting or reliable to provide a valid basis for therapeutic use. The anticonvulsant effect of cannabidiol is sufficiently promising to warrant further properly designed clinical trials. There is still a major lack of long term pharmacokinetic data and information on drug interactions. For all the present and probable future uses, pure cannabinoids, administered orally, rectally or parenterally, have been shown to be effective, and they are free of the risks of chronic inflammatory disease of the airways and upper respiratory cancer that are associated with the smoking of crude cannabis. Smoking might be justified on compassionate grounds in terminally ill patients who are already accustomed to using cannabis in this manner. Future research will probably yield new synthetic analogues with better separation of therapeutic effects from undesired psychoactivity and other side effects, and with solubility properties that may permit topical administration in the eye, or aerosol inhalation for rapid systemic effect without the risks associated with smoke inhalation.”

http://www.ncbi.nlm.nih.gov/pubmed/11854770

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