BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.
OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews.
SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS.
DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence.
MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
BACKGROUND: Tremor is a relatively common symptom in Multiple Sclerosis (MS). It can negatively affect several aspects of the patients' life and is one of the most disabling symptoms in MS. Pharmacological treatment of MS-related tremor was studied for several years, though treatment is still challenging. This study will review all studies on the pharmacological treatment of tremor in MS and update the treatment recommendations.
METHODS: Any relevant English-language clinical trial that investigated the pharmacological treatment of MS-related tremor in adults was eligible in this study. We searched Medline (PubMed), Scopus, EMBASE, and Web of Science. Bias assessment was performed by the CASP (Critical Appraisal Skills Programme) checklist. All methods followed PRISMA guidelines.
RESULTS: The initial search resulted in 3024 articles; 26 articles were included as eligible studies, 13 articles had a low risk of bias, and remained for full manuscript review. The results of studies on 5-HT3 receptor antagonists as a single dose treatment were inconsistent. Botulinum toxin A had significant effects on MS-related tremor, but adverse effects and injection procedures limited its application. The application of cannabis-based medicine to treat MS-related tremor could not be recommended due to inconclusive therapeutic effects and several side effects. Levetiracetam had inconsistent results, and other anti-epileptic drugs were not studied precisely. Isoniazid has minor therapeutic effects and possible adverse effects in the treatment of MS-related tremor.
CONCLUSION: Further well-designed comparative clinical trials with a large sample size can improve clinical management of tremor in patients with MS.
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder of the central nervous system (CNS) that can cause cognition, mobility, and sensory impairments. It is considered one of the most common non-traumatic causes of disability in the world. The aim of the present article was to review the clinical evidence related to medicinal plants in the management of MS symptoms. Electronic databases, including the Cochrane Library, Pubmed, and Scopus, were searched for entries from 1966 to February 2017. Only clinical studies were included in this review. Different medicinal plants have positive effects on MS, including Andrographis paniculata, Boswellia papyrifera, Ruta graveolens, Vaccinium spp., Camellia sinensis, Panax ginseng, Aloysia citrodora, Ginkgo biloba, Oenothera biennis, and Cannabis sativa. C. sativa had the highest level of clinical evidence, supporting its efficacy in MS symptoms. Proanthocyanidins, ginkgo flavone glycosides, ginsenosides, epigallocatechin-3-gallate, cannabinoids (including delta-9-tetrahydrocannabinol and cannabidiol), boswellic acid, and andrographolide were presented as the main bioactive components of medicinal plants with therapeutic benefits in MS. The main complications of MS in which natural drugs were effective include spasticity, fatigue, scotoma, incontinence, urinary urgency, nocturia, memory performance, functional performance, and tremor. Herbal medicines were mostly well tolerated, and the adverse effects were limited to mild to moderate. Further well-designed human studies with a large sample size and longer follow-up period are recommended to confirm the role of medicinal plants and their metabolites in the management of MS.
We performed a systematic review of the scientific literature assessing the use of exogenous cannabinoids in the treatment of movement disorders including Huntington's disease, Parkinson's disease, Tourette's syndrome, tics, essential tremor, tremor associated with multiple sclerosis, Wilson's disease, dystonia, and myoclonus. Databases searched for articles published in English include: Pubmed, Web of Science, PsycINFO, and Clinicaltrials.gov. A total of 21 case series and clinical trials evaluating the use of cannabinoids in the treatment of movement disorders were identified. All studies either consisted of small sample sizes, or the primary outcome was not the effect of exogenous cannabinoid treatment on a specific movement. None of the studies reviewed were powered to detect a difference with the treatment of a cannabinoid agonist. Therefore, currently no conclusions can be made on the efficacy of cannabinoids in the treatment of movement disorders.
OBJETIVO: Determinar la eficacia de la marihuana medicinal en varias condiciones neurológicas.
MÉTODOS: Se realizó una revisión sistemática de la marihuana medicinal (1948 a noviembre de 2013) para abordar el tratamiento de los síntomas de la esclerosis múltiple (EM), trastornos de la epilepsia, y movimiento. Se calificaron los estudios de acuerdo con el esquema de la Academia Americana de Neurología de clasificación de los artículos terapéuticos.
RESULTADOS: Treinta y cuatro estudios cumplieron los criterios de inclusión; 8 fueron clasificados como Clase I.
CONCLUSIONES: Los siguientes fueron estudiados en pacientes con EM: (1) La espasticidad: extracto de cannabis oral (OCE) es eficaz, y Sativex y el tetrahidrocannabinol (THC) son probablemente eficaces, para reducir las medidas centradas en el paciente; es posible tanto OCE y el THC son eficaces para reducir tanto las medidas centradas en el paciente y objetivos a 1 año. (2) El dolor central o espasmos dolorosos (incluyendo dolor relacionado con la espasticidad, con exclusión de dolor neuropático): OCE es eficaz; THC y Sativex son probablemente eficaces. (3) la disfunción urinaria: Sativex es probablemente eficaz para reducir los huecos de la vejiga / día; THC y OCE son probablemente ineficaz para reducir las quejas de la vejiga. (4) Temblor: THC y OCE son probablemente ineficaces; Sativex es posiblemente ineficaz. (5) Otras condiciones neurológicas: OCE es probablemente ineficaz para el tratamiento de las discinesias inducidas por levodopa en pacientes con enfermedad de Parkinson. Cannabinoides orales son de la eficacia desconocida en los síntomas relacionados no-corea de la enfermedad de Huntington, síndrome de Tourette, distonía cervical, y la epilepsia. Los riesgos y beneficios de la marihuana medicinal deben sopesarse cuidadosamente. El riesgo de efectos psicopatológicos adversos graves fue casi un 1%. Comparación de la eficacia de la marihuana medicinal vs otras terapias es desconocido para estas indicaciones.
A pesar de que los extractos de la planta de cannabis se han utilizado con fines medicinales desde hace miles de años, es sólo en los últimos 2 décadas que nuestra comprensión de la fisiología de cannabinoides y la presentación de pruebas para el beneficio terapéutico de los cannabinoides ha comenzado a acumularse. Esta revisión proporciona un fondo a los avances en nuestra comprensión de los receptores cannabinoides y el sistema endocannabinoide, y luego se examina cómo los cannabinoides pueden ayudar en el tratamiento de la esclerosis múltiple (EM). La relativa escasez de tratamientos para los síntomas relacionados con la EM ha llevado a la experimentación por los pacientes con MS en un número de áreas incluyendo el uso de extractos de cannabis. Una cantidad creciente de evidencia está emergiendo confirmar los informes anecdóticos de mejoría de los síntomas, en particular para la rigidez muscular y espasmos, dolor neuropático y el sueño y trastornos de la vejiga, en los pacientes con EM tratados con cannabinoides. Los ensayos que evalúan un papel en el tratamiento de otros síntomas tales como temblores y nistagmo no han demostrado ningún efecto beneficioso de los cannabinoides. Los perfiles de seguridad de los cannabinoides parecen aceptables, aunque un período prolongado de titulación lenta mejora la tolerabilidad. No ha surgido ninguna preocupación sobre su seguridad. Ahora se están abordando cuestiones metodológicas en el diseño del ensayo y la aplicación del tratamiento. Además, la evidencia experimental reciente está empezando a sugerir un efecto de los cannabinoides en los procesos más fundamentales importantes en la EM, con evidencia de anti-inflamación, el fomento de la remielinización y neuroprotección. Los ensayos están en curso para probar si los cannabinoides pueden tener un papel más largo plazo en la reducción de la discapacidad y la progresión de la EM, además de la mejora del síntoma, cuando se establezcan las indicaciones.
ANTECEDENTES: la desactivación de temblor o ataxia es frecuente en la esclerosis múltiple (EM) y hasta el 80% de los pacientes experimentan temblor o ataxia en algún momento de su enfermedad. Una variedad de tratamientos disponibles, que van desde la neurocirugía estereotáctica para la farmacoterapia o la neurorrehabilitación.
OBJETIVOS: Evaluar la eficacia y tolerabilidad de los tratamientos tanto farmacológicos y no-farmacológicos de la ataxia en los pacientes con EM.
ESTRATEGIA DE BÚSQUEDA: LOS RECURSOS ELECTRÓNICOS DE LAS SIGUIENTES BÚSQUEDAS: Cochrane MS registro de ensayos del Grupo (junio de 2006), el Registro Cochrane Central de Ensayos Controlados (The Cochrane Library, Número 2, 2006), MEDLINE (enero 1966 hasta junio 2006), EMBASE (enero 1988 a junio de 2006) y en el National Health Service National Research Register (NRR), incluido el Consejo de Investigación Médica Directorio de Ensayos Clínicos (Número 2, 2006). Búsquedas manuales en las bibliografías de los artículos pertinentes, en las revistas médicas y neurología y libros de resúmenes de la neurología y las principales conferencias de MS (2001-2006) se llevaron a cabo también. Se buscó a través de comunicación directa con expertos y compañías farmacéuticas .
CRITERIOS DE SELECCIÓN: ciego, los ensayos aleatorios que eran controlados con placebo o que compararon dos o más tratamientos. Ensayos que probaban fármacos debe haber tenido tanto participante y el cegamiento del evaluador. Los ensayos que evalúan intervenciones quirúrgicas o los efectos de la fisioterapia, donde los participantes no podían haber sido cegados al tratamiento, deben haber tenido evaluadores independientes cegados al tratamiento. Se incluyeron ensayos entrecruzados.
RECOPILACIÓN Y ANÁLISIS DE DATOS: Tres revisores independientes extrajeron los datos y los resultados de los ensayos se resumieron. Un meta-análisis no se realizó debido a la insuficiencia de las medidas de resultado y los problemas metodológicos con los estudios revisados.
RESULTADOS PRINCIPALES: Se incluyeron diez ensayos controlados aleatorios que cumplieron con los criterios de inclusión. Seis estudios controlados con placebo (tratamiento farmacológico) y cuatro estudios comparativos (una neurocirugía estereotáctica y tres neurorehabilitación) fueron revisados. No existen medidas de resultado estandarizadas se usaron en los estudios. En general, los tratamientos farmacológicos fueron poco satisfactorias y datos sobre neurocirugía y rehabilitación no es suficiente para dar lugar a un cambio en la práctica.
CONCLUSIONES DE LOS REVISORES: La eficacia absoluta y comparativa y la tolerabilidad de los tratamientos farmacológicos para el tratamiento de la ataxia en la EM están mal documentadas y no se pueden hacer recomendaciones para guiar su indicación. Aunque los estudios sobre neurocirugía y rehabilitación neurológica mostró resultados prometedores, las indicaciones absolutas para el tratamiento con esos métodos no se pueden desarrollar. Medidas estandarizadas y validadas de ataxia y temblor deben desarrollarse y emplearse en grandes ensayos aleatorios controlados con cuidado.
Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.
OBJECTIVES:
To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
SEARCH METHODS:
We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews.
SELECTION CRITERIA:
We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS.
DATA COLLECTION AND ANALYSIS:
We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence.
MAIN RESULTS:
We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes •
PGIC:
cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS:
Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
