cannabidiol and Multiple-Sclerosis--Chronic-Progressive

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

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

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®. Our cohort included MSS-SP patients, that at the time of Sativex® treatment, are treated (n=7), not treated (n=11) or that had terminated interferon-β-1b (IFN-β-1b) therapy (n=12). By Methylation Sensitive High Resolution Melting (MS-HRM), we characterized the methylation profile of CNR1 and CNR2 promoter region, while the relative mRNA transcript levels of these two genes were evaluated in the same samples by Quantitative Real-Time PCR (qRT-PCR) analysis. We did not find different pattern of cytosine-phosphate-guanine (CpG) methylation in the CNR1/CNR2 promoter region of all MSS-SP patients treated with Sativex®. In addition, CNR1 and CNR2 expression did not significantly differ in MSS-SP patients not treated with IFN-β-1b vs. them that have suspended, while in MSS-SP patients treated with IFN-β-1b during Sativex® therapy we found a specific decrease of the CNR2 expression levels. 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.

Topics: Cannabidiol; Dronabinol; Drug Combinations; Female; Humans; Interferon beta-1b; Leukocytes, Mononuclear; Male; Methylation; Middle Aged; Multiple Sclerosis, Chronic Progressive; Promoter Regions, Genetic; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

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

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

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

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

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

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