BY LIZETTE BORRELI
A proof-of-concept clinical trial suggests an oral cannabis spray may ameliorate spasticity and pain in people with motor neuron disease, according to a report published online on December 13 in The Lancet Neurology.
Current treatments for spasticity in motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), include baclofen, dantrolene, and benzodiazepines, However, the study authors noted, these therapies have not been found to be wholly effective for improving spasticity, and the drugs are associated with undesirable side effects, such as muscle weakness or fatigue.
In CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease), a randomized, double-blind, placebo-controlled, phase 2 clinical trial, researchers found 55 percent of patients treated with nabiximols mouth spray (Sativex, GW Pharmaceuticals) reported overall improvements in spasticity and pain, compared with 13 percent in the placebo group.
Nabiximols was well-tolerated; the side effects ranged from mild to moderate with a profile typical of cannabinoids (nausea, dizziness, asthenia, and confusion were common). A total of 21 (72 percent) of participants in the nabiximols group had at least one potentially treatment-related adverse event, compared with four in the placebo group (13 percent), none of the patients permanently discontinued treatment during the double-blind phase.
"This study is, to our knowledge, the first randomized controlled trial of safety and efficacy of a pharmacological treatment for spasticity and the first trial of nabiximols in motor neuron disease," first author Nilo Riva, MD, of the IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and colleagues wrote.
Nabiximols is an oral spray that combines equal parts delta-9 tetrahydrocannabinol and cannabidiol (THC-CBD). Outside the US, many countries have licensed nabiximols for the treatment of spasticity in MS. This suggests a potential for efficacy in improving spasticity in other diseases.
For their analysis, the researchers enrolled 60 patients (59 were included in the final analysis), aged between 18 to 80 years, from four tertiary motor neuron disease centers in Italy in between January 2013 and December 2014.
Prior to the trial, patients had to have at least three months of spasticity symptoms associated with known or suspected ALS or primary lateral sclerosis (PLS) who were already taking an anti-spasticity medication for at least 30 days before enrollment and throughout the study.
The team randomized patients to either add-on treatment with nabiximols (n=29) or placebo (n=30) for six weeks. Each 100 µL actuation of nabiximols contained 2.7 mg THC and 2.5 mg CBD. During the first 14 days of treatment, participants self-titrated to a maximum of 12 actuations per 24 hours; the dose was maintained for four weeks. After dose titration, the average number of daily actuations was 8.03 in the nabiximols group and 11.2 in the placebo group (p<0.0001).
Using the Modified Ashworth Scale (MAS), which measures muscle tone intensity, the researchers rated the spasticity of each participant's joints at baseline and at six weeks.
To record spasticity levels, pain, spasm frequency, and sleep disruption, participants filled out a daily symptom diary.
At six weeks, an improvement in spasticity was seen by a mean of 0.11 in the nabiximols group compared to a deterioration of a mean of 0.16 in the placebo group (adjusted effect estimate –0.32, 95% CI –0.57 to –0.069; p=0.013).
The researchers noted greater improvements in self-reported pain scores on a scale of 0 to 10; nabiximols (-0.97 vs -0.06). In patient-reported global impression of change also improved (p=.001).
No significant changes were seen in sleep quality, spasms, spasticity, strength, upper and lower motor neuron tests, and scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised, did show some benefit.
The study authors said the study's findings warrant the need for further research on the effects of nabiximols in different pain subtypes.
Study limitations included the MAS, which may not fully represent patients' experience of spasticity, and self-reported measures could also inaccurately represent spasticity.
The Italian Research Foundation for Amyotrophic Lateral Sclerosis funded the study. The researchers reported several conflicts of interest: Mora reported grants and nonfinancial support from the Italian Ministry of Health and grants from Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica and EU Joint Programme — Neurodegenerative Disease Research Project. Comi reported receiving personal fees from Almirall, Bayer, Biogen, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Serono Symposia International Foundation, Receptos, and Teva.
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Riva N, Mora G, Soraru G, et al. Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2018; Epub 2018 Dec 13.