An oromucosal spray containing cannabis extracts helped reduce spasticity in motor neuron disease patients, including those with amyotrophic lateral sclerosis (ALS), in the phase II CANALS trial in Italy.
Motor neuron disease patients taking first-line anti-spasticity drugs followed by nabiximols (Sativex), a cannabis derivative of equal parts delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), showed significant improvements in scores on the Modified Ashworth Scale at 6 weeks, reported Giancarlo Comi, MD, of the San Raffaele Scientific Institute in Milan, and colleagues in The Lancet Neurology.
“There is no cure for motor neuron disease so improved symptom control and quality of life are important for patients,” co-author Nilo Riva, MD, also of the San Raffaele Scientific Institute, said in a statement.
“Our proof-of-concept trial showed a beneficial effect of THC-CBD spray in people on treatment-resistant spasticity and pain,” Riva added. “Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer term phase III trials.”
The CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) study is the first randomized controlled trial of the safety and efficacy of a pharmacological treatment for motor neuron disease spasticity, as well as the first trial of nabiximols for it, the researchers noted.
Previously, nabiximols has been shown to help relieve spasticity in multiple sclerosis patients. Preclinical studies of transgenic mice also supported the hypothesis that cannabinoids could exert an anti-spastic effect in ALS.
In this double-blind trial, researchers studied 59 adults with ALS or primary lateral sclerosis (PLS) from four tertiary motor neuron disease centers in Italy in 2013 and 2014. Patients had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria or primary lateral sclerosis according to Pringle’s criteria, and experienced spasticity symptoms for at least 3 months before the trial. They also were on a stable dose of any anti-spasticity medication for 30 days before enrolling and throughout the study.
The investigators randomized patients to nabiximols mouth spray (n=29) or placebo (n=30) for 6 weeks. Each 100 µL actuation of nabiximols contained 2.7 mg THC and 2.5 mg CBD. Participants self-titrated during the first 14 treatment days to a maximum of 12 actuations per 24 hours, then maintained that dose for 4 weeks. After dose titration, the mean number of daily actuations was 8.03 in the nabiximols group and 11.2 in the placebo group (P<0.0001).
Physicians rated the spasticity of each participant’s joints on the Modified Ashworth Scale at baseline and at 6 weeks. Patients also kept a daily symptom diary, recording spasticity levels, pain, spasm frequency, and sleep disruption.
At 6 weeks, Modified Ashworth Scale scores improved by a mean of 0.11 in the nabiximols group, but deteriorated by 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 number of patients treated with nabiximols who reported improvements (55%; 16/29 participants) was higher than placebo (13%; 4/30). Self-reported pain scores also improved (-0.97 vs -0.06) in the nabiximols group.
Nabiximols was well tolerated and adverse events were mild to moderate and typical of cannabinoids; nausea, dizziness, asthenia, and confusion were common. Twenty-one patients (72%) in the nabiximols group reported at least one potentially treatment-related adverse event, but there were no serious adverse events and no one permanently discontinued treatment.
While the results of this study are promising, the trial had several limitations, observed Marianne de Visser, MD, PhD, of the Amsterdam University Medical Centre in the Netherlands, in an accompanying editorial.
“First, there was a bias towards patients with exclusive or predominant involvement of upper motor neurons (n=16) in the nabiximols group, in whom spasticity is the prevailing symptom,” de Visser wrote. “These patients could have benefited more than the 13 patients with classic amyotrophic lateral sclerosis, which involves both upper and lower motor neurons”.
Riva and colleagues did not distinguish between upper and lower limb spasticity, or whether or not patients had bulbar spasticity, she noted; these patients may be differently affected by spasticity.
And while the Modified Ashworth Scale has been used in previous positive studies of the efficacy of other anti-spastic treatments, de Visser wrote, “as Riva and colleagues acknowledge, it lacked sensitivity in studies of the efficacy of cannabinoids in patients with multiple-sclerosis-related spasticity, and new spasticity numeric ratings or visual analogue scales are being adopted.”
The trial had other limitations, the researchers noted. The study had a double-blind design, but the side effects of THC-CBD might have unmasked that. Other adverse effects may appear with long-term exposure. The sample size was too small and study duration too short to observe any potential neuroprotective effect of cannabinoids in slowing disease progression, as preclinical ALS studies have suggested, they added.
This study was funded by Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA) and Fondazione Vialli e Mauro (CANALS Project). GW Pharma provided the study drug and placebo.
Researchers reported relationships with Abbvie, Biogen, Excemed, Merck Serono, Novartis, Teva, Genzyme, Almirall, Kedrion, CSL Behring, Baxter, Chugai, Roche, Sanofi-Aventis, and Receptos.
The editorialist declared no competing interests.