CME Author: Vicki Brower
Study Authors: Nilo Riva, Gabriele Mora, et al., for the CANALS Study Group
Target Audience and Goal Statement:
Neurologists, pain physicians, internists, family physicians, and nurses
The goal was to explore the safety and effects of a standardized oromucosal spray (nabiximols, Sativex) containing a defined combination of delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on spasticity related to motor neuron disease.
Does nabiximols improve the symptoms of spasticity and pain in patients with amyotrophic lateral sclerosis (ALS) and other motor neuron diseases? If so, do the benefits outweigh the side effects?
Study Synopsis and Perspective:
Motor neuron disease patients receiving first-line anti-spasticity drugs followed by nabiximols 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.
They said that they believe that their study, called CANALS (Cannabis Sativa Extract in Amyotrophic Lateral Sclerosis and other Motor Neuron Disease) is the first randomized, double-blind, placebo-controlled trial of a drug for spasticity, as well as the first study of nabiximols in motor neuron disease.
Nabiximols had previously been shown to help relieve spasticity in multiple sclerosis (MS), the indication for which the agent is approved in the U.S. Preclinical studies of transgenic mice also supported the hypothesis that cannabinoids could exert an anti-spastic effect in ALS.
In the double-blind, proof-of-principle trial by Comi and co-authors, the team 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 ALS as defined by revised El Escorial criteria or PLS according to Pringle’s criteria, and had to have had spasticity symptoms for at least 3 months before the start of trial.
Participants also had to have been taking 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 days of treatment to a maximum of 12 actuations per 24 hours, and 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).
The researchers rated the spasticity of each participant’s joints on the Modified Ashworth Scale (MAS) at baseline and at 6 weeks. Patients also kept a daily symptom diary, recording their spasticity levels, pain, spasm frequency, and sleep disruption.
At 6 weeks, MAS scores had 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 percentage of patients treated with nabiximols who reported improvements (55%; 16/29 participants) was higher than in the placebo group (13%; 4/30). Self-reported pain scores also improved (-0.97 vs -0.06) in the nabiximols group.
A second encouraging result, the researchers found, was that the pain-relief score significantly improved in the treated patients vs the placebo group.
Comi and colleagues noted that the mechanism of action for pain in patients with ALS is not well understood, with musculoskeletal, cramps, contracture, spasticity, and neuropathic pain all thought to be possibly implicated.
The Lancet Neurology, Dec. 13, 2018; doi: 10.1016/S1474 (18)30406-X
Study Highlights: Explanation of Findings
An oromucosal spray containing two cannabis extracts helped reduce spasticity in motor neuron disease patients, including those with ALS, in the phase II CANALS proof-of-principle trial; the treatment also resulted in reduced pain.
“There is no cure for motor neuron disease so improved symptom control and quality of life are important for patients,” study 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. Despite these encouraging findings, however, we must first confirm that THC-CBD spray is effective and safe in larger, longer-term phase III trials.”
The team reported that nabiximols was well tolerated, with adverse events that were mild to moderate and typical of those for cannabinoids — i.e., nausea, dizziness, asthenia, and confusion. A total of 21 patients in the nabiximols group (72%) had at least one potentially treatment-related adverse event, but there were no serious adverse events and none of the patients had to permanently discontinue treatment.
The researchers said that interestingly, when patients given placebo crossed over to the treatment group during the open-label phase of the trial, there was a 50% reduction in the incidence of adverse events seen in patients who were already receiving the active drug. The investigators interpreted this to mean that a substantial number of adverse events could be related to the titration phase, which would be consistent with previous reports in MS.
This emphasizes the need to clinically monitor patients who are prescribed cannabinoids, especially in the first weeks of exposure, and the titration phase, Comi and colleagues said. On the other hand, no patients dropped out of the randomized study, whereas in the open-label part of the study, only five patients (8%) withdrew due to tolerability issues, which is similar to the rate in earlier studies.
Regarding nabiximols’ mechanism of action on spasticity, the CB1 receptors on central nervous system synapses appear to be the main targets of the cannabinoids, the researchers stated. Such targeting with cannabinoids then inhibits presynaptic calcium influx and reduces the release of glutamatergic neurotransmitters.
“THC, a partial agonist at both CB1 and CB2 receptors, mimics the negative feedback action of the endocannabinoid [THC and CBD], and thus reduces the excitatory effects of glutamate in spasticity,” the team explained, adding that CBD might have pain relief and anti-inflammatory properties via inhibiting tumor necrosis factor-alfa and enhancing signaling of the adenosine receptor A2A.
Writing in an accompanying editorial, Marianne de Visser, MD, PhD, of Amsterdam University Medical Center in the Netherlands, explained that because of the often life-threatening nature of motor neuron disease, spasticity and pain are typically not the first symptoms considered for alleviation.
Notably, she said, a Cochrane review of spasticity in motor neuron disease identified only one randomized controlled trial of moderate-intensity, endurance-type exercise versus usual activities in 25 patients with ALS, and concluded that further research was needed.
“In addition, available antispasticity drugs — i.e., baclofen, dantrolene, benzodiazepines, gabapentin, and levetiracetam — have been reported to reduce spasticity in patients with ALS, but no controlled studies have been done,” she continued. “Additionally, these medications can be associated with increased muscle weakness or fatigue.”
De Visser called the Riva et al. study promising, but also pointed to several limitations: “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. These patients could have benefited more than the 13 patients with classic amyotrophic lateral sclerosis, which involves both upper and lower motor neurons.”
The researchers also did not distinguish between upper and lower limb spasticity, or whether or not patients had bulbar spasticity, which could be important, de Visser said, since these patients may be differently affected by spasticity.
And while the MAS has been used in previous positive studies of the efficacy of other anti-spastic treatments, “as Riva and colleagues acknowledge, it lacked sensitivity in studies of the efficacy of cannabinoids in patients with MS-related spasticity, and new spasticity numeric ratings or visual analogue scales are being adopted,” de Visser wrote.
She recommended that before additional studies are done in ALS patients, research should be conducted first to determine how frequently spasticity is present in patients with motor neuron diseases, and whether reducing spasticity improves quality of life: “Natural history studies including all subtypes of motor neuron disease and better outcome measures of spasticity are required,” de Visser said.
Judy George wrote the original story for MedPage Today.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner