Action Points
- Although there is no
cure for motor neuron diseases such as amyotrophic lateral sclerosis
(ALS), improved symptom control of spasticity and pain are imprortant
for quality of life.
- In this phase II randomized, double-blind,
placebo-controlled trial, patients with ALS or other motor neuron
diseases who were treated with nabiximols, a cannabis derivative
comprised of 50% delta-9 tetrahydrocannabinol (THC) and 50% cannabidiol
(CBD), had statistically improved measures of both spasticity and pain.
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.
Questions Addressed:
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.
Source Reference:
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
.
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Reviewed by
Robert Jasmer, MD
Associate Clinical Professor of Medicine, University of California,
San Francisco and Dorothy Caputo,
MA, BSN, RN, Nurse Planner
Óscar Fernández
Lucienne Costa-Frossard2, 
Paloma Montero
Lluis Ramió