Nabiximols, a cannabinoid-based oral spray (Sativex, GW Pharmaceuticals) approved outside the United States for various multiple sclerosis (MS) symptoms, shows benefit in improving spasticity and pain in motor neuron disease when administered as an add-on to standard therapy, new research suggests.

“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,” write the authors in their article published online December 13 in Lancet Neurology.

“Our results suggest that the study drug is well tolerated and provides first evidence of efficacy in terms of controlling spasticity in patients with motor neuron disease.”

Current treatments commonly used for spasticity in motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the most common and severe of these diseases, including baclofen, dantrolene, and benzodiazepines, lack evidence of efficacy in this context and are associated with undesirable side effects including increased muscle weakness or fatigue.

Nabiximols, an oral spray combining equal parts delta-9 tetrahydrocannabinol and cannabidiol (THC-CBD), has meanwhile gained favor in the treatment of spasticity in MS in countries outside of the United States where it is licensed, suggesting potential for efficacy in spasticity in other diseases.

For the current proof-of-concept study, first author Nilo Riva, MD, of the IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and colleagues enrolled 60 patients with at least 3 months of spasticity symptoms associated with known or suspected ALS or primary lateral sclerosis (PLS) who were already taking an anti-spasticity regimen for at least 30 days prior to enrollment.

Patients were randomized to add-on treatment with nabiximols at an escalated dose to a predefined level titrated over 14 days or placebo for 6 weeks.

The study reached its primary endpoint with improvement in spasticity, assessed by change in the spasticity score of the Modified Ashworth Scale (MAS), which measures intensity of muscle tone, by a mean of 0.11 (SD, 0.48) in the nabiximols group (n = 59) compared with a deterioration of a mean of 0.16 (SD, 0.47) in the placebo group (n = 30; P = .01) over the course of the study.

Greater improvements were also observed in pain scores, reported on a scale of 0 to 10, with nabiximols (-0.97 vs -0.06) and in patient-reported global impression of change (P = .001).

Although there were no significant differences in other secondary endpoints, including sleep quality, spasms, spasticity, strength, upper and lower motor neuron tests, and scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale — Revised, the scores suggested some benefit, Riva told Medscape Medical News.

“Although the effects on spasms, sleep disruption, and spasticity NRS scores were not significant, the direction of change was consistently in favor of the active treatment, and the pain NRS score improved significantly in nabiximols recipients,” Riva said.

The improvement was especially notable considering the patients’ existing regimens were falling short, Riva explained.

“The first-line anti-spasticity medications, including general muscle relaxants such as baclofen or benzodiazepines, usually work for some time, but as disease evolves, which can happen in months in ALS, the muscle rigidity may increase and a good number of patients require new management options,” said Riva.

Improvement in pain, which is also reported with the use of cannabinoids in other conditions, is also notably important, considering that it is a common complaint among people with motor neuron disease, Riva added.

“Although pain is an often neglected symptom in motor neuron disease, its prevalence has been reported to be as high as 51% to 80%, it negatively affects quality of life, and it necessitates specific treatment in 37% to 39% of patients.”

Similar to a previous study of cramps in ALS, no significant changes specifically in the intensity of spasms were seen in the study.

There were no serious adverse events. Although 21 (72%) of participants in the nabiximols group had at least one potentially treatment-related adverse event, compared with four in the placebo group (13%), none of the patients permanently discontinued treatment during the double-blind phase.

Non-serious adverse events were described as modest and were consistent with those common to cannabinoid treatment: three patients in the nabiximols group temporarily discontinuing treatment, one because of nausea and anxiety, one who had influenza and experienced a fall, and one who had disease progression.

Although nabiximols contain THC, the psychoactive component of cannabis, Riva noted that the levels are much lower than those typically associated with cannabis.

“The maximal levels of THC in blood (C_max) reached with this oromucosal spray medication are about 60 times lower than the levels reached through THC inhalation, so no psychoses-like effects were expected,” Riva said.

“The medication has been used in Europe by tens of thousands of multiple sclerosis patients [for] years without major psychoactive cases.”

Meanwhile, the THC is believed to have an important role in the anti-spasticity effect of nabiximols, Riva added. “The muscle relaxant effect of the medication has been related to low and continuous levels of THC, as well as analgesia.

“Cannabidiol alone has shown effect on epilepsy area, but not in a relevant manner on muscle relaxation or pain to my knowledge.”

After the 6-week double-blind phase of the study, all participants had the opportunity to enroll in an open-label phase, and among them, two patients did not continue and seven patients ended up withdrawing from the open-label phase because of side effects or disease progression.

Meanwhile, participants who had been in the placebo group showed substantial improvements in mean MAS scores during the open-label phase.

“The (extension findings) further support nabiximols’ efficacy, even if the open-label design excludes the possibility of drawing any definitive conclusion,” Riva said.

Limitations of the study include that the MAS, despite being the most used and best validated objective measure of spasticity, may not fully represent patients’ experience of spasticity, and self-reported measures may also fall short in accurately representing spasticity, the authors noted.

“The ideal objective measure of the highly complex symptom of spasticity does not exist,” they said.

In an accompanying commentary, Marianne de Visser, MD, PhD, professor of neuromuscular disorders at Amsterdam University Medical Centre, the Netherlands, noted that limitations of the study include a bias towards patients who primarily had involvement of upper motor neurons in the nabiximols group.

“These patients (with upper motor neuron involvement) could have benefited more than the 13 patients with classic ALS, which involves both upper and lower motor neurons,” de Visser said.

Further commenting to Medscape Medical News, de Visser added that focusing on spasticity as a prevailing symptom, in general, could be a limitation.

“As yet, there is still uncertainty of how much spasticity contributes to the disease burden in the so-called classical type of ALS — not only spasticity but also flaccid weakness,” she explained.

Although the cannabinoids have shown efficacy and safety in MS, de Visser noted that responses could be different in patients with motor neuron disease.

“The literature on the use of nabiximols in MS seems to be reassuring regarding side effects,” she said. “However, ALS/motor neuron disease is a totally different disease, so we need the larger trials as well in order to assess the adverse effects.”

“The evidence provided (in the current research), albeit in a proof-of-principle study, is encouraging, ” she added.

“Further studies with larger numbers of ALS patients are needed to assess whether nabiximols is not only leading to reduction of spasticity but also reduces disease burden and improves quality of life.”

GW Pharmaceuticals has already made waves in the cannabis-based drug market in the United States this year with its oral drug Epidiolex (cannabidiol), the first drug containing a purified drug component derived from cannabis to receive approval from the US Food and Drug Administration.