BOSTON — A new study finds measurable benefit on lower-limb spasticity in patients with progressive multiple sclerosis (MS) with a tetrahydrocannabinol-cannabidiol (THC-CBD) oromucosal spray (Sativex, GW Pharmaceuticals).
"Our findings confirm the clinical beneficial effects of the combination of THC and CBD on MS spasticity, with improvement on the modified Ashworth scale in the lower limbs, but we did not find corresponding changes in our measures of corticospinal excitability and on the monosynaptic component of the stretch reflex," lead author Letizia Leocani, MD, PhD, University Hospital San Raffaele, Milan, Italy, concluded.
She suggested further work should be undertaken to explore other spinal and supraspinal mechanisms that may be involved in generating spasticity in MS, such as other descending pathways, or possibly spinal interneuronal maladaptive organization.
The results, from a small randomized crossover study, were presented at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.
Sativex "Probably Effective"
Sativex is approved for use in several European countries, including the United Kingdom, Italy, Germany, and France, as well as Canada and New Zealand, for patients who do not respond adequately to other antispastic medications, Dr. Leocani told delegates here. The product is also being developed for use in cancer pain and neuropathic pain. It is marketed in Europe under license to Almirall SA, which supported this trial.
Sativex is not currently approved in the United States, although the company Web site notes a phase 3 trial aimed at supporting a submission to the US Food and Drug Administration is planned to start this year.
In April, results of a review of the evidence supporting the use of medical marijuana in neurologic diseases by the American Academy of Neurology's Guideline Development Subcommittee concluded that certain forms medical marijuana can be helpful to treat some symptoms of MS.
In particular, for spasticity in MS, they concluded that oral cannabis extract is effective and that Sativex, also called nabiximols, and THC are "probably effective" for reducing patient-centered measures. For central pain or painful spasms, including spasticity-related pain but excluding neuropathic pain, they concluded that oral cannabis extract is effective and that Sativex and THC were probably effective in this setting.
In this study, the researchers set out to assess the effect of treatment on objective measures of spasticity or corticospinal excitability in a double-blind, placebo-controlled crossover study.
A total of 43 participants with progressive MS and clinical evidence of spasticity, defined as a modified Ashworth scale (MAS) score greater than 1, signifying increased resistance over the whole range of motion. They had to be receiving stable medication and be negative for THC on screening.
They were then randomly assigned to a 2-week titration period followed by 2 weeks of stable-dose treatment of the oromucosal THC-CBD spray or a placebo formulation. About half, 20, were female. The patients' Expanded Disability Status Scale scores range from 3.5 to 6.5 (mean, 5.7).
After a 2-week washout period, patients went on to a second crossover treatment cycle in a double-blind fashion.
Clinical and neurophysiological measures taken before and after treatment included the MAS, spasticity, pain and sleep numeric rating scales, the 10-minute walk, the Fatigue Severity Scale, and transcranial magnetic stimulation to measure bilateral soleus H-wave amplitude to M-wave amplitude ratio, motor evoked potential amplitude at 120% threshold and 100% stimulator output, and intracortical inhibition/facilitation.
Five patients withdrew from the study; 2 were on active treatment and withdrew for dizziness and 1 for subjective treatment. Three withdrew after washout from the active treatment: 1 for acute pancreatitis, 1 to enter a rehabilitation program, and 1 for family reasons, Dr. Leocani reported. The data for 4 patients were not analyzed because of positive results on THC urine testing after the washout, she noted.
The researchers found a significant treatment effect on the MAS score, with more improvement seen for active treatment vs placebo (–18.2 ± 33.6 vs –6.7 ± 26.6; P = .029).
MAS responders, defined as those with at least 20% improvement at week 4 vs baseline, were seen more frequently during active treatment (50%) than during placebo (23.5%).
Adverse effects, including previously reported effects such as dizziness, subjective weakness, and hypotension, were more common with treatment than placebo, but the proportion of adverse effects did not significantly differ, Dr. Leocani said.
Table. Adverse Events by Treatment
|Measure||THC-CBD Spray, n (%)||Placebo, n (%)|
|Dizziness||7 (20.6)||2 (5.9)|
|Subjective weakness||2 (5.9)||1 (2.9)|
|Vertigo||1 (2.9)||1 (2.9)|
|Total||14 (41.1)||4 (11.8)|
The number of daily puffs of the medication taken by patients was lower on active treatment, with a mean of 6.97 per day vs 9.56 on placebo. The maximum daily number of puffs allowed was 12.
"We did not find significant effects on other clinical measures: pain and sleep scales, Fatigue Severity Scale, frequency of spasms, or the neurophysiological measures," she said, including the H-wave amplitude to M-wave amplitude ratio, motor evoked potential amplitude, or intracortical excitation/inhibition.
Asked for comment on these findings, Jerry Wolinsky, MD, Bartels Family and Opal C. Rankin Professor of Neurology at The University of Texas Medical School at Houston, who comoderated the session where these results were presented, pointed out that although Sativex is not approved in the United States, another tetrahydrocannabinoid, dronabinol (Marinol), is available under restricted use and can be used for medical indications, such as spasticity.
Other drugs are already approved for this indication, Dr. Wolinsky said. Baclofen is one; tizanidine another; and dantrolene another, used less because its effects are less center and more directly on the muscle, he said.
In addition, drugs applied for other indications are now being used off label for spasticity; these include some benzodiazepines, such as clonazepam (particularly for night-time spasticity), and antiepileptic medications, including gabapentin and lamotrigine, which, he noted, is "surprisingly helpful from time to time."
"So there are a number of things available," Dr. Wolinsky told Medscape Medical News. "We're always looking for something better, but to my way of looking at the data that's come out for Sativex specifically is that the results are present, but not so dramatic that I would necessarily think that anything is being held back from my patients by not having this drug available in the United States at this time."
The study was supported by an institutional grant from Almirall. The authors have disclosed no relevant financial relationships. Dr. Wolinsky reports that he received compensation for service on Steering Committees or data monitoring boards for Novartis, Roche, Sanofi, and Teva; reimbursement for services as consultant to AbbVie, Alkermes, Athersys, Bayer HealthCare, Celgene, EMD Serono, Genentech, Genzyme, Novartis, Roche, Janssen RND, Teva, and XenoPort; royalty payments through the University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International; and research support from Genzyme, Sanofi, and the National Institutes of Health through the University of Texas Health Science Center at Houston.
MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting. Abstract LB1.3. Presented September 13, 2014.
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