July 27, 2012 — Compared with those taking a placebo, almost twice as many patients with multiple sclerosis (MS) prescribed an oral cannabis extract reported relief from muscle stiffness, a new study has found.

The cannabis agent also proved better at relieving symptoms of body pain and muscle spasm, and sleep disturbances.

Results of the phase 3 Multiple Sclerosis and Extract of Cannabis (MUSEC) study confirm the patient-rated benefits of cannabis on MS symptoms that were found in the earlier Cannabinoids in Multiple Sclerosis (CAMS) study, researchers say.

"The evidence behind using cannabinoids for symptom relief is pretty strong now, and the MUSEC study is another piece of evidence to support that view; in fact, it's probably the strongest evidence so far," said study lead author John Peter Zajicek, PhD, professor and chair of clinical neurology at the University of Plymouth, United Kingdom (UK).

The study was published online July 12 in the Journal of Neurology, Neurosurgery and Psychiatry.

The double-blind trial conducted at 22 centers in the UK enrolled 279 patients with MS who were 18 to 64 years of age and had troublesome muscle stiffness. Patients were randomly assigned to receive a standardized oral cannabis extract (CE), which contained tetrahydrocannabinol (THC), or a matched placebo capsule.

Before the 10-week maintenance phase, the study included a pretreatment screening period and a dose titration phase. The starting dose for the CE was 2.5 mg (one capsule) twice daily, with doses individually titrated upward by 5 mg/day every 3 days for up to 12 days, with a maximum total daily dose of 25 mg.

At the end of the treatment period, researchers used an 11-point category rating scale (CRS) to evaluate patients' perceived change in muscle stiffness (a rating of 0 indicated very much better; 5 no difference, and 10 very much worse). This numerical tool is clinically relevant, is reproducible, and, compared with another commonly used scale — the Ashworth Scale, is a more patient-oriented measure of efficacy, according to the authors.

A similar rating scale was used to measure secondary outcomes that included perceived relief from body pain, muscle spasms, and sleep disturbances compared with pretreatment.

The analysis of 277 patients found that the proportion of those who reported relief (0 to 3 on the CRS) was 29.4% in the cannabis group and 15.7% in the placebo group (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.24 - 4.13; P = .004, 1-sided).

The study showed similar results in rates of relief for body pain, spasms, and sleep quality. At all visits (weeks 4, 8, and 12), rates of self-reported relief from these symptoms were consistently higher with CE than with placebo, and results were generally statistically significant (P < .025).

Responses to a number of MS-specific questionnaires supported these findings. Changes from baseline in symptoms such as effects of spasticity on activities of daily living, ability to walk, physical and psychological impact, and social functioning, as well as muscle stiffness, sleep quality, spasms, pain, and discomfort, were almost always in favor of the CE group.

"The MUSEC study looked at the symptoms of MS and found that from the patient perspective, all the endpoints were positive," said Dr. Zajicek.

At the end of the study, only 24.5% of CE participants were taking the 25.0 mg dose compared with 69.4% of placebo participants.

It is not surprising that central nervous system (CNS) symptoms such as disorientation and confusion occurred at a higher rate in the CE group (24.5% vs 7.5% for placebo), although most of these symptoms were mild. "Like all cannabis derivatives, if you take THC, which is a major active ingredient in the treatment drug, you can get a euphoria, a high, and a sort of clouding of cognition," said Dr. Zajicek.

The greatest between-group difference in adverse event rates was seen during the titration phase of the study, likely because of fast escalation of the dose to the maximum tolerated. "One of the problems of the study was that we pushed up the dose a bit high too quickly, so quite a few people dropped out," noted Dr. Zajicek. "But despite that, we still had evidence of good effects."

In total, 34 patients in the CE group (23.8%) and 20 in the placebo group (14.9%) discontinued study medication before the end of the study.

Researchers continue to search for an agent that does not have this cognitive side effect, but in the meantime, physicians can try to keep the dose low enough to get a benefit without causing this effect, said Dr. Zajicek. "The difficulty is to titrate it to the right dose for each person," he said.

Although results of this study confirm the ability of cannabinoid agents to manage MS symptoms, it is probably more important to people with MS — and all neurodegenerative diseases — to have access to a drug that actually works on the disease itself, said Dr. Zajicek. "There's a desperate need for more treatments that help to slow down the course of these diseases."

The Cannabinoid Use in Progressive brain Disease (CUPID) trial, a 3-year trial of almost 500 patients with progressive MS, on which Dr. Zajicek was lead investigator, did investigate this aspect with this agent, but initial results, presented at the Association of British Neurologists' Annual Meeting in May of this year, showed that the THC agent was no better than placebo in reducing disease progression.

No significant effect was seen on disability, as measured by the Expanded Disability Status Scale, or on patient report, assessed using the Multiple Sclerosis Impact Scale 29.

However, results did show evidence of a significant effect for patients at lower levels of disability, said Dr. Zajicek. Overall, progression of disease in this group of progressive MS patients was less than expected, making measuring a drug effect more challenging.

CUPID was funded by the Medical Research Council (MRC) and was managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership, the Multiple Sclerosis Society, and the Multiple Sclerosis Trust.

In a statement issued May 24, Doug Brown, MD, head of biomedical research at the MS Society, pointed out that currently no treatments are available for patients with progressive MS to slow or stop worsening disability.

"The MS Society is committed to supporting research in this area, and this was an important study for us to fund," he said. "While this study sadly suggests THC is ineffective at slowing the course of progressive MS, we will not stop our search for effective treatments. We are encouraged by the possibility shown by this study that THC may have potential benefits for some people with MS, and we welcome further investigation in this area."

Full results of the CUPID trial are expected later this year.

Still, Dr. Zajicek is convinced that drugs containing THC can work to curb progression of MS, and that future studies will further bear this out.

"There are multiple theoretical reasons for why this kind of drug should help," he said. "Firstly, it's anti-apoptotic, so it prevents cell death. Secondly, it reduces the release of excitatory neurotransmitters, so it reduces glutamate release, which is implicated with cell death in nerve cells. Thirdly, it's an antioxidant, so it reduces free radical damage. Then there are other theoretical reasons why it might be helpful, for example, it might interfere with protein folding, it has anti-inflammatory action, and it reduces migration of inflammatory cells."

Invited to comment on this study, MS expert Lily Jung Henson, MD, neurologist and chief of staff at Issaquah Hospital, Swedish Medical Center, in Seattle, Washington, said it was "very nicely done."

However, she noted that the study was limited by the side effects that the authors discussed in the paper, and by the subjective nature of the rating scales used by researchers.

"I worry that patients will sacrifice cognitive functioning for pain relief," Dr. Jung Henson told Medscape Medical News. "I also wonder if the high dropout rate in the CE group is adequately explained."

J Neurol Neurosurg Psychiatry. Published online July 12, 2012. Abstract