The largest study ever undertaken into treatment of symptoms in multiple sclerosis (MS) has found that cannabis has no significant effect on muscle spasticity, as measured by an independent assessment of spasticity known as the Ashworth scale.

However, a majority of patients taking the drug felt that it had reduced the symptoms of their spasticity, as well as their pain. There was also some evidence that cannabis treatment led to improved mobility.

This major British study of more than 600 patients with stable MS and spasticity, supported by the Medical Research Council and the MS Society of Great Britain and Northern Ireland, is published in this week's edition of The Lancet.

There is no clear explanation for the difference between the objective and subjective findings on the impact of cannabis on spasticity but the research team suggest that this may reflect a reduction in the manifestations of spasticity rather than an effect on muscle stiffness per se.

Background

Multiple sclerosis is a common nervous system disease which causes a range of chronic symptoms, including muscle stiffness and spasms (spasticity), pain, tremor and bladder problems.

Orthodox treatments often provide inadequate relief for these symptoms and, as a result, many people with MS have experimented with alternatives, including cannabis and cannabinoids (its major active components).

There have been many anecdotal reports of the success of cannabis in treating MS symptoms, particularly spasticity, and it has been estimated that 1-4% of the total UK MS population are using it in one form or another for symptom relief. However, there is little scientific evidence that these drugs work, with four previous (very small) trials failing to demonstrate objective benefits.

Patients and treatments

The trial was set up to test the theory that cannabis and cannabinoids have a beneficial effect on spasticity and may also help to alleviate other MS-related symptoms.
This study was led by Dr John Zajicek, Consultant Neurologist and Associate Medical Director of Research & Development at Plymouth Hospitals NHS Trust who is based at the Peninsula Medical School, Plymouth

The other principal investigator was Professor Alan Thompson, Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, University College Hospitals, London.

A total of 657 patients, with stable MS and muscle spasticity defined as 'problematic' were recruited to the trial from 33 centres across the UK over a period of two years. Each patient was randomly assigned to one of three treatment groups for a period of 15 weeks:

• treatment with whole cannabis extract;
• treatment with a synthetic version of one of the cannabinoids, known as Tetrahydrocannabinol (THC);
• treatment with placebo - an inactive (dummy) preparation made up to look just like one or other of the active treatments.
The trial treatments were administered in addition to participants' own standard MS medication which was optimised before they entered the trial.

All the treatments were given orally. The study was 'double-blind', meaning that neither the patients nor the professionals treating and assessing them were told which treatment group they were in. This is widely recognised as the best way to produce the most objective results in clinical trials.

The first five weeks of the study were devoted to establishing the best tolerated dose for each individual patient, based on body weight. Patients then remained on a stable dose for weeks 6-13 before being gradually taken off the medication in week 14.

Measuring the impact of treatment

Trained assessors rated spasticity in 10 pairs of muscle groups in the patients' arms and legs before treatment started and at intervals during treatment, using the 'Ashworth score', a tool designed to provide an independent measure of biological impairment.

Patients' scores at the end of the treatment period were compared with their pre-treatment scores to establish the effectiveness of treatment.
The Ashworth score of spasticity was regarded from the outset as the 'primary outcome measure' of the study - the main evidence against which treatment with cannabis would be judged.

At the same time, the researchers set out to measure various 'secondary outcomes', including mobility, general wellbeing and patients' subjective assessment of the impact of treatment on their various symptoms.

Assessors measured mobility before, during and after treatment using a questionnaire known as the Rivermead Mobility Index. Mobility was also assessed by comparison of time taken to complete a 10-metre walk before treatment and at the end of the treatment period.

Patients' subjective experiences were assessed through four commonly used self-completion questionnaires, designed to measure neurological disability, coping with daily living, wellbeing and mood, and severity of symptoms.

At the end of the study, patients were seen by their study doctors and asked four specific questions about the overall effect of treatment on four key symptoms: spasticity, tremor, pain and bladder function.

Key results

The main findings after analysis of all the data were as follows:

• Neither of the cannabis-derived treatments had a significant effect on muscle spasticity as measured by the Ashworth score.
• There was a very small improvement in scores for all three treatment groups, and these improvements were slightly greater in the cannabis groups than the placebo group. However, none of these changes reached statistical significance.
• The questionnaire designed to assess patients' subjective experience of changes in nine symptoms of MS showed that significantly more patients on cannabis than placebo detected improvements in pain, sleep quality, spasms and spasticity, although no subjective treatment effect was seen on irritability, depression, tiredness, tremor or energy
• When patients were seen by their doctors and asked directly about the overall effect of treatment on four specific symptoms, a majority of those on cannabis perceived an improvement in spasticity and pain, compared with a significantly smaller proportion of those on placebo
• There was no evidence that cannabis treatment had any impact on neurological disability, coping with daily living, or wellbeing and mood, using the generic questionnaires. The Rivermead Mobility Index suggested no improvement in mobility
• However, mobility as measured by walking time was significantly improved with active treatment
• In general the trial medications were well-tolerated, with no major side-effects being reported

Special attention was given to keeping the trial 'blind', given the potential for patients on the cannabis-derived treatments to guess their medication. To retain objectivity, the assessor monitoring spasticity using the Ashworth scale was not given details of discussions patients had with their treating physician about well-being and side effects. During evaluations, the assessor was not allowed access to scores from previous visits.

At the end of the study, analysis showed around three-quarters of patients taking cannabis-derived treatments guessed they were taking active medication and around half of the placebo group correctly guessed they were on placebo. Interestingly, there were unexpectedly fewer relapses in both the active treatment groups. This particular study was not set up to investigate relapses, but the researchers believe this finding may warrant further investigation.

Implications

Objective findings

The primary outcome measure of the trial was constructed around the Ashworth scale and 'powered' (the number of patients needed in the study to show clinically significant change) on a previous study of Tizanidine in MS. Based on their findings, the researchers pose the following questions:

1. Is the Ashworth scale sensitive enough to identify small but clinically significant effects on spasticity?
2. Would a higher dosage measurably impact spasticity? - although the evidence suggests that higher doses would not have been tolerated.

Subjective findings

What explains the patients' subjective reports of reduced spasticity and pain? As far as spasticity is concerned, the researchers suggest that this may reflect a reduction in the manifestations of spasticity rather than an effect on muscle stiffness per se.
The reports of pain relief are consistent with previous suggestions that cannabis may be an effective analgesic and could play a more specific role than simple painkillers in managing chronic nervous system pain.

This study raises interesting questions about the importance of patients' perceptions compared with independent assessments in clinical trials.

Cannabinoids in MS - conclusions

The researchers conclude that cannabinoids may be clinically useful in treating some MS-related symptoms, but they believe that further research is needed 'using outcome measures which more adequately assess the impact of symptoms in chronic disease'.