People with advanced multiple sclerosis (MS) are commonly affected by serious symptoms that can significantly affect their everyday life. Two of the most common symptoms of MS are spasticity and neuropathic pain – both of which increase with disease progression. As MS worsens, patients usually experience worsening disability, impaired activities of daily living and quality of life. Therefore, symptomatic treatments are of the utmost importance when considering the well-being of patients with MS.
Current first-line treatments for spasticity and neuropathic pain are often of limited benefit. In addition, many anti-spasticity drugs and analgesics are poorly tolerated and may carry risks of serious side effects – including misuse and addiction. In recent years, there has been increasing demand for cannabis and cannabinoid-based drugs for MS-associated symptoms.
A growing body of evidence suggests that cannabinoid therapy may be useful for both spasticity and pain relief; however, a thorough understanding of the use of these drugs in this setting is still required. A recent review of the existing evidence aimed to assess the benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
Design and Methods of the Review
Researchers searched a number of clinical trial databases from inception up to December 2021, in order to identify relevant studies. Randomised parallel or cross-over trials which evaluated any cannabinoid-based therapy for adults (aged 18 and over) with MS were included for review. A total of 25 RCTs with 3,763 patients – of whom 2290 received cannabinoids – were included in the final review.
The researchers assessed bias using the Cochrane Risk of bias 2 tool; and rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), and withdrawals due to adverse events (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders and physical dependence.
Patient-reported outcome measures, including differences in spasticity and chronic pain, were included as critical or important outcomes.
The Population Sample
Participants of the studies included for review ranged from ages 18 to 60. The length of the studies ranged from 3 weeks to 48 weeks and compared a range of cannabis-based therapies, including nabiximols (an oromucosal spray containing cannabidiol and tetrahydrocannabinol), synthetic tetrahydrocannabinol-like cannabinoids, oral tetrahydrocannabinol extract of Cannabis Sativa, inhaled herbal cannabis and dronabinol – all of which were compared with placebo. Eight of the studies identified were ongoing trials.
The Effect of Cannabinoids on Spasticity
To measure the effect of cannabinoids on spasticity, the researchers noted the number of participants who reported a reduction of 30% or more in the spasticity Numeric Rating Scale (NRS) at follow-up appointments. It was found that 502 per 1,000 participants reported at least a 30% reduction following administration of a medical cannabis product, compared with 287 per 1,000 following placebo.
The researchers rated the quality of evidence relating to spasticity as moderate, based on the GRADE approach. The evidence was downgraded due to a risk of bias. Nonetheless, it remains likely that cannabis was associated with an increase in the number of patients with a reduction of spasticity when compared to placebo. These findings were based on evidence from five studies in 1,143 people.
The Effect of Cannabinoids on Pain
The researchers noted the number of patients reporting a reduction of 50% or greater in pain intensity, using NRS scores. They found that 458 per 1,000 participants reported at least a 50% reduction in pain intensity following medical cannabis. This compared to 167 per 1,000 who reported the same following placebo.
While this presents seemingly promising results, the researchers report that this finding was based on “very low” quality evidence. This was due to a serious risk of bias and very serious imprecision. Furthermore, evidence was collected from only one study, which included only 48 participants. Therefore, there is a direct need for more high-quality RCTs to determine the potential of cannabis for neuropathic pain associated with multiple sclerosis.
Patient Global Impression of Change (PGIC)
The Patient Global Impression of Change (PGIC) is used to reflect the patients’ beliefs about the efficacy of treatment. It is a 7-point scale ranging from “very much worse”, to “very much improved”. The report of “much improved” or “very much improved” following medical cannabis was considered significant for the needs of this review. Compared with 209 per 1,000 participants who reported a change of “much improved” or “very much improved”, 323 per 1,000 reported the same following medical cannabis.
The researchers concluded that, compared with placebo, cannabinoids “probably increase the number of people who perceive their well-being as ‘very much’ or ‘much’ improved”. This finding was based on moderate-quality evidence from eight studies (1,215 participants).
The researchers also found low-quality evidence that cannabinoids may slightly increase the number of patients who discontinue treatment due to unwanted side effects when compared to placebo. Low-quality evidence also suggests that cannabinoids may be associated with an increased prevalence of nervous system and psychiatric disorders when compared to placebo.
Nonetheless, low-quality evidence also suggests that cannabinoids were not associated with serious harmful effects or adverse events. Generally, cannabinoid-based therapies were well-tolerated.
Overall, the findings of this review provide moderate-certainty evidence for an antispastic effect of nabiximols (as an add-on therapy to other anti-spasticity medications). The authors conclude that there are “reasonable grounds to assume that people with MS would value the benefit identified in our review.”