A new phase 3 clinical trial in Nature Medicine reports a ‘comprehensively characterised’ cannabis-based product shows sustained benefit in chronic low back pain.
Reducing the variability in the composition of cannabis-based products is key for reproducible results, new research suggests.
There has been increasing interest in the use of cannabis-based medicines for chronic pain management in recent years, but the broader uptake and recommendation of its use over other pharmacological approaches (e.g., opioids, non-steroidal anti-inflammatory drugs etc.) has been slowed by concerns regarding the quality of the evidence supporting its use.
Small sample sizes, short study periods, differences in the doses used and inconsistencies in the quality of cannabis-containing products are among some of the key concerns regarding the use of cannabis for chronic pain.
A research team led by members of the Department of Anaesthesiology and Intensive Care Medicine at the Hannover Medical School in Germany undertook a phase 3 randomised placebo-controlled trial investigating the safety and efficacy of VER-01, a cannabis-containing product, to address some of these concerns.
The findings, published in Nature Medicine, report that 12 weeks of daily oral VER-01 doses demonstrated a greater reduction in self-reported pain intensity compared to placebo (mean difference 0.5 points on an 11-point scale).
“As naturally occurring botanical substances, cannabis plants exhibit substantial heterogeneity. Variability in the botanical raw material and manufacturing processes contributes to a substantial variety of product compositions, including levels of bioactive constituents. To ensure reproducible results, it is therefore essential to adequately characterise the investigational product and establish consistency across batches,” the researchers wrote.
“The investigational product VER-01 was comprehensively characterised using chromatographic and spectrometric methods to quantify cannabinoids, terpenes, flavonoids, carotenes, phytosterols, vitamins and fats, and chromatographic fingerprinting confirmed batch-to-batch consistency across multiple lots of VER-01.”
Eight hundred and twenty adults who had been diagnosed with chronic low back pain for at least three months participated in the new study. Patients whose pain could be linked to a specific somatic cause, such as a herniated vertebral disk, were excluded. Three hundred and ninety-four participants received VER-01 and 426 received the placebo. Both treatments (119 microliters/day) were administered via an oral syringe for 12 weeks following three weeks of dose titration.
Across the two groups 22% of participants had a neuropathic component to their chronic pain and 24% were suffering from severe pain at baseline (defined as a score of seven or higher on an 11-point numerical rating scale, where 0 indicates no pain and 10 indicates the worst pain imaginable). Hypertension (35% of participants) and obesity (32%) were the most common comorbidities, and 99% of participants reported previous analgesic use.
After 12 weeks of treatment, there was a greater reduction in self-reported pain intensity – the trial’s primary outcome – among patients receiving VER-01 compared to those who received placebo (1.9 versus 1.4). The reduction in pain intensity associated with VER-01 was more prominent in the subgroup of patients who had neuropathic pain (mean difference 1.5 compared to placebo, 95% confidence interval 0.9-2.2) and in patients with severe pain at baseline (mean difference 1.0, 95% CI 0.1-1.8).
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The proportion of patients who experienced at least a 30% reduction in their pain was higher in the VER-01 arm compared to placebo (54% versus 40%), as was the proportion of patients with at least a 50% reduction (32% versus 23%) and the proportion with at least a two-point reduction on the 11-point rating scale (47% versus 37%).
Greater improvements were also seen in the VER-01 arm compared to the placebo arm for key secondary outcomes, including neuropathic pain symptoms, the number of rescue medications required (an average of 10.5 versus 18.3), sleep quality (mean difference of 0.7 points in an 11-point self-reported scale) and physical functioning (average change of 3.1 versus 2.0 points on the Roland Morris Disability Questionnaire).
“This is an excellent study. We have long argued that studies on cannabis or cannabis-based substances need to provide high level of evidence: this is it. The pain relief was clinically significant and would be meaningful to the many people living with chronic pain,” said Dr Jan Vollert (PhD), a lecturer from the University of Exeter in the United Kingdom, in a statement to media.
“It is only one trial, and we will need further studies to confirm the findings, but this is a good signal that the compound could help patients. Previous studies have found mixed results with other compounds, and most were not of great quality, so this is a very clear step in the right direction.”
Treatment-emergent adverse effects were reported by a greater proportion of patients receiving VER-01 compared to placebo (83% versus 67%), although the serious adverse events occurred at similar rates between the two groups (6% versus 7%).
The most common treatment-related adverse events in the VER-01 group included headache, nasopharyngitis, dizziness, fatigue, nausea and dry mouth, with the latter four effects occurring in a greater proportion of participants receiving VER-01 compared to those who received placebo.
There were no reports of drug abuse, dependence or withdrawal over the course of the study based on urine drug tests, behavioural checklists and international classification criteria. Interestingly, a higher proportion of patients in the placebo arm were satisfied with the tolerability of treatment after the initial 12-week period compared to patients in the VER-01 arm (79% versus 68%).
The phase 3 trial also included three other phases that tested the efficacy of the VER-01 treatment beyond the initial 12-week period, with the researchers reporting there were no signs of diminishing returns. “Participants experienced further reductions in NRS pain intensity during the 6-month treatment period of phase B, with a decrease of 3 points compared to the phase A baseline. Participants who completed phase B and participated in phase C were able to maintain their pain reduction over an additional 6-month period,” they wrote.
“These results are of high clinical relevance,” the researchers concluded. “VER-01 presents a promising new nonaddictive, safe and effective treatment option, particularly for long-term use. These findings highlight the importance of further research with VER-01 in other chronic pain conditions and suggest that VER-01 could play an important role in modern pain management.”
A key limitation of the study was that VER-01 was only tested against placebo, rather than other pharmacological pain management approaches. “However, a dedicated follow-up study, evaluating VER-01 against standard opioid therapy, has already been conducted and will be published separately,” the researchers noted.
