1.9 million euros for research into neuropathic pain
The Dutch government is supporting research into the use of medicinal cannabis in the treatment of neuropathic pain with € 1.9 million. The grant has been awarded to a joint project of the Centre for Human Drug Research (CHDR), a Dutch independent institute that specializes in clinical drug research, and the Leiden University Medical Center (LUMC). Neurologist Geert Jan Groeneveld (CSO / CMO at CHDR and professor of Clinical Neuropharmacology at the LUMC) and Albert Dahan (professor of Anesthesiology at the LUMC) will conduct the research.
The research intends to lead to a specific recommendation of an optimal delta-9-tetrahydrocannabinol (THC) – cannabidiol (CBD) dosage for the treatment of neuropathic pain in a particular subgroup of patients. In addition, it contributes to evidence for the effectiveness of medicinal cannabis. Bedrocan’s raw materials will be used for the production of the research material.
The research does not look at the entire plant, but purely at the pharmacological effect of THC and CBD. Groeneveld: “We want to approach this research exactly as a drug developer would. As a clinical pharmacologist, you extract the proven pharmacological components from a plant and do research with it. That is also innovative in this research”.
The researchers will very accurately measure the pharmacodynamics and pharmacokinetics of THC and CBD, the effects of both substances on pain and brain function and how the substances behave in the human body.
“We are going to isolate the THC and CBD from Bedrocan cannabis and administer them in tablet form in different proportions. We will then look at the influence of CBD on the effects of THC , and investigate which THC-CBD combination is best for the treatment of neuropathic pain”, said Groeneveld. The Dutch company Echo Pharmaceuticals from Leiden will produce the tablets for the research.
The study consists of two parts. In the first part, healthy subjects will be administered the tablets with different THC and CBD ratios. The first part of the research will show whether the adverse effects of THC, such as getting high or feeling anxious, can be reduced by administering CBD simultaneously. According to Groeneveld, the scientific literature has so far provided conflicting results about this: “To be honest, I do not expect much from CBD alone as a treatment for neuropathic pain. From a pharmacological point of view, it is likely that THC affects pain, but this is less the case for CBD. CBD could have an effect on inflammation, but there is no reason to use CBD as a treatment for inflammatory pain. We already have Ibuprofen for that. It will only become interesting if the adverse effects of THC, such as feelings of anxiety, can be alleviated by administering CBD at the same time. “
Search for the ideal ratio between THC and CBD
THC (9-tetrahydrocannabinol) and CBD (cannabidiol) are the two most studied active ingredients of the cannabis plant. THC is known for its analgesic effect, but it also causes psychoactive side effects. CBD could lead to pain-relieving effects through other mechanisms. It is believed that CBD may also influence the psychotropic effects of THC by modulating THC binding to the CB1 receptor. However, it is still unclear what the ideal ratio of THC to CBD would be to take advantage of the CB1 modulating effects of CBD while preserving the positive effects of THC on pain. In addition, it is still unclear whether the analgesic effects that some patients experience as a result of CBD use are due to a pharmacological action of CBD, or simply because CBD prevents the metabolism of concomitantly used pain killers. The latter will also be investigated in these studies.
Patients with neuropathic pain conditions
The effects on pain in patients will not be investigated until the second part of the study, after the results of the first study are known. This will provide information on which THC:CBD ratio works best. The second part of the study will take place among a diverse group of 200 patients with different neuropathic pain conditions. Groeneveld: “We are going to phenotype this group very well in advance. This means that we want to know exactly how the neuropathic pain manifests itself specifically in this group. Do patients have demonstrable nerve damage, do they have a personality disorder, are they depressed, or do they have sleep disorders? All these are variables that we are going to map.”
Subsequently, the participants in a crossover study will receive placebo for five weeks, and after a wash-out period, they will receive five weeks of cannabinoid treatment or vice versa. Pain will be measured in each treatment period. Groeneveld: “In patients with clear pain relief, we want to further investigate whether there is a correlation between their variables, such as sleeping problems, anxiety or peripheral nerve damage, and the response to treatment with THC.”
The first part of the study will start in the spring of 2021, and Groeneveld expects the first results in the summer. The second part of the study with the pain patients will start in the autumn and will last at least two years.
1.9 million euros for research into neuropathic pain and the ideal ratio between THC and CBD to combat this pain.
There is a lack of good evidence that any cannabis-derived product works for any chronic neuropathic pain.
Neuropathic pain is pain coming from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines to those used for pain from damaged tissue.
Several products based on the cannabis plant have been suggested as treatment for pain, including neuropathic pain. These products include inhaled herbal cannabis, and various sprays or tablets containing active cannabis ingredients obtained from the plant, or made synthetically.
Some people with neuropathic pain claim that cannabis-based products are effective for them, and that is often highlighted in the media.
In November 2017 we searched for clinical trials that used cannabis products to treat conditions with chronic neuropathic pain in adults. We found 16 studies involving 1750 people. Studies lasted 2 to 26 weeks. Studies compared different cannabis-based medicines. Ten studies compared an oromucosal (mouth) spray with a plant-derived combination of tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and cannabidiol (CBD), an anti-inflammatory ingredient of cannabis, against a fake medication (placebo). Two studies each compared inhaled herbal cannabis and cannabis plant-derived THC with placebo, and one study compared a man-made cannabinoid mimicking the effects of THC (nabilone) with placebo. One study compared nabilone with a pain killer (dihydrocodeine).
Key results and quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results.
There was no high-quality evidence.
All cannabis-based medicines pooled together were better than placebo for the outcomes substantial and moderate pain relief and global improvement. All cannabis-based medicines pooled together were better than placebo in reducing pain intensity, sleep problems and psychological distress (very low- to moderate-quality evidence).
There was no difference between all cannabis-based medicines pooled together and placebo in improving health-related quality of life, stopping the medication because it was not effective, and in the frequency of serious side effects (low-quality evidence).
More people reported sleepiness, dizziness and mental problems (e.g. confusion) with all cannabis-based medicines pooled together than with placebo (low-quality evidence). There was moderate-quality evidence that more people dropped out due to side effects with cannabis-based medicines than with placebo.
Herbal cannabis was not different from placebo in reducing pain and the number of people who dropped out due to side effects (very low-quality evidence).
The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain.
To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.
In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles.
We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm.
Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient’s global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a ‘Summary of findings’ table.
We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane ‘Risk of bias’ tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.
Cannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).
Cannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).
We found no information about long-term risks in the studies analysed.
We are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence).
Cochrane Bottom line There is a lack of good evidence that any cannabis-derived product works for any chronic neuropathic pain. Background Neuropathic pain is pain coming from