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cannabis for neuropathic pain

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 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.

Study characteristics

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.

Primary outcomes

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).

Secondary outcomes

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.

Subgroup analyses

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

Cannabis Gaining Acceptance as Treatment for Neuropathic Pain?

Experts may be moving toward accepting cannabis as a useful tool to treat neuropathic pain (NP), a recent debate on the topic suggests.

During the debate, one expert argued for, and another against, there being sufficient evidence for the use of cannabis to treat neuropathic pain, but in the end, they agreed that some patients do benefit.

The discussion took place at the Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual online meeting because of the COVID-19 pandemic.

The cannabis plant has 460 constituents. The two main components are tetrahydrocannabinol (THC) and cannabidiol (CBD). It can be consumed by swallowing oil extracts, by the sublingual route, or by smoking or eating the plant. Cannabis medications already in use include oral THC (nabilone, dronabinol) and an oral mucosal spray (nabiximols [Sativex]).

Arguing that therapeutic cannabis is helpful for neuropathic pain, Elon Eisenberg, MD, professor of neurology and pain medicine, Israel Institute of Technology, Haifa, cited a number of encouraging randomized controlled trials (RCTs) and meta-analyses of studies on the subject.

Opioid Substitute

He discussed three relevant articles. One was a 2016 viewpoint article published in JAMA that concluded that “cannabis seems to be a substitute, a rather good one, for opioids,” said Eisenberg.

A “comprehensive” 440-page review, published by the National Academies Press in 2017, evaluated the evidence to that point and “came to the conclusion there is substantial evidence that cannabis is an effective treatment for chronic pain in adults,” said Eisenberg.

And a 2018 position paper from the European Pain Federation determined that “the quantity and quality of evidence is such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain,” he said.

He noted that the most recent results from an Israeli prospective cohort registry study that is following more than 851 patients who are taking cannabis over a year are positive. Analyses show a steady reduction in pain intensity and improvements in catastrophizing and disability. Importantly, he said, participants are using fewer opioids.

However, about 40% of patients in that registry study experienced some adverse event, although most were not serious, said Eisenberg

Not Convinced

Arguing on the other side ― that therapeutic cannabis is not helpful for neuropathic pain ― was Nadine Attal, MD, PhD, professor of therapeutics and pain at the University Versailles Saint Quentin, France.

She questioned the quality of some of the research to date and stressed that studies should consider NP as a primary outcome ― not spasticity or pain in general. They should also be double-blind, randomized, and placebo controlled, she said.

In addition, she said these studies should enroll at least 10 patients per group and should continue for 3 weeks or longer.

Attal wondered which of the many plant derivatives (phytocannabinoids) are used in cannabis studies.

She discussed four meta-analyses or reviews on the topic, some of which she said are “heterogeneous” and don’t provide convincing evidence for cannabis use in NP.

For example, one review only examined marijuana, and all studies in it were short term. One of the studies in this review was of spasticity.

Another review included two studies of cancer pain, and the most positive study in NP used short-term inhaled THC.

“There is no evidence to date that cannabinoids, including nabiximols or oral THC, administered for at least 3 weeks are more effective than placebo in neuropathic pain,” she concluded.

Some Responders

However, Attal acknowledged that cannabis might be effective for some patients. In her experience, which has been borne out by some observational studies, patients with paroxysmal pain, or sudden stabbing pain, seem to get more relief from cannabis.

“It’s absolutely possible that there’s a subgroup of symptoms or a subgroup of patients with specific symptoms who are much better responders to cannabis than others,” she said.

Asked if patients experience increased pain after withdrawing from cannabis, Eisenberg said he has observed that many patients stop taking cannabis when they start feeling better, but he hasn’t seen severe withdrawal symptoms.

However, there are other concerns related to cannabis use, said Eisenberg.

A major concern regards driving a vehicle. In Israel, getting behind the wheel is prohibited within 6 hours of using cannabis.

But Eisenberg pointed out that published data on the safety of cannabis and driving were based on recreational users. “We need to keep in mind that recreational users typically use other substances, so we’re not sure the data is accurate,” he said.

There are increasing reports of stroke, transient ischemic attack, and myocardial infarction among cannabis users. This is especially concerning because many of these cases involve young male adults who have no risk factors, said Eisenberg.

One delegate asked whether legal issues make it difficult to properly investigate cannabis in large studies.

Eisenberg noted that legal concerns may help explain why there have not been any new RCTs for about 2 years.

“In the US, you can’t do clinical trials; cannabis is still regarded as schedule I substance,” he said.

Some physicians “are reluctant to deal with cannabis unless they get better data,” he said. “Doing research on cannabis seems to be somehow out of the mainstream.”

Moreover, the research is difficult to carry out, owing to the complexity of the cannabis plant, which has many constituents. Perhaps it’s a matter of identifying and adding particular components to better demonstrate reduced pain, said Eisenberg.

Another complicating factor is that bioavailability differs considerably from one patient to another, “sometimes even by 10-fold,” he said.

Attal’s group will be starting a study next January that will enroll a large sample of patients with neuropathic pain or spasticity. In that study, cannabis will be dispensed through pharmacies and primary care. The aim of the study is “to see how it works in a real-life setting,” she said

Those participating in the virtual session were asked to vote on which side they agreed with. About 57% voted in favor of cannabis use, 14% voted against, and 28% had no opinion.

Eisenberg has received research grants from Rafa Laboratories, Saga Medical Ltd, Israel Pain Association, and Teva Israel. Attal has received support from MSD, Sonofi, Ipsen, Novartis, Aptinyx, Air Liquide, Lilly, and Grunenthal.

Congress of the European Academy of Neurology (EAN) 2020. Presented May 25, 2020.

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Medscape Medical News © 2020

Cite this: Cannabis Gaining Acceptance as Treatment for Neuropathic Pain? – Medscape – Jun 02, 2020.

At the recent European Academy of Neurology meeting, experts debated for and against cannabis use, but generally they agree that some patients do benefit.