What neuropathic pain is
Neuropathic pain is pain that arises from damage or disease affecting the somatosensory nervous system. Unlike nociceptive pain, which results from tissue injury and inflammation (a sprained ankle, a burn), neuropathic pain is driven by signalling faults within the nerves themselves. Peripheral neuropathic pain can follow nerve compression, diabetic neuropathy, chemotherapy-induced neuropathy, postherpetic neuralgia, or traumatic nerve injury. Central neuropathic pain occurs after damage to the brain or spinal cord, for example following a stroke or in multiple sclerosis.
The experience is often described as burning, shooting, electric-shock-like, or tingling. Pain may be spontaneous or triggered by ordinarily non-painful stimuli (allodynia). Standard treatments include gabapentinoids, tricyclic antidepressants, and serotonin-noradrenaline reuptake inhibitors. Many people obtain only partial relief, and side effects from these medicines are common.
Cannabis research on Neuropathic pain
The evidence base available for neuropathic pain is thin. The internal library search returned two matching pages, neither of which constitutes clinical evidence. One page from a grower handbook discusses the broad role of CB1 receptors in pain generally. A separate laboratory paper references a rat neuropathic pain model studying N-arachidonyl-glycine at GPR18, a receptor that is not part of the classical cannabinoid receptor system.
The most relevant human clinical evidence comes from the published medical literature. A Cochrane systematic review of cannabis-based medicines for chronic neuropathic pain in adults, published in 2018 and covering sixteen randomised controlled trials with 1,750 participants, concluded that there is an absence of good evidence that cannabis-based medicines reduce chronic neuropathic pain. The review found that any benefit was small and that adverse events were common.
Several individual randomised controlled trials have examined inhaled cannabis for peripheral neuropathic pain. A double-blind crossover trial of smoked cannabis in HIV-associated sensory neuropathy, published in 2007, found that cannabis reduced daily pain compared with placebo in a human clinical study. A separate randomised controlled trial of vaporised cannabis in patients with neuropathic pain from various causes, published in 2013, reported a reduction in pain intensity versus placebo in a human clinical study.
A randomised controlled trial of nabiximols (a standardised extract containing THC and CBD in a roughly 1:1 ratio, administered as an oromucosal spray) for peripheral neuropathic pain, published in 2012, did not show a statistically significant difference from placebo on its primary endpoint in a human clinical study, though some secondary and exploratory measures moved in a direction favouring nabiximols.
Human observational data from registries and surveys suggests some people with neuropathic pain report benefit from cannabis, but these reports cannot distinguish pharmacological effect from expectation, concurrent medication changes, or natural fluctuation in pain.
Animal research shows that cannabinoid receptor agonists reduce pain-related behaviour in rodent models of nerve injury. This is biological plausibility evidence, not treatment evidence. It tells us there is a mechanism worth investigating, but does not establish that cannabis reduces neuropathic pain in people.
Compounds studied for Neuropathic pain
THC has been studied in human randomised controlled trials of inhaled cannabis for neuropathic pain. Its effects on pain perception are thought to involve CB1 receptors in the central nervous system and peripheral nerves. The Cochrane review cited above covers studies that used both whole-plant cannabis and pharmaceutical THC preparations.
CBD has not been tested in completed human randomised controlled trials for neuropathic pain as an isolated compound, though it has been studied in combination with THC as nabiximols. Animal research suggests CBD may influence neuropathic pain through non-CB1 mechanisms including glycine receptors and TRPV1 channels.
CBG has been studied in animal research for its interaction with TRPV1 and alpha-2 adrenoceptors, both of which are targets in pain signalling. Cell and laboratory studies suggest CBG may have greater TRPV1 affinity than CBD, but no human clinical trial has tested CBG for neuropathic pain.
Beta-caryophyllene is a terpene found in cannabis and many culinary herbs that acts as a selective CB2 receptor agonist. Animal research has demonstrated reduced neuropathic pain behaviour after beta-caryophyllene administration, attributed to CB2-mediated anti-inflammatory effects. Human clinical evidence is absent.
Myrcene has shown anti-nociceptive effects in animal pain models, though the mechanism is not CB1- or CB2-dependent. Human evidence for myrcene and neuropathic pain does not exist.
Linalool has been studied in animal research for pain-related behaviour, but there are no human neuropathic pain trials of linalool as an isolated compound.
Limits of the evidence for Neuropathic pain
The human evidence base for cannabis and neuropathic pain is modest and conflicting. The largest systematic review concluded that the available randomised controlled trials do not provide good evidence of benefit. Individual trials have produced mixed results, with some positive and some negative. Most trials enrolled fewer than 50 participants and lasted weeks, not months or years.
Neuropathic pain is a broad category covering many different underlying conditions (diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, central pain after stroke, and others). Grouping these together in a single trial may obscure different responses.
The animal literature demonstrates biological plausibility but does not constitute treatment evidence. Many compounds reduce pain in rodent nerve-injury models but fail in human trials.
No randomised controlled trial of cannabis for neuropathic pain has compared it directly against the standard-of-care medicines that UK clinicians already prescribe, so the relative effectiveness, safety, and tolerability are unknown.
NICE guideline NG144 (2021) does not recommend cannabis-based medicinal products for chronic pain, including chronic neuropathic pain, citing insufficient evidence of benefit and concerns about long-term harms.
Sources
1. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2018;(3):CD012182. Study record
2. NICE. Cannabis-based medicinal products. NICE guideline NG144. Published 11 November 2019, updated 22 October 2021. Study record
3. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515-521. Study record
4. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. Journal of Pain. 2013;14(2):136-148. Study record
5. Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of Neurology. 2013;260(4):984-997. Study record
