The body's endocannabinoid system:
Neuropathic pain:
The effectiveness of cannabinoids in the treatment of neuropathic pain:
How to choose a dose of cannabinoids:
The body's endocannabinoid system consists of three main components: endogenous ligands (anandamide and 2-arachidonoylglycerol), G-protein receptors, and enzymes that metabolize and recycle the ligands. Read more
Animal studies have shown the analgesic properties of cannabinoids and the role of CB1 and CB2 receptors in the endocannabinoid system in modulating acute, chronic, and neuropathic pain. Read more
Clinical pharmacology of cannabinoids
Cannabinoid and endocannabinoid systems
Neuropathic pain is a debilitating pain syndrome that affects 6-10% of the general population. Read more
Neuropathic pain occurs in 57% of combat-wounded patients with limb loss. Read more
Neuropathic pain underlies phantom pain, affecting 45-85% of patients who have had upper and/or lower limb amputations, and phantom pain occurs predominantly within two time periods after amputation: the first month or approximately 1 year. Read more
Neuropathic pain responds poorly to drug therapy. Read more
Less than half of patients with neuropathic pain achieve significant relief with currently recommended medications, such as pregabalin, gabapentin, duloxetine, and tricyclic antidepressants. Read more
Neuropathic pain is characterized by a combination of various pain symptoms (constant or intermittent spontaneous pain, e.g. burning, stabbing, squeezing, which may accompany pain caused by touch or cold), paresthesia and/or dysesthesia (tingling, numbness, etc.), as well as sensory deficits in the painful area along with other deficits (motor, cognitive, etc.). Read more
Mechanism of neuropathic pain development: The role of macroglia activation in the development of neuropathic pain. Nerve damage activates microglia in the dorsal horn of the spinal cord. Microglia mediate neuroinflammation in the central nervous system (CNS). Activated microglia are characterized by increased expression of the P2X4R purinoreceptor, which leads to signaling by fibronectin and chemokine (C-C motif) ligand 21 (CCL21) and the trafficking of P2X4R to the microglial cell surface. P2X4R is activated by ATP and this in turn releases bioactive diffusible factors such as BDNF, which downregulates the potassium chloride transporter KCC2 via TrkB, causes an increase in intracellular chloride ion levels and leads to a collapse of the transmembrane anion gradient in dorsal horn neurons, which in turn causes depolarization of these neurons upon stimulation by GABA and glycine. This causes increased excitability in the dorsal horn pain network and may be the cause of neuropathic pain. Read more
The evoked pain can spread to neighboring areas, leading to peripheral and central sensitization. The sensitization of nociceptive pathways is based on maladaptive structural changes, a number of intercellular interactions, and changes in molecular signaling (changes in ion channels; activation of immune cells; mediators derived from glial cells; epigenetic regulation). Read more
A systematic review (16 studies, 1750 participants), 2-26 weeks in duration, compared the effects of an oromucosal spray containing a plant-based combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid that mimics THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-based THC (dronabinol) (two studies) versus placebo (15 studies), and an analgesic (dihydrocodeine) (one study). The quality of evidence was rated very low to moderate by GRADE. Read more
Cannabis-based medicines may increase the number of patients achieving 50% or more pain relief compared with placebo (21% vs 17%). More participants dropped out of studies due to side effects with cannabis-based medicines (10% of participants) than with placebo (5% of participants). No information was found on long-term risks. The researcher did not obtain convincing evidence that herbal cannabis reduces average pain intensity (very low-quality evidence), but herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). Read more
Cannabis extracts in experimental neuropathic pain demonstrated antinociceptive effects comparable to gabapentin. Read more
Reduction in neuropathic pain under the influence of cannabinoids was explained by disruption of connections in the CNS. Read more
The vast majority of studies on the effectiveness of cannabinoids in neuropathic pain evaluated the effectiveness of THC [6], however, it has recently been proven that the gene-encoded protein FKBP5, which functions as a chaperone, facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, and is considered a new target of CBD for the treatment of neuropathic pain. Thus, CBD has been shown to be an antagonist of FKBP5. CBD directly binds to FKBP5, stabilizing this protein and inhibiting the assembly of the IKK complex and the activation of NF-κB, thus blocking the NF-κB-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. In addition, systemic administration of CBD inhibited the activation of microglia. Read more
Of the five secondary cannabinoids found in cannabis in smaller amounts: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC) and Δ9-tetrahydrocannabivarin (THCV), four showed cannabimimetic activity, while one was effective in alleviating chronic neuropathic pain. Read more
An anonymous online survey of 227 patients with spinal cord injury regarding cannabis use found that 87.9% reported that cannabis reduced the intensity of their neuropathic pain by more than 30%, and 92.3% of patients reported that cannabis helped them better manage their neuropathic pain symptoms. The majority of participants (83.3%) also reported that they had replaced their pain medications with cannabis, with opioids (47.0%), gabapentinoids (42.8%), and over-the-counter pain medications (42.2%) being the most commonly substituted categories. These findings suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain in patients with spinal cord injury and may help limit the need for certain pain medications, including opioids. Read more
When inhaled, the number needed to treat (NNT) to achieve a 30% reduction in pain was 3.2 compared to placebo with the low dose of cannabis, 2.9 compared to placebo with the medium dose, and 25 compared to the low dose. This indicates that cannabis has analgesic efficacy, with the low dose producing the same effect as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychiatric effects were of limited duration and reversible within 1-2 hours. Read more
Another clinical trial has shown that medical cannabis is safe and highly effective for the treatment of neuropathic pain and associated sleep disturbances. This retrospective observational study enrolled 99 patients with chronic neuropathic pain. These patients received medical cannabis by inhalation of dried flowers with a THC content of <12-22% at a maximum daily dose of 0.15-1 g. Up to six follow-up examinations were performed at 4-6 week intervals. Pain severity, sleep disturbance, overall improvement, side effects, and tolerability of therapy at follow-up consultations were assessed in an interview and compared with baseline data using the nonparametric Wilcoxon signed-rank test. During 6 weeks of therapy, the median pain score decreased from 7.5 to 4.0 (p < 0.001). The proportion of patients with severe pain (>6 points) decreased from 96% to 16% (p < 0.001). Sleep disturbance also decreased significantly with a median score of 8.0 to 2.0 (p < 0.001). These positive changes were maintained for up to 6 months. No serious adverse events were observed. Mild adverse events were reported: dry mouth (5.4%), fatigue (4.8%), and increased appetite (2.7%). Read more
A systematic review of 36 studies (7217 participants) found the efficacy of cannabis and nabiximol for the treatment of neuropathic pain. However, the use of cannabis, nabiximol, and delta-9-tetrahydrocannabinol was associated with a higher incidence of adverse events than in the control group. Read more
A systematic review found that, compared with placebo, an oral spray of a plant extract with equal THC to CBD content caused a modest reduction in pain intensity. There were no withdrawals from the study due to adverse events, although there was an increased risk of dizziness and sedation, and a modestly increased risk of nausea. Synthetic products with a high THC to CBD ratio were associated with a small improvement in pain severity, a modest increase in sedation, and a significant increase in the risk of nausea. Use of whole plant extracts with high THC and CBD content (oral) was associated with a significantly increased risk of withdrawal from the study due to adverse events and dizziness. Read more
It has been proven that dronabinol at a dose of 10 mg is better tolerated than at a dose of 20 mg, the mild analgesic effect corresponds to the effect of 60 mg of codeine. Nabiximols can be dosed in inhalations per day: low dose (1–4 inhalations/day), medium dose (6–10 inhalations/day), high dose (11–16 inhalations/day). Inhalation provides relief from acute pain (benefit from immediate effect), while oral administration provides a long-acting effect, which is advisable for constant pain. Read more