September 07, 2018
New imaging findings show how tetrahydrocannabinol (THC), the psychoactive component of cannabis, works in the brain to effectively treat chronic neuropathic pain.
Results of a small randomized, double-blind, crossover trial show that THC-induced pain relief was associated with reduced functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex.
"The main message of this paper is that THC, the psychoactive component in cannabis, does seem to exert a beneficial effect on proven chronic nerve pain.
This effect seems to involve a breakdown in functional connectivity between brain regions that process different dimensions that construct the experience of pain," study author Haggai Sharon, MD, who leads the Consciousness & Psychopharmacology research team at Sagol Brain Institute, Tel Aviv, Israel, told Medscape Medical News.
The study was published online September 5 in Neurology.
Although previous research has shown that treatment of chronic pain remains the number one medical use for cannabis, the underlying neurologic changes associated with clinical benefit remain unknown.
Sharon said the researchers expected these mechanisms to be "complex and involve large-scale brain changes" because humans naturally feature cannabis receptors in many regions of the brain, including the ACC.
A previous neuroimaging study showed THC was associated with decreased ACC activity in healthy participants.
Those investigators note that peripheral changes alone could not sufficiently explain the dissociative properties of THC on pain, supporting the role of the brain — and the amygdala in particular — in modulating sensory improvements.
For the current study, researchers enrolled 17 individuals with chronic neuropathic lower-limb pain (mean age, 33 years). All were recruited at The Institute of Pain Medicine at the Tel-Aviv Sourasky Medical Center in Israel.
The researchers restricted the study to men; women "were excluded due to evidence that menstruation-related hormonal fluctuations may alter pain sensitivity," they note.
After exclusions, investigators assessed the effect of a single sublingual dose of THC or placebo on visual analog scale (VAS) scores and resting-state brain connectivity of the ACC in 15 participants using functional MRI (fMRI).
Participants completed the State-Trait Anxiety Inventory–State questionnaire and underwent heart rate and blood pressure measurements at each session. They also underwent nontask resting state fMRI, followed by receiving either 0.2 mg/kg THC oil or placebo placed sublingually. The average THC dose was 15.4 mg.
Investigators obtained a second fMRI scan about 2 hours after THC or placebo administration. Following a washout period that averaged 3 weeks, participants crossed over to the other intervention group and repeated the protocol.
The fMRI data were acquired by using a 3T MRI scanner, and functional scans were obtained by using T2-weighted echoplanar images.
Sharon and colleagues also performed graph theory analysis, which allowed them to examine the interconnectivity of 11 brain regions. They looked at the ACC, amygdala, secondary somatosensory cortex, middle cingulate cortex, and dorsolateral prefrontal cortex (DLPFC), among others.
Pain Scores, Imaging Findings Align
The reduction in VAS pain ratings reported after THC administration was significant compared with preintervention scores (P < .05) and between THC and placebo (P < .005). In contrast, VAS scores did not differ significantly before and after administration of the placebo.
In addition, the researchers reported a reduction in functional connectivity between the ACC and the sensorimotor cortex, which correlated with changes in subjective pain ratings after THC treatment. They also specifically reported changes in three clusters within the sensorimotor cortex: the right and left secondary somatosensory cortex and the right motor cortex.
No such relationships were observed between pain scores and functional connectivity among these brain structures following placebo administration.
Buoyed by results showing connectivity changes among these brain regions, the investigators then expanded the study to all regions considered part of the so-called chronic pain network.
They reported significant changes in global efficiency of the middle cingulate cortex between THC and placebo interventions, for example, again using graph theory analysis.
In addition to a reduction in the whole network, decreases in the DLPFC cluster aligned with the lower pain scores following THC administration. Again, these changes were not observed with the placebo.
Anxiety scores, blood pressure, and heart rate measures did not change significantly after administration of THC vs placebo.
New Insights for Drug Development
THC may provide relief by disrupting the synchrony and integration between the ACC and sensorimotor cortex pain-processing pathways.
"The relation between analgesia and a mind-altering substance that induces clinical dissociation in many domains is fascinating," Sharon said. "Moreover, delineating these mechanisms may assist in better patient selection and control of side effects ... and drive new insights into analgesic drug development."
The current findings reinforce "the seminal role of nonsensory aspects of pain as building the aversive experience that accompanies pain and offer a new insight into analgesia," Sharon said.
"It isn't just about numbing the sensations but [THC] can also act by modulating the subjective suffering."
Interestingly, the research also showed that the higher the functional connectivity between the ACC and sensorimotor cortex at baseline — before administration of THC — the greater the benefit in terms of pain relief.
"Our results suggest that this regional functional connectivity may also serve to predict the extent of pain relief induced with THC," the investigators write.
"This was a major and unexpected surprise," Sharon added. "Characterizing predictors for response is, of course, of major importance, as the question of correct patient selection for pharmacotherapy in chronic pain is a crucial one."
Larger studies are now warranted to examine the reproducibility of the results, the investigators note. Future trials should also examine different cannabinoids, as well as include patients with conditions other than chronic radicular pain to determine whether the findings are specific to neuropathic pain only or apply to other chronic pain states.
"We plan to further explore predictors for response at the individual patient level, better understand the relation between dissociative effects on cognitive emotional and sensory processing and clinical analgesia, and the relation of these processes to secondary autonomic and homeostatic regulatory mechanisms," Sharon said.
Commenting on the findings for Medscape Medical News, Mark S. Wallace, MD, professor of clinical anesthesiology and chief of the Division of Pain Medicine in the Department of Anesthesiology, University of California San Diego, described the findings as "interesting."
"I would also be interested in seeing the effects of different doses," Wallace said.
"We have shown [before] that there is a therapeutic window of THC on pain relief, with high doses actually worsening pain and low doses relieving pain," he added.
The study was funded by the Yahel Foundation, Recanati New York, and the Ministry of Science, Technology and Space in Israel. Sharon and Wallace have disclosed no relevant financial relationships.