Altered Brain Connectivity Patterns Associated With THC-Induced Analgesia

A reduction in the functional connectivity between the sensorimotor cortex and the anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) may be associated with δ-9-tetrahydrocannabinol (THC)-associated analgesia in patients with chronic radicular neuropathic pain, according to a study published in Neurology. In addition, the level of this reduction may be associated with the degree of THC efficacy.

A total of 15 patients with radicular pain of neuropathic origin in the lower limbs and a score ≥40 on a 100-point visual analog scale (VAS) were enrolled. Nine patients were randomly assigned to receive sublingual THC oil (0.2 mg/kg THC, for an average dose of 15.4±2.2 mg) during a first consultation and placebo oil at a second consultation, 1 week later, and 6 patients received placebo first, followed by THC.

At each treatment session, patients evaluated their pain using the VAS and filled the State-Trait Anxiety Inventory-State questionnaire, which assesses anxiety. Their heart rate and blood pressure were also recorded. Patients were scanned using functional magnetic resonance imaging at rest (no task; 6 minutes long). They were then administered placebo or THC and scanned again 1 hour (at rest) and 2 hours post-administration (time of peak THC plasma concentration). Analysis of temporal correlations of the resting state blood oxygenation level-dependent signal allowed the researchers to evaluate functional connectivity between brain regions.

Patients who received THC vs placebo oil reported greater reductions in perceived ongoing pain before and 2 hours after drug administration (reduction in VAS score post- vs preadministration: THC, 18.8±5.6 [P <.005]; placebo, 8.7±5.5; THC vs placebo, P <.05). THC-related analgesia was associated with a reduction in functional connectivity between the anterior cingulate cortex and the sensorimotor cortex, including the right and left secondary somatosensory cortex, as well as with the right motor cortex.

Functional connectivity between the anterior cingulate cortex and right and left somatosensory cortices, as well as with the primary motor cortex before THC administration, was correlated with improved analgesia (as indicated by reduced VAS scores) after THC administration (Pearson correlation coefficient, r, 0.679 [P <.01]; r, 0.66 [P <.01]; and r, 0.8 [P <.005], respectively). Reduced local efficiency and clustering coefficient, which co-varied with a reduction of VAS scores after THC administration, indicated a reduction in the whole network (local efficiency network, P =.018; clustering coefficient network, P =.0087) and in the right DLPFC cluster (local efficiency, P-FDR =.0435, clustering coefficient, P-FDR =.0037).

Limitations of the study include the small patient cohort and the lack of women participants, which may reduce generalizability of the findings.

“These results suggest that the [anterior cingulate cortex] and the DLPFC, 2 major cognitive-emotional modulation areas, and their connections to somatosensory areas, are functionally involved in the analgesic effect of THC in chronic pain,” concluded the investigators. “This effect may therefore be mediated through induction of functional disconnection between regulatory high-order affective regions and the sensorimotor cortex. Moreover, baseline functional connectivity between these brain areas may serve as a predictor for the extent of pain relief induced by THC.”

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Reference

Weizman L, Dayan L, Brill S, et al. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity [published online September 5, 2018]. Neurology. doi: 10.1212/WNL.0000000000006293