Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB 1 ) and 2 (CB 2 ) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] − 24.83, 95% confidence interval [ 95% CI] − 34.89, − 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB 1/2 -non-selective) and AM1241 (CB 2 -selective) (MD − 28.73, 95% CI − 45.43, − 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB 2 -selective) increased paw withdrawal threshold (MD 0.89, 95% CI 0.79, 0.99, p < 0.00001), and ACEA (CB 1 -selective), AM1241 and JWH015 (CB 2 -selective) reduced spontaneous flinches (MD − 4.85, 95% CI − 6.74, − 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB 1/2 -non-selective), JWH015 and AM1241 (CB 2 -selective) in osteolysis-bearing females (MD 8.18, 95% CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB 2 -selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95% CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB 1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD − 0.19, 95% CI − 0.35, − 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95% CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB 1 and CB 2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB 1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.