Accepted

Buprenorphine is a Schedule III analgesic that is recommended as the firstline long-acting opioid for the treatment of chronic pain due to its ceiling effect on respiratory depression, adverse effect profile, and analgesic efficacy. However, prescription drug coverage policies commonly require that patients try and fail multiple Schedule II conventional opioids before approval of on-label use of buprenorphine for chronic pain.

Conventional MRI of patients with trigeminal neuralgia (TN) does not typically reveal associated brain lesions. Here, we identify a unique group of TN patients that present with a single brainstem lesion, who do not fulfill diagnostic criteria for multiple sclerosis (MS). We aim to define this new clinical syndrome, which we term TN associated with solitary pontine lesion (SPL-TN), using a clinical and neuroimaging approach. We identified 24 cases of SPL-TN, 18 of which had clinical follow-up for assessment of treatment response. Lesion mapping was performed to determine the exact location of the lesions and site of maximum overlap across patients. Diffusion tensor imaging was used to assess the white matter microstructural properties of the lesions. Diffusivity metrics were extracted from the (1) SPL-TN lesions, (2) contralateral, unaffected side, (3) MS brainstem plaques from 17 patients with TN secondary to MS, (4) and healthy controls. We found that 17/18 patients were non-responders to surgical treatment. The lesions were uniformly located along the affected trigeminal pontine pathway, where the site of maximum overlap across patients was in the area of the trigeminal nucleus. The lesions demonstrated abnormal white matter microstructure, characterized by lower fractional anisotropy, and higher mean, radial, and axial diffusivities compared to the unaffected side. The brainstem trigeminal fiber microstructure within a lesion highlighted the difference between SPL-TN lesions and MS plaques. In conclusion, SPL-TN patients have identical clinical features to TN, but have a single pontine lesion not in keeping with MS, and are refractory to surgical management.

Genetic variation in melanocortin-1 receptor (MC1R) has a known role in red hair. Studies on responses to noxious stimuli in red-haired individuals have also been conducted, with mixed findings. To investigate a possible divergence between variants responsible for red hair and pain sensitivity, we performed a gene-wide association analysis in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. All genotyped (17) MC1R variants were tested for association with heat pain temporal summation and sensitivity. Our analyses showed an association for pain sensitivity with the 5'-UTR, tagged by rs3212361, and one missense variant, rs885479 (R163Q), previously shown to be weakly associated with red hair. For both variants, the minor allele was protective. These results were validated in the 500,000-person U.K. Biobank (UKBB) cohort, where the minor alleles of rs3212361 and rs885479 were associated with a reduced count of persistent pain conditions as well as individual pain conditions. Haplotype association analysis revealed a possible joint effect from the two individual variants. The 5'-UTR variant rs3212361 was further identified as an expression quantitative trait locus (eQTL), associated with reduced transcript levels of MC1R in the brain and in the peripheral tibial nerve. Hair colour association analysis of the loss-of-function 5'-UTR rs3212361 allele identified association with red hair, and red hair colour itself was associated with a reduced count of persistent pain conditions. Together, our results suggest that primarily different mechanisms – affecting expression levels versus protein activity – mediated by different genetic variants in the MC1R locus contribute to red hair and pain.