Cross-sectional Assessment of the Consequences of a GTP Cyclohydrolase 1 Haplotype for Specialized Tertiary Outpatient Pain Care

Objectives: Reduced-function variants of the guanosine triphosphate cyclohydrolase gene (GCHI) have been associated with reduced pain in well-defined cohorts of patients and healthy volunteers. We addressed the question whether this genetic association plays a role in outpatient pain therapy. Methods: In a cross-sectional observational study, 523 patients were enrolled in 3 different tertiary care outpatient pain centers at German University hospitals. Of the 519 Caucasian patients, data from 424 could be analyzed for functional associations of the formerly named "pain-protective" GCHI haplotype with the key characteristics of pain therapy being (1) actual pain, (2) opioid dosing, and (3) pain therapy duration. Results: With an allelic frequency of 14.2% the pain-protective haplotype was not rarer among pain patients than in the general population (P = 0.344). However, a tendency toward gene dose-dependent effects of the GCHI haplotype was observed in all the 3 therapy parameters. Carriers of the haplotype tended to have lower actual 24-hour pain scores (n = 424; P = 0.18), require lower opioid doses (P = 0.096), and were significantly shorter on specialized pain therapy (P = 0.004). The latter applied predominantly to differences between homozygous carriers and heterozygous (α-corrected t test: P=0.06) or non-carriers (P=0.011) of the haplotype. Conclusions: The results strength the support for a modest yet reproducible and consistent pain-protective effect associated with a GCHI haplotype known to reduce GCH1 and thus BH4 up-regulation. Pending independent verification, the results might point to a prophylactic role of decreased GCH1 up-regulation delaying the need for pain therapy.