Cross-sectional assessment of the consequences of a GTP cyclohydrolase 1 haplotype for specialized tertiary outpatient pain care.
OBJECTIVE
Reduced-function variants of the guanosine triphosphate cyclohydrolase gene (GCH1) 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" GCH1 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 GCH1 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 (alpha-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 GCH1 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.
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Alexandra
A
Doehring
Rainer
R
Freynhagen
Norbert
N
Griessinger
Michael
M
Zimmermann
Reinhard
R
Sittl
Nils von
Nv
Hentig
Gerd
G
Geisslinger
Jörn
J
Lötsch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care; D000700:Analgesics / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy / Q000235:genetics*; D010147:Pain Measurement / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
D000700:Analgesics; D000701:Analgesics, Opioid; D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin