ABSTRACT
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
Subject(s)
Analgesics, Opioid/administration & dosage , Cyclic AMP Response Element-Binding Protein/genetics , Pain, Postoperative/drug therapy , Pain, Postoperative/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Chromosomes, Human, Pair 2/genetics , DNA Modification Methylases/genetics , Female , Genome-Wide Association Study , Genotype , Humans , Linkage Disequilibrium , Male , Middle Aged , Pain Measurement , Pain, Postoperative/etiology , Psychiatric Status Rating Scales , Plastic Surgery Procedures/adverse effects , Substance-Related Disorders/genetics , Young AdultABSTRACT
The purpose of this study was to investigate how grading according to our new gagging reflex index correlated with patient background and subsequent management. After obtaining institutional approval and informed consent, 110 patients with a gagging problem were enrolled. The patients completed the State-Trait Anxiety Inventory (STAI), the Dental Anxiety Scale (DAS), and a health questionnaire at initial consultation. On the second visit, an intra-oral examination was carried out and the severity of gag reflex determined according to our new, 5-level Classification of Gagging Problem (CGP) index: normal gagging but not desensitised (G1 = score 1); mild gagging (G2 = score 2); moderate gagging (G3 = score 3); severe gagging (G4 = score 4); and very severe gagging (G5 = score 5). No difference was found in grade based on age or STAI or DAS scores. The CGP score in male patients was significantly higher than that in female. The management classification method and degree of desensitisation were investigated retrospectively in each patient at 3 months and 1 year after initial consultation. The higher the CGP grade, the more often intravenous sedation or general anaesthesia was required due to difficultly in desensitisation. The present results suggest that determining whether it is possible to examine the molar area without inducing the gag reflex offers the key to deciding the treatment strategy.
