Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the μ-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost–PPLpre]: 12 s) compared with subjects not carrying this allele (PPLpost–PPLpre: 15 s, p = 0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3′ untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5 μg/kg) compared with subjects not carrying this allele (median: 2.5 μg/kg, p = 0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3′ untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.
aDepartment of Oral Health and Clinical Science, Division of Dental Anesthesiology (Orofacial Pain Center/Suidoubashi Hospital), Tokyo Dental College, 2-9-18 Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan
bDepartment of Anesthesiology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka-shi, Saitama 350-1298, Japan
cDivision of Psychobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan
dDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
eDepartment of Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba 285-8741, Japan
fDepartment of Anesthesiology, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba 285-8741, Japan
gDivision of Psychobiology, Department of Neuroscience, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai-shi, Miyagi 980-8574, Japan
hLaboratory of Medical Genomics, Department of Human Genome Technology, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu-shi, Chiba 292-0818, Japan
iDepartment of Dental Anesthesiology, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba 261-8502, Japan
*Corresponding author. Tel.: +81 3 3304 5701; fax: +81 3 3329 8035.
Received February 10, 2009
Received in revised form September 1, 2009
Accepted September 4, 2009.