Ken-ichi Fukuda

Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype

AIMS The association between SNPs of the human OPRM1 gene encoding the micro-opioid receptor and postoperative analgesic requirements in surgical patients remains controversial. Here, we evaluate whether any of the five tag SNPs (A118G, IVS2+G691C, IVS3+G5953A, IVS3+A8449G and TAA+A2109G) representing the four linkage disequilibrium blocks of the OPRM1 gene influences postoperative analgesic requirements. MATERIALS & METHODS We studied 138 adult Japanese patients who underwent major open abdominal surgery under combined general and epidural anesthesia and received continuous postoperative epidural analgesia with opioids. RESULTS The 118G homozygous (GG) patients required 24-h postoperative analgesics more than 118A homozygous (AA) and heterozygous (AG) patients. Tag SNP haplotypes also were associated with 24-h postoperative analgesic requirements. CONCLUSIONS These results suggest that OPRM1 gene tag SNP genotypes and haplotypes can primarily contribute to prediction of postoperative analgesic requirements in individual patients undergoing major open abdominal surgery.

Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery

ABSTRACT 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.

Genome-wide association study identifies a potent locus associated with human opioid sensitivity

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.

Clinical application of adenosine and ATP for pain control

This review summarizes clinical application of adenosine and adenosine 5′-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation/sensitization pain models and in patients with chronic neuropathic pain. Adenosine compounds, in low doses, can reduce allodynia/hyperalgesia more consistently than spontaneous pain, suggesting that these compounds affect neuronal pathophysiological mechanisms involved in central sensitization. Such pain-relieving effects, which are mostly mediated via central adenosine A1 receptor activation, have a slow onset and long duration of action, lasting usually for hours or days and occasionally for months. With acute perioperative pain, treatment with a low-dose infusion of adenosine compounds and the A1 receptor-mediated central antisensitization mechanisms may play only a minor part in the total perioperative pain experience. By administering sufficient doses of adenosine compounds during surgery, however, significant and long-lasting perioperative pain relief can be achieved via central A1 receptor-mediated antinociceptive/analgesic actions as well as via peripheral A2a or A3 receptor-mediated antiinflammatory actions. Thus, adenosine compounds have significant potential for alleviating various types of pain.

OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis.

Background:Although a number of studies have investigated the association of the OPRM1 A118G polymorphism with pain response, a consensus has not yet been reached. Methods:The authors searched PubMed, EMBASE, and the Cochrane Library to identify gene-association studies that explored the impact of the OPRM1 A118G polymorphism on postoperative opioid requirements through July 2013. Two evaluators independently reviewed and selected articles on the basis of prespecified selection criteria. The authors primarily investigated the standardized mean difference (SMD) of required amounts of opioids between AA homozygotes and G-allele carriers. The authors also performed subgroup analyses for race, opioid use, and type of surgery. Potential bias was assessed using the Egger’s test with a trim and fill procedure. Results:Three hundred forty-six articles were retrieved from databases, and 18 studies involving 4,607 participants were included in the final analyses. In a random-effect meta-analysis, G-allele carriers required a higher mean opioid dose than AA homozygotes (SMD, −0.18; P = 0.003). Although there was no evidence of publication bias, heterogeneity was present among studies (I2 = 66.8%). In the subgroup meta-analyses, significance remained robust in Asian patients (SMD, −0.21; P = 0.001), morphine users (SMD, −0.29; P <0.001), and patients who received surgery for a viscus (SMD, −0.20; P = 0.008). Conclusions:The OPRM1 A118G polymorphism was associated with interindividual variability in postoperative response to opioids. In a subpopulation, identifying OPRM1 A118G polymorphism may provide valuable information regarding the individual analgesic doses that are required to achieve satisfactory pain control.

Diversity of Opioid Requirements for Postoperative Pain Control Following Oral Surgery—Is It Affected by Polymorphism of the μ-Opioid Receptor?

We experience individual differences in pain and sensitivity to analgesics clinically. Genetic factors are known to influence individual difference. Polymorphisms in the human OPRM1 gene, which encodes the μ-opioid receptors, may be associated with the clinical effects of opioid analgesics. The purpose of this study was to determine whether any of the 5 common single-nucleotide polymorphisms (SNPs) of the OPRM1 gene could affect the antinociceptive effect of fentanyl. Fentanyl was less effective in subjects with the G allele of the OPRM1 A118G SNP than in those with the A allele, and subjects with the G allele required more fentanyl for adequate postoperative pain control than those with the A allele. In the future, identifying SNPs might give us information to modulate the analgesic dosage of opioid individually for better pain control. Factors underlying individual differences in sensitivity to pain other than genetic factors may include environmental and psychological factors. We therefore examined the effects of preoperative anxiety on the analgesic efficacy of fentanyl in patients undergoing sagittal split mandibular osteotomy (SSMO). From among the patients enrolled in the study, 60 patients (male/female: 18/42, age: 24.6 ± 6.7 years) who gave informed consent were examined for correlations between preoperative trait/state anxiety, as measured by the state-trait anxiety inventory (STAI) on the day before surgery, and postoperative consumption of patient-controlled analgesia (PCA) fentanyl and visual analog scale (VAS) assessment by patients. Levels of trait and state anxieties measured by the STAI were correlated with neither the consumption of PCA fentanyl nor postoperative VAS assessment. These findings suggest that psychological factors are unlikely to affect postoperative pain or the use of analgesics.

Association between Genetic Polymorphisms in Ca(v)2.3 (R-type) Ca2+ Channels and Fentanyl Sensitivity in Patients Undergoing Painful Cosmetic Surgery

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca2+ channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Cav2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Cav2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity.

Pain Management for Nerve Injury following Dental Implant Surgery at Tokyo Dental College Hospital

By allowing reconstruction of compromised occlusion, dental implants contribute to an improvement in quality of life (QOL) and diet. Injury to a nerve during such treatment, however, can result in a sudden decline in QOL. And once a nerve has been injured, the chances of a full recovery are slim unless the damage is only slight. If such damage causes neuropathic pain severe enough to prevent sleep, the patients QOL will deteriorate dramatically. While damage to skin tissue or bone invariably heals over time, damage to nerves does not, indicating the need to avoid such injury while performing implant insertion, for example. This means not relying solely on X-ray images, which can be rather unclear, but also using computed tomography to allow preoperative planning and intraoperative execution to be performed as accurately as possible. Moreover, if sensory damage does occur it is essential to avoid breaking the bond of trust between dentist and patient by giving false assurances of recovery. In such cases, appropriate measures must be taken promptly. This paper describes pain management for nerve injury following dental implant surgery at the Orofacial Pain Center of Tokyo Dental College Suidoubashi Hospital.

A rabbit model for evaluation of surgical anesthesia and analgesia: characterization and validation with isoflurane anesthesia and fentanyl analgesia.

PurposeWith a clamp test, quantitative estimation of the level of surgical anesthesia/analgesia is not easy. We have developed a rabbit pain model allowing for quantitative evaluation of the level of surgical anesthesia/analgesia using both electrical and mechanical stimuli as simulated surgical stimuli. We evaluated whether this model allows for accurate tracing of dynamically changing levels of surgical anesthesia/analgesia induced by isoflurane and fentanyl.MethodsEight rabbits tracheotomized and vascularly cannulated under 3% isoflurane anesthesia were placed on a sling that allowed for free movement of the head and extremities. After the isoflurane concentration was reduced stepwise to 1.5% and then to 0%, four graded doses of fentanyl (5, 10, 20, and 40 µg·kg−1) were injected intravenously at intervals of 120 min. At each dose, anesthetic/analgesic end-point variables were determined, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and the threshold voltage of subcutaneous electrical stimulation (2, 5, and 50 Hz) required to evoke the head lift (HLT: pain detection/arousal threshold: sedative/hypnotic index) and the escape movement (EMT: pain tolerance threshold: analgesic index).ResultsWith increasing doses of isoflurane and fentayl, HLTs and EMTs, especially those at 5 Hz, increased dose-dependently and proportionately to increases in the number of nonresponders to clamping the forepaw, a standard indicator of the anesthetic/analgesic level.ConclusionUsing the HLT and EMT, especially at 5 Hz, combined with a clamp test, this rabbit model allows for repeated, quantitative, and distinctive evaluation of the dynamically changing levels of both sedative/hypnotic and analgesic components of surgical anesthesia/analgesia.

Association between 5-hydroxytryptamine 2A receptor gene polymorphism and postoperative analgesic requirements after major abdominal surgery

Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women.