Masakazu Hayashida

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.

Association between KCNJ6 (GIRK2) Gene Polymorphisms and Postoperative Analgesic Requirements after Major Abdominal Surgery

Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5′-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean±SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45±9.27 mg, 10.84±2.24 mg, and 13.07±2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

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.

Detection of acute tolerance to the analgesic and nonanalgesic effects of remifentanil infusion in a rabbit model.

Although acute tolerance to analgesia develops rapidly with remifentanil, it is unknown whether acute tolerance also develops to its nonanalgesic effects. We investigated the analgesic and cardiorespiratory effects of remifentanil during a continuous infusion in a rabbit model. Ten tracheotomized New Zealand White rabbits with arterial and venous accesses were placed on a sling that allowed for reasonably free movement. In spontaneously breathing conscious animals, remifentanil was infused IV at a constant-rate of 0.3 &mgr;g · kg−1 · min−1 for 360 min. Sedative/analgesic and cardiorespiratory variables were assessed repeatedly during remifentanil infusion, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and subcutaneous electrical stimulation thresholds required to elicit head lift (HLT: pain detection/arousal threshold) and escape movement responses (EMT: pain tolerance threshold). Within 60–120 min of starting the infusion, the number of nonresponders, HLT, EMT, and Paco2 increased significantly, whereas blood pressure, heart rate, and respiratory rate decreased. Thereafter, all variables returned towards preinfusion levels despite continuing infusion. These results indicate that during a remifentanil infusion acute tolerance develops for both its analgesic and cardiorespiratory effects.

Candidate gene polymorphisms predicting individual sensitivity to opioids.

Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. Studies using gene knockout mice have revealed that genes encoding some metabolic enzymes, opioid transporters, and opioid system signal transduction mediators may be candidate genes to predict appropriate kinds and doses of opioids for individuals. Recently, various databases on knockout mice, pharmacogenetics, and gene polymorphisms have been rapidly consolidated. Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.

Effect of cardiopulmonary resuscitation on intubation using a Macintosh laryngoscope, the AirWay Scope, and the gum elastic bougie: A manikin study.

BACKGROUND Physicians could encounter difficult intubation during cardiopulmonary resuscitation (CPR) in trauma patients due to the patients movement from continuous chest compression and to cervical stabilisation. Therefore, first, we evaluated the impact of chest compression with or without cervical stabilisation on intubation with a Macintosh laryngoscope. Next, we compared difficulty in intubation among the Macintosh laryngoscope, AirWay Scope (AWS), and gum elastic bougie (GEB) with the Macintosh laryngoscope in three simulated CPR scenarios in a randomised, controlled, cross-over study design. METHODS Twenty-three anaesthetists intubated the trachea of a manikin (ALS Skill Master, Laerdal Medical Japan, Tokyo, Japan) using the Macintosh laryngoscope, AWS, and GEB in the control scenario, chest compression scenario, and chest compression with cervical stabilisation scenario. Difficulty in intubation was rated on a 5-point scale and the intubation time was measured. RESULTS Continuous chest compression increased difficulty in intubation with the Macintosh laryngoscope, compared with the control scenario. Concurrent application of cervical stabilisation further increased the difficulty, compared with application of chest compression alone. Of the three devices compared, the AWS facilitated the easiest intubation, and the GEB facilitated the second-easiest intubation in all scenarios, though the intubation time was slightly longer with the GEB than with other devices. CONCLUSION CPR employing continuous chest compression with or without cervical stabilisation caused difficult intubation with the Macintosh laryngoscope. The AWS and GEB facilitated the easiest and second-easiest intubation, respectively, even during CPR employing continuous chest compression with or without cervical stabilisation in a manikin.

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.

Effects of Topical Application of Clonidine Cream on Pain Behaviors and Spinal Fos Protein Expression in Rat Models of Neuropathic Pain, Postoperative Pain, and Inflammatory Pain

Background:Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Methods:Clonidine (30, 100, and 300 &mgr;g/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. Results:In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Conclusions:Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located &agr;2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.