Yuzuru Kaneko

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.

Reduction of potential respiratory pathogens by oral hygienic treatment in patients undergoing endotracheal anesthesia.

AbstractPurpose. This study was conducted to evaluate the usefulness of mechanical and chemical prophylactic oral cleansing treatments for reducing potential respiratory pathogens existing in the oral cavity. Methods. Thirty-two patients scheduled to undergo oral and maxillofacial surgery that required endotracheal anesthesia were randomly allocated to one of the two groups, the oral cleansing group (n = 16) or the noncleansing group (n = 16). Culture and polymerase chain reaction (PCR) methods were used to detect and enumerate pathogens. Oral cleansing was carried out with an electric toothbrush capable of automatically supplying and aspirating povidone-iodine solution before surgery, followed by rinsing twice a day after surgery. Cephazolin (3 g·day−1) was given to all patients for 5 days after surgery. Results. The PCR detection rates of Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Porphyromonas gingivalis in gargle samples before treatment were 87.5%, 68.8%, 53.1%, and 40.6%, respectively. Oral cleansing reduced the detection rates and numbers of methicillin-sensitive Staphylococcus species, S. pneumoniae, and H. influenzae. In contrast, there was no significant reduction of methicillin-resistant Staphylococcus species, S. pneumoniae, H. influenzae, or P. aeruginosa in subjects who underwent systemic cephazolin administration without oral cleansing. Conclusion. The combination of mechanical and chemical oral cleansing resulted in a significant reduction of potential respiratory pathogens in the oral cavity.

Lack of Pain Reduction by a Vibrating Local Anesthetic Attachment: A Pilot Study

A vibrating dental local anesthesia attachment (Vibraject, LLC, Calif) based on the concept of the gate-control theory has been used in clinical practice. The theoretical advantage of the vibrating needle is that it reduces the injection pain. We evaluated the effectiveness of Vibraject in combination with an electrical injection device. Injections were given into the alveolar mucosa adjacent to the root apex of the maxillary lateral incisor in 10 volunteers. Vibraject was randomly applied to either the left or right side of the injection. No statistically significant decrease in pain scores was found at needle insertion or anesthetic injection. The clinical efficacy of Vibraject remains controversial.

Cortical Representation Area of Human Dental Pulp

To elucidate the dental pulp-representing area in the human primary somatosensory cortex and the presence of A-beta fibers in dental pulp, we recorded somatosensory-evoked magnetic fields from the cortex in seven healthy persons using magnetoencephalography. Following non-painful electrical stimulation of the right maxillary first premolar dental pulp, short latency (27 ms) cortical responses on the magnetic waveforms were observed. However, no response was seen when stimulation was applied to pulpless teeth, such as devitalized teeth. The current source generating the early component of the magnetic fields was located anterior-inferiorly compared with the locations for the hand area in the primary somatosensory cortex. These results demonstrate the dental pulp representation area in the primary somatosensory cortex, and that it receives input from intradental A-beta neurons, providing a detailed organizational map of the orofacial area, by adding dental pulp to the classic “sensory homunculus”.

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.

Amnesia for electric dental pulp stimulation and picture recall test under different levels of propofol or midazolam sedation

Aim:  To compare the amnesic effect of propofol and midazolam to electric dental pulp stimulation (invasive) and picture recall test (non‐invasive) at two sedation levels with the aid of bispectral index (BIS) monitoring.

Remifentanil decreases mandibular bone marrow blood flow during propofol or sevoflurane anesthesia in rabbits.

PURPOSE The purpose of this study was to investigate the effect of remifentanil on the blood flow in rabbit oral tissues during propofol or sevoflurane anesthesia. MATERIALS AND METHODS Thirty-two male tracheotomized Japanese white rabbits were anesthetized with propofol (P group) or sevoflurane (S group) under mechanical ventilation. Animals were further divided into 4 groups: adenosine triphosphate (ATP) treatment in the P group (P-ATP) (n = 8), remifentanil treatment in the P group (P-Remi) (n = 8), ATP treatment in the S group (S-ATP) (n = 8), and remifentanil treatment in the S group (S-Remi) (n = 8). Blood pressure, heart rate, common carotid artery blood flow (CABF), lingual mucosal blood flow (LMBF), and mandibular bone marrow blood flow (BMBF) were measured during each period before and during infusion of ATP or remifentanil. RESULTS Mean arterial pressure (MAP), CABF, LMBF, and BMBF showed a significant decrease in all 4 groups during infusion of the drug. Similarly, LMBF and BMBF showed significant decreases in both the ATP and remifentanil groups, whereas the decreases in MAP and CABF measured as percent change were greater in the ATP groups than in the remifentanil groups. A significant correlation was observed between CABF and BMBF in the S-Remi group. In both the P and S groups, the correlations between MAP and LMBF or BMBF were relatively strong when ATP was administered. CONCLUSIONS Our findings suggest that infusion of remifentanil during propofol or sevoflurane anesthesia reduces BMBF and LMBF, as does deliberate hypotension by use of ATP, without a major decrease in MAP.

A comparison of propofol and dexmedetomidine for intravenous sedation: a randomized, crossover study of the effects on the central and autonomic nervous systems.

We compared, in volunteers, the effect of propofol (PROP) and dexmedetomidine (DEX) sedation on autonomic nervous activities and subjective feelings during psychological stresses. In a crossover design, 25 subjects received PROP and DEX titrated to a bispectral index value of 75 to 85. Heart rate, heart rate variability, and salivary &agr;-amylase (objective indices) and a faces anxiety scale (subjective index) were assessed. Subjects were asked their preference between 2 sedatives. Objective indices showed similar changes in both groups. The faces anxiety scale decreased only in the PROP group and subjects preferred PROP. Propofol more effectively suppressed anxious feelings compared with DEX during sedation.

Negative Pressure Pulmonary Edema After Oral and Maxillofacial Surgery

Negative pressure pulmonary edema (NPPE) following upper airway obstruction (UAO) has been reported in several clinical situations. The main cause of NPPE is reported to be increased negative intrathoracic pressure. We present a case of NPPE that occurred after general anesthesia for plate removal after jaw deformity surgery. After completion of the surgery, administration of inhaled anesthetics was stopped and the patient opened his eyes on verbal command. Immediately after extubation, the patient stopped breathing and became cyanotic. Acute UAO following laryngospasm was suspected. Soon after reintubation, pink, frothy fluid came out of the endotracheal tube, and a tentative diagnosis of NPPE was made. Continuous positive airway pressure was applied. In addition, furosemide and dexamethasone were administered. By the next day, the symptoms had almost disappeared.