Yoshihiko Koukita

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.

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.

Low dose of fentanyl reduces predicted effect-site concentration of propofol for flexible laryngeal mask airway insertion

AbstractPurposeIn contrast to reports on the classical laryngeal mask airway (classical LMA; CLMA), no report has calculated the 50% and 95% effect-site concentrations (EC50 and EC95, respectively) of propofol required for flexible LMA (FLMA) insertion. This study was designed to determine the EC50 and EC95 of propofol for FLMA insertion, using probit analysis, and to investigate whether supplemental 0.25 μg·kg−1 fentanyl decreased these concentrations.MethodsFifty-nine unpremedicated patients who were scheduled for elective minor oral surgery were randomly allocated to a saline-propofol group (S-P group; n = 30) or a fentanyl-propofol group (F-P group; n = 29). Each group was further divided into four subgroups, in which the propofol EC for FLMA insertion was set at 2.5, 3.0, 3.5, and 4.0 μg·ml−1, respectively, in the S-P group and 1.8, 2.0, 2.5, and 3.0 μg·ml−1, respectively, in the F-P group,. The experiment was assessed as ”successful” when FLMA insertion within 1 min was possible.ResultsThe EC50 and EC95 in the S-P group were 3.29 (95% confidence interval [CI], 2.83–3.93) and 4.73 (95% CI, 3.94–12.22) μg·ml−1, and those in the F-P group were 2.13 (95% CI, 1.42–2.60) and 3.54 95% CI, (2.78-34.78) μg·ml−1, respectively. The EC50 in the F-P group was significantly lower than that in the S-P group. There were no significant differences in bispectral index (BIS), hemodynamic variables, respiratory rate, and arterial oxygen saturation (

Effects of intravenous adenosine 5′-triphosphate on intraoperative hemodynamics and postoperative pain in patients undergoing major orofacial surgery: a double-blind placebo-controlled study

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Association between the rs7583431 single nucleotide polymorphism close to the activating transcription factor 2 gene and the analgesic effect of fentanyl in the cold pain test

) between the S-P and F-P groups.ConclusionThe propofol EC50 for FLMA insertion was decreased by supplemental 0.25 μg·kg−1 fentanyl without BIS, hemodynamic, or respiratory depression.

Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test

PurposeChronic orofacial pain is often refractory to conventional pain therapies. We conducted an open-label study to determine whether adenosine 5′-triphosphate (ATP) could alleviate chronic intractable orofacial pain, and if so, which type of pain could respond to ATP.MethodsIn 8 and 16 patients with non-neuropathic and neuropathic intractable orofacial pain, respectively, ATP was intravenously infused at a rate of 100 µg·kg−1·min−1 over 120 min. The magnitudes of spontaneous pain and brush-evoked allodynia were graded with a visual analog scale (VAS). When a VAS score for spontaneous pain was decreased by 50% or more by ATP, the patient was classified as a responder.ResultsThe patients could be clearly divided into 10 responders and 14 non-responders. Ten of the 16 patients (62.5%) with neuropathic pain, but none of the 8 patients with non-neuropathic pain, responded to ATP. In particular, all of 8 patients with neuropathic pain following pulpectomy, with or without subsequent tooth extraction, responded to ATP. In the 10 responders, VAS scores for spontaneous pain decreased slowly but progressively during the infusion period, and eventually, ATP reduced the VAS scores for spontaneous pain and allodynia by 82 ± 15% and 74 ± 9%, respectively. In these responders, the analgesic and anti-allodynic effects of ATP outlasted the infusion period for medians of 7 and 12 h, respectively.ConclusionIntravenous ATP did not relieve non-neuropathic orofacial pain. However, it exerted slowly expressed but long-lasting analgesic and anti-allodynic effects in patients with neuropathic orofacial pain, especially in those suffering from neuropathic pain following pulpectomy and/or tooth extraction.

Comparison of Risk Factors in Patients With Acute and Chronic Orofacial Pain

PurposeWe conducted a double-blind placebo-controlled study to investigate the effects of the intraoperative intravenous infusion of adenosine 5′-triphosphate (ATP) on intraoperative hemodynamics and postoperative pain in patients undergoing major orofacial surgery.MethodsThirty patients (age, 16–42 years; 16 males/14 females) scheduled for sagittal split ramus osteotomy were assigned in a double-blind fashion to receive intraoperative intravenous infusion of ATP (n = 15) or saline (n = 15). Anesthesia was induced and maintained with propofol, fentanyl, and vecuronium. Local anesthesia was added for intraoperative analgesia. In the ATP group, ATP was infused at a rate of 160 μg·kg−1·min−1 throughout surgery. Postoperative pain was managed with intravenous patient-controlled analgesia (PCA) with morphine. The intensity of postoperative pain was assessed with a verbal numeric rating scale (NRS). Morphine consumption was also assessed.ResultsThere were no differences in demographic, anesthetic, and surgical data between the ATP and placebo groups. Intraoperatively, ATP effectively suppressed responses of blood pressure and heart rate to painful surgical stimuli. There were no differences in postoperative NRS scores between the two groups. However, postoperative morphine consumption was significantly less in the ATP group, compared with the placebo group, throughout the 72-h postoperative observation period. Cumulative morphine consumption for 72 h postoperatively was 47% less with ATP, compared with placebo. No adverse effect of ATP was observed.ConclusionOur data suggest that intraoperative ATP infusion can blunt hemodynamic responses to surgical stimuli and produce prolonged analgesia in patients undergoing major orofacial surgery.

Propofol-remifentanil is More Effective than Propofol-fentanyl in Decreasing Intraoperative Blood Loss during Sagittal Split Ramus Osteotomy.

The purpose of this study was to determine which anesthetic was preferable for ambulatory anesthesia: propofol alone or sevoflurane alone. A crossover study was performed to compare the recovery profile and patient satisfaction after 2 anesthesia methods. Twenty healthy patients with severe anxiety toward dental treatment undergoing 2 sessions of day-case dental treatment received either propofol or sevoflurane anesthesia. The order of these methods was randomized. The depths of anesthesia were kept constant using bispectral index (BIS) monitoring. Observations on recovery profiles were performed in the emergence phase, in the recovery phase, and 24 hours after discharge. Patient satisfaction and preference were obtained by a questionnaire. Most of the recovery profiles in the emergence phase such as time to eye opening to respond to verbal command, time to BIS ≥ 75, and time to extubation were shorter in the sevoflurane group than in the propofol group. All recovery profiles in the recovery phase showed no differences between the 2 groups. Based on the subjects satisfaction and preference, propofol was evaluated as a better anesthetic for ambulatory anesthesia than sevoflurane. Higher patient satisfaction and a greater preference for future dental treatment were revealed for propofol anesthesia. Propofol may be more suitable for ambulatory anesthesia for dental treatment.