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The effect of circadian changes on the Current Perception Threshold (CPT) and Pain Tolerance Threshold (PTT) values were examined in a group of 11 healthy volunteers. Three frequencies, 5 Hz, 250 Hz, and 2000 Hz, were used to stimulate nerve fibers during each test. No significant circadian changes of CPT or PTT, tested with all the frequencies, were found. This means that the time of day is not important for pain measurements.

Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg · kg(-1)), at 120 min after subcutaneous injection of saline, a μ-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg · kg(-1)), a κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg · kg(-1)), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg · kg(-1). C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3-30 mg · kg(-1)) and high (56-100 mg · kg(-1)) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of μ-opioid receptors, but at high doses, this μ-opioid receptor-mediated antinociception is antagonized by concomitant activation of κ-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.

Opioid analgesics are commonly used for the treatment of acute as well as chronic, moderate to severe pain. Well-known, however, is the wide interindividual variability in sensitivity to opioids that exists, which has often been a critical problem in pain treatment. To date, only a limited number of studies have addressed the relationship between human genetic variations and sensitivity to opioids, and such studies are still in their early stages. Therefore, revealing the relationship between genetic variations in many candidate genes and individual differences in sensitivity to opioids will provide valuable information for appropriate individualization of opioid doses required for adequate pain control. Although the methodologies for such association studies can be diverse, here we summarize protocols for investigating the association between genetic polymorphisms and sensitivity to opioids in human volunteers and patients undergoing painful 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.

Opioid analgesics are commonly used for the treatment of acute as well as chronic, moderate to severe pain. Well-known, however, is the wide interindividual variability in sensitivity to opioids that exists, which has often been a critical problem in pain treatment. To date, only a limited number of studies have addressed the relationship between human genetic variations and sensitivity to opioids, and such studies are still in their early stages. Therefore, revealing the relationship between genetic variations in many candidate genes and individual differences in sensitivity to opioids will provide valuable information for appropriate individualization of opioid doses required for adequate pain control. Although the methodologies for such association studies can be diverse, here we summarize protocols for investigating the association between genetic polymorphisms and sensitivity to opioids in human volunteers and patients undergoing painful surgery.

A 60-year-old woman in severe hemorrhagic shock underwent urgent laparotomy to control massive hematemesis. Severe metabolic acidosis due to hemorrhagic shock and hyperkalemia as well as hypocalcemia associated with rapid blood transfusion were aggressively corrected with administration of sodium bicarbonate, insulin, and calcium chloride. Following rapid transfusion of the last 8 units of red cell concentrate (RCC), however, cardiac arrest occurred because of hyperkalemia and did not respond to cardiopulmonary resuscitation. Blood gas analysis revealed that the serum K(+) concentration had increased from 4.05 to 8.24 mEq/L over a 7-minute period, while the Ca(2+) concentration had decreased from 1.43 to 0.53 mmol/L. Rapid transfusion of irradiated RCC containing a high concentration of K(+), an extreme decrease in the circulating blood volume to dilute the exogenously administered K(+) and citrate, and severe metabolic acidosis impeding the intracellular shift of K(+) seemed to have contributed to the extremely rapid development of fetal hyperkalemia accompanied by hypocalcemia. Anesthesiologists must be aware that hyperkalemia due to rapid blood transfusion can develop extremely rapidly in patients in severe hemorrhagic shock.

Intensity of postoperative pain and postoperative analgesic requirements are widely varied among patients. The most determinant significant aspect of postoperative pain is the site and type of surgery. For example, open abdominal surgery usually causes intense postoperative pain. Even in patients after the same type of surgery, however, there are wide individual variations in pain intensity and analgesic requirements. A variety of environmental factors can lead to such differences. In addition, genetic factors also can contribute to such differences. For example, a single nucleotide polymorphism A118G of human micro-opioid receptor gene (OPRM1) may decrease analgesic efficacy of opioids and increase postoperative opioid requirements. Full elucidation of genetic factors that can affect pain sensitivity and/or opioid sensitivity may open new avenues for personalized pain treatment.

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 micro-opioid receptors, may be associated with the clinical effects of opioid analgesics. The study demonstrated whether any of five 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 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.

IV fentanyl en bolus can provoke cough reflex. We evaluated the effects of the IV fentanyl dose on the incidence and onset time of fentanyl-induced cough.Tree hundred and eighteen ASA physical status I - II patients scheduled for oral surgery under general anesthesia were randomly assigned to receive 1 microg x kg(-1), 3 microg x kg(-1) or 5 microg x kg(-1) of IV fentanyl (n = 106 for each group). We recorded, in each patient, presence/absence and onset time, if present, of cough reflex for 60 seconds after fentanyl injection.The incidences of fentanyl-induced cough were 6.6%, 22.5%, and 44.3% in the 1 microg x kg(-1), 3 microg x kg(-1), and 5 microg x kg(-1) groups, respectively. The onset times of fentanyl-induced cough were 29.0 +/- 11.8 seconds, 22.5 +/- 7.9 seconds, and 19.5 +/- 7.0 seconds in the 1 microg x kg(-1), 3 microg x kg(-1), and 5 microg x kg(-1) groups, respectively.The results indicated that the incidence of fentanyl-induced cough increased, and the onset time decreased, with the increasing dose of fentanyl.

This study was conducted to examine whether pretreatment with intravenous atropine could prevent bradycardia and hypotension during induction of total intravenous anesthesia with propofol and remifentanil in a prospective randomized placebo-controlled manner. Seventy patients, aged 24-78 years, were randomly divided into two groups, and received 0.5 mg atropine or placebo saline 1 min before induction of intravenous anesthesia with remifentanil at 0.4 microg/kg/min, propofol at a target blood concentration of 3 microg/ml, and vecuronium 1.5 mg/kg. Immediately after tracheal intubation, the infusion rate of remfentanil and the target concentration of propofol were reduced to and kept at 0.1 microg/kg/min and 2 microg/ml, respectively, for 10 min. Noninvasive blood pressure (BP) and heartrate (HR) were measured and recorded every minute. Intravenous atropine could prevent a fall in HR, but not a fall in BP, during induction of intravenous anesthesia with propofol and remifentanil of our dosing regimen. Our data suggested that a fall in HR induced by propofol-remifentanil anesthesia was mainly caused by centrally mediated sympatholytic and/or vagotonic actions of propofol and remifentanil, whereas a fall in BP was mainly the result of their direct vasodilating actions.

EPARIN-INDUCED THROMBOCYTOPENIA (HIT), presenting as severe thrombocytopenia and possible vascular thrombosis resulting from platelet activation secondary to immune response to heparin-platelet factor 4 (PF4) complexes, is a critical concern in patients with this disorder and at risk of exposure to heparin. 1 Patients with HIT requiring cardiopulmonary bypass (CPB) present complex issues regarding the choice of an alternative agent to heparin for anticoagulation during CPB. Alternative anticoagulants include lepirudin, bivalirudin, danaparoid, and argatroban. 2 Argatroban seems to be a reasonable option, especially for patients with renal failure because it is metabolized and eliminated primarily via a hepatic route. 3-5 Furthermore, its anticoagulant effect is spontaneously reversed within 2 to 4 hours because of its short elimination half-life (39-53 minutes), and its anticoagulant effect can be conveniently monitored with the activated coagulation time (ACT). 3-5 Although several case reports described the successful management of anticoagulation with argatroban in on-pump cardiac surgery, 6-9 the lack of an effective antidote may pose a significant problem. At present, reports describing the use of argatroban for adult on-pump cardiac surgery are quite limited in number. Therefore, there is no consensus regarding precautions necessary with the use of argatroban for CPB. A patient presented with renal failure and a history of HIT; the patient underwent on-pump cardiac surgery using argatroban. Initially, the authors could not achieve a target ACT for CPB using an argatroban dosing protocol described previously, 8 and after achieving adequate anticoagulation with a higher dose, prolonged, severe coagulopathy after CPB was encountered.

Intractable chronic pain resists any therapy, and the mechanism of the pain varies from patient to patient even with the same disease. Therefore, patients with chronic pain tend to look for a doctor who would successfully attenuate their pain. Consequently, a patient may visit several doctors only to get similar treatments after wasting time and money. To avoid the situation, pharmacological classification (so called drug challenge test) to determine the mechanism of a patient's pain is conducted. Drugs tested are morphine, ketamine, lidocaine, thiopental, phentolamine, midazolam, ATP clomipramine, PGE1, and neurotropin. A test for each drug is conducted on a separate day. As each drug has a different pain-attenuating mechanism, mechanism of a patient's pain will be clarified when an effective drug is found. A drug is administered as a bolus several times or continuously intravenously. According to the results of our tests conducted in sixty-five patients with neuropathic pain due to peripheral nerve injuries, ketamine proves to be the most effective in alleviating pain followed by ATP, morphine and thiopental. Therapies based on the results were provided to the patients.

Aims: The association between SNPs of the human OPRM1 gene encoding the µ-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.

Intractable chronic pain is very difficult to treat. Nowadays, small amounts of drugs, that have different actions on the mechanism of pain relief are administered intravenously, and the effects of the test drugs on individual chronic pain patients are investigated by using the evaluation method of the visual analogue scale (VAS). This will enable elucidation of the mechanisms of pain in each chronic pain patient. Based on this information, drugs that are effective for the treatment of individual chronic pain patients can be prescribed. Drugs that are used for the drug challenge tests are phentolamine, barbiturate, morphine, lidocaine, ketamine, benzodiazepine, adenosine-3-phosphate (ATP), neurotropine, and prostaglandine E1. Phentolamine is effective for the management of sympathetically maintained pain. Barbiturate and morphine are effective for the treatment of deafferentation pain and nociceptive pain, respectively. Lidocaine is effective for the treatment of neuropathic pain; ketamine, for allodynia; and benzodiazepine, for anxiety-related pain. ATP exerts a positive effect in total pain management. Neurotropine and prostaglandine E1 are effective for the management of neuropathic pain and ischemic pain, respectively. These tests aid in the selection of drugs that maybe useful for the treatment of intractable chronic pain in patients.

Aim of the study In this study, we investigated the effects of processed Aconiti tuber (PAT), an oriental herbal medicine, at analgesic doses on acute morphine antinociception in morphine-naive mice and morphine tolerance in morphine-tolerant mice. Materials and Methods In acute experiments, mice received subcutaneous (s.c.) morphine (2, 5, or 10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg). The mechanical nociceptive threshold (MNT) and thermal nociceptive latency (TNL) were measured with the tail pressure test and tail flick test, respectively, before, and at 30, 60, 90, and 120 min after s.c. morphine injection. In chronic experiments, mice received s.c. morphine (10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg) once daily for 11 days. MNT was measured before, and at 60 min after, and TNL was measured before, and at 30 min after, daily morphine injections on days 1–11. Results PAT at analgesic doses inhibited the acute antinociceptive effect of morphine dose-dependently in morphine-naive mice. In contrast, PAT at analgesic doses potentiated the chronic antinociceptive effect of morphine dose-dependently by inhibiting the development of morphine tolerance dose-dependently. These effects of PAT on acute and chronic morphine antinociception were mediated through activation of kappa-opioid receptors. Conclusions These results indicated that chronic co-administration of PAT at analgesic doses with morphine could provide better-maintained morphine analgesia in a long-term morphine treatment after initial inhibition of acute morphine antinociception for a brief period of time.

To identify risk factors for reversible psychomotor dysfunction after prolonged sedation with isoflurane during mechanical ventilation in the intensive care unit (ICU).Retrospective case series.General ICU at Tonami General Hospital.The records of 335 patients, aged from 10 months to 93 years, who were sedated with isoflurane for more than 12 hours, were reviewed. The presence or absence of reversible psychomotor dysfunction after weaning from mechanical ventilation during isoflurane sedation, and its type and duration, if present, were recorded. Data on patients' demographics, duration of isoflurane inhalation, minimum alveolar concentration (MAC)-hours of isoflurane, and concomitant medical treatments were recorded.Twelve patients (3.6%) developed reversible psychomotor dysfunction, including systemic or localized tremor, chorea, and hallucination, which lasted 10 minutes to 6 days after weaning from mechanical ventilation during isoflurane sedation. Such psychomotor dysfunction occurred in 42% (8 of 19) of patients aged 4 years or less, while only in 1.3% (4 of 316) of those older than 4 years (P0.0001). It occurred in 0% (none of 167) of patients receiving isoflurane for 24 hours or less, while in 7.1% (12 of 168) of patients receiving it for more than 24 hours (P = 0.0004). Other factors examined, including gender, MAC-hours, and drugs co-administrated with isoflurane, did not affect its incidence.Four years of age or less and isoflurane inhalation for more than 24 hours were considered to be significant risk factors for the development of reversible psychomotor dysfunction after prolonged sedation with isoflurane.

In the previous studies, we demonstrated that an oriental herbal medicine, processed Aconiti tuber (PAT), at subanalgesic doses could inhibit or reverse the antinociceptive tolerance to morphine. In the present study, we compared the effect of PAT, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidin)cyclohexyl)-benzeneacetamide methane sulfonate hydrate (U50488H), a selective kappa opioid receptor (KOR) agonist, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, on the antinociceptive tolerance to morphine in the same experimental condition. Mice received subcutaneous morphine (10 mg/kg), and oral PAT at a subanalgesic dose (0.3 g/kg for mechanical or 1.0 g/kg for thermal test), or intraperitoneal U50488H at a subanalgesic dose (3 mg/kg), or MK-801 at a subanalgesic dose (0.1 mg/kg) once daily for 14 days. The mechanical nociceptive threshold was measured before, and at 60 min by tail pressure testing, and thermal nociceptive latency was measured before, and at 30 min by hot plate testing, after daily morphine injections. PAT and U50488H could not only inhibit the development of morphine tolerance but also reverse the already-developed morphine tolerance, while MK-801 could only inhibit the development of morphine tolerance but not reverse the already-developed morphine tolerance, in both mechanical and thermal nociceptive tests. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance, and that PAT may be superior to some NMDA receptor antagonists which do not reverse already-developed morphine tolerance.

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 microg/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 alpha2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

The effect of linear polarized light irradiation around the lumbar sympathetic ganglion area upon the skin temperature of legs may be similar to that of irradiation of near stellate ganglion area upon arms.Linear polarized light irradiation was induced with SUPER LIZER (Tokyo Iken, Tokyo, Japan). The C probe of SUPER LIZER was placed on the left side of the supine at the level of L2.Seven-minute irradiation around the lumbar sympathetic ganglion area increased significantly the skin temperature of the irradiated side leg.These results suggest that linear polarized light irradiation around the lumbar sympathetic ganglion area might be useful and beneficial for clinical application.

We describe a complication of epiduroscopy with encephalopathy and rhabdomyolysis associated with the contrast medium iotrolan.A 76-yr-old man with failed back surgery syndrome underwent epiduroscopy. Sufficient lysis could not be achieved in the epidural space above the level of L4 due to dense adhesions and scar tissue. After epidural injections of iotrolan and mepivacaine, he developed motor weakness and hypoesthesia in both legs, which lasted for three hours. He also became confused, agitated, disoriented, and developed neck stiffness and tremors involving the head and legs. Computed tomography revealed diffuse contrast enhancement within the intracranial cerebrospinal fluid (CSF) spaces, indicating an intraoperative dural tear. Marked increases in serum creatinine phosphokinase and myoglobin indicated subsequent acute rhabdomyolysis. Crystalloid infusion and semi-recumbent positioning facilitated iotrolan absorption from the CSF, and the patient recovered uneventfully.Dural tear during epiduroscopy may allow access of contrast media into the CSF. Neurotoxicity secondary to iotrolan within the CSF was a likely contributing factor to the encephalopathy and subsequent rhabdomyolysis. This is an instructive example of the importance of diagnosing inadvertent dural tear during epiduroscopy under iotrolan, for avoidance of adverse events such as encephalopathy and rhabdomyolysis.

BACKGROUND Adenosine and remifentanil are potent IV analgesics with ultrashort half-lives. The antinociceptive effect of IV adenosine has not been clearly characterized. We compared the antinociceptive effects of adenosine and remifentanil in rabbits. METHODS Sixteen rabbits, placed on a sling allowing reasonably free movement, received IV adenosine (400 microg x kg(-1) x min(-1)) or remifentanil (0.4 microg x kg(-1) x min(-1)) over 240 min. RESULTS Both drugs produced profound antinociception, as assessed by the number of animals unresponsive to clamping the forepaw and the electrical stimulation threshold of escape movement. With remifentanil, the antinociceptive effect increased rapidly, reaching its peak at 60 min, and then began to decline despite continued infusion. After stopping the infusion, it decreased rapidly and disappeared within 30 min. The vasodilating effect of IV adenosine was immediate in onset and ultrashort in duration. The antinociceptive effect of adenosine increased slowly but progressively during the infusion, reaching its peak only when the infusion ended. Then it decreased slowly over the following 360 min after terminating the infusion. CONCLUSION Remifentanil had a rapid onset and short duration of action, and probably showed signs of tolerance development, whereas the antinocieptive effect of adenosine was slow in onset and long-lasting, despite its ultrashort plasma half-life and the immediate on-off profiles of its vasodilating effect.

Portable disposable infusers are widely used for treatment of various types of pain including postoperative pain and cancer pain, because they are simple to use, of lightweight, and inexpensive. In Japan, nine series of infusers are available from eight manufacturers. Volumes and flow rates of various infusers used for pain therapy widely vary from 40 to 500 ml and from 0.5 to 15 ml x hr(-1), respectively. Several infusers have flow selectors and/or patient-controlled analgesia circuits. Such a wide variety enables us to select optimal infusers for individual patients and thus to offer adequate pain control to those patients suffering from severe pain.

In the previous studies, we demonstrated that an oriental herbal medicine processed Aconiti tuber (PAT) at subanalgesic doses could inhibit the development of mechanical antinociceptive tolerance to morphine using the tail pressure test. In the present study, we evaluated whether PAT could inhibit thermal antinociceptive tolerance to morphine using the high temperature (55 degrees C) hot plate test. Mice received subcutaneous morphine (10mg/kg), and oral PAT at doses that did not inhibit the hot plate response (0.3, 0.5, 1.0, and 2.0 g/kg), once daily for 14 days. The thermal nociceptive latency was measured at 30 min after daily morphine injections. Compared with placebo, oral PAT partially and dose-dependently inhibited the development of morphine tolerance in morphine-naive mice, and reversed already-developed morphine tolerance in morphine-tolerant mice. These data suggested that PAT at subanalgesic doses could dose-dependently inhibit and reverse thermal antinociceptive tolerance to morphine.

Objective: No systematic study has been conducted to investigate effects of deep hypothermic circulatory arrest (DHCA) on electroencephalographic bispectral index (BIS) and suppression ratio (SR). Thus, the effects of DHCA were evaluated on BIS and SR. Design: A prospective clinical study. Setting: University hospital (single institute). Participants: Twenty consecutive patients undergoing thoracic aortic surgery using DHCA under narcotics-sevoflurane anesthesia. Interventions: BIS and SR were monitored during cardiopulmonary bypass, simultaneously with nasopharyngeal temperature (NPT). Measurements and Main Results: BIS decreased to 0 with induction of deep hypothermia and rose again with rewarming, although rates of BIS changes in response to cooling and rewarming varied widely among patients. Typically, BIS decreased slowly until NPT reached 26°C during cooling and then it began to decrease rapidly and reached 0 at 17°C, in inverse proportion to SR, which increased rapidly with deep hypothermia and reached 100% at 17°C. When SR was 50% or more, BIS was determined by SR according to the expression: BIS = 50 − SR/2. With rewarming, BIS rose again and returned to precooling baseline levels. Time to the beginning of the BIS recovery significantly correlated with duration of DHCA. Conclusions: With induction of deep hypothermia, BIS decreased in a biphasic manner to 0 at rates varying among patients. With rewarming, BIS rose again at rates extremely widely varying among patients. The rate of BIS recovery was related to duration of DHCA. BIS may be capable of conveniently tracing suppression and recovery of a part of cerebral electrical activity before, during, and after DHCA.

Neuropathic pain is often refractory to conventional pain therapies and thus requires exploration of effective drugs. We evaluated if processed Aconiti tuber (PAT), a traditional oriental herbal medicine that has been used as an analgesic, relieves neuropathic pain in the rat chronic constriction injury (CCI) model. Ten to 14 days after CCI in the right hind paw, six groups of rats received oral placebo, or PAT at 0.5, 1, 2, 3, or 5 g/kg. Additional groups received oral PAT, 2 g/kg, after pretreatment with intraperitoneal naloxone; intraperitoneal nor-binaltorphimine (norBNI); or intrathecal norBNI. As indicators of mechanical allodynia and thermal hyperalgesia, the pressure threshold of paw withdrawal (PWT) in response to linearly increasing pressure, and latency to paw withdrawal (PWL) in response to radiant heat, were measured before and after drug administration. Oral PAT dose-dependently increased PWT and PWL, which had been decreased due to CCI. The increases in PWT and PWL by oral PAT were inhibited by intraperitoneal and intrathecal norBNI: a selective kappa-opioid receptor antagonist, but not by intraperitoneal naloxone. These results indicate that oral PAT can alleviate mechanical allodynia and thermal hyperalgesia, dose-dependently, via spinal kappa-opioid receptor mechanisms in a rat CCI neuropathic pain model.

Opiate analgesics are widely used and abused drugs. Individual differences in opiate sensitivity can hamper effective pain treatments and increase risks of drug abuse. Although genetic factors might affect individual differences in opiate sensitivity, scientific evidence for specific genetic mechanisms that underlie these differences has been sparse. Recent studies using inbred and knockout mice have revealed that the mu opioid peptide (MOP) receptor encoded by the Oprm1 gene has a mandatory role in the analgesic and addictive properties of opiate drugs. Increasing evidence suggests that differences in Oprm1 gene sequences affect the amount of Oprm1 mRNA and sensitivity to opiates, and >100 polymorphisms have been identified in the human OPRM1 gene, some of which are related to vulnerability to drug dependence in some populations. Rapid advances in this research field are leading to improved understanding of the relationships between gene polymorphisms and opiate sensitivities that will enable more-accurate prediction of the opiate sensitivity and opiate requirements in individual patients.

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.

No study has been performed on the analgesic effect of adenosine 5'-triphosphate (ATP) on postherpetic neuralgia (PHN). We conducted an open-label trial of ATP in patients with PHN, and compared ATP with ketamine and lidocaine.Twelve patients with PHN were studied. On separate days, ketamine (0.3 mg.kg(-1)), lidocaine (2 mg.kg(-1)), and ATP (100 microg.kg(-1).min(-1) or less for 120 min) were administrated intravenously. The intensity of spontaneous pain as well as tactile allodynia was assessed using a visual analog scale (VAS). When the VAS score for spontaneous pain was decreased by more than 50%, the patient was classified as a responder.Five, 6, and 6 patients responded to ketamine, lidocaine, and ATP, respectively. In 6 ATP responders, pain relief developed slowly and lasted for 9 (median) h (range: 3-72 h). All 5 ketamine responders and only 1 of 7 ketamine nonresponders responded to ATP (5/5 vs 1/7, P0.05, chi2 test) whereas 2 of 6 responders to lidocaine and 4 of 6 nonresponders to lidocaine responded to ATP (2/6 vs 4/6, P0.05). The ketamine responders responded to ATP more often than did the lidocaine responders (5/5 vs 2/6, P0.05).Intravenous ATP exerted slowly developing and long-lasting analgesic effects in half of patients with PHN. Patients with ketamine-responsive PHN were likely to respond to ATP.

UNLABELLED 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 microg kg(-1)x 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 PaCO(2) 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. IMPLICATIONS Using a new rabbit model, we found that during continuous, constant-rate remifentanil infusion acute tolerance developed within the first few hours, not only to its analgesic but also to its cardiovascular and respiratory effects, albeit in slightly different time courses.

We experienced a post-radiation therapy patient who had a narrow trachea, and presented with unexpected difficulty for intubation. His trachea was narrowest at 2 cm below the glottis. The fiberscope barely could pass the narrowest part of the trachea. We speculate that the radiation therapy induced his tracheal constriction. Careful attention is necessary when examining the post-radiation therapy patients. Multiple cervical radiographs are necessary in such a case.

Background The analgesic efficacy of opioids is well known to vary widely among individuals, and various factors related to individual differences in opioid sensitivity have been identified. However, a prediction model to calculate appropriate opioid analgesic requirements has not yet been established. The present study sought to construct prediction formulas for individual opioid analgesic requirements based on genetic polymorphisms and clinical data from patients who underwent cosmetic orthognathic surgery and validate the utility of the prediction formulas in patients who underwent major open abdominal surgery. Methods To construct the prediction formulas, we performed multiple linear regression analyses using data from subjects who underwent cosmetic orthognathic surgery. The dependent variable was 24-h postoperative or perioperative fentanyl use, and the independent variables were age, gender, height, weight, pain perception latencies (PPL), and genotype data of five single-nucleotide polymorphisms (SNPs). To examine the utility of the prediction formulas, we performed simple linear regression analyses using subjects who underwent major open abdominal surgery. Actual 24-h postoperative or perioperative analgesic use and the predicted values that were calculated using the multiple regression equations were incorporated as dependent and independent variables, respectively. Results Multiple linear regression analyses showed that the four SNPs, PPL, and weight were retained as independent predictors of 24-h postoperative fentanyl use (R2 = 0.145, P = 5.66 × 10-10) and the two SNPs and weight were retained as independent predictors of perioperative fentanyl use (R2 = 0.185, P = 1.99 × 10-15). Simple linear regression analyses showed that the predicted values were retained as an independent predictor of actual 24-h postoperative analgesic use (R2 = 0.033, P = 0.030) and perioperative analgesic use (R2 = 0.100, P = 1.09 × 10-4), respectively. Conclusions We constructed prediction formulas, and the possible utility of these prediction formulas was found in another type of surgery.

We describe a case of coronary spasm in a 59-year-old man undergoing an emergent abdominal aortic replacement for ruptured aortic aneurysm. The patient was brought to the operating room in a state of hypovolemic shock, and was successfully resuscitated through intensive volume expansion by rapid infusion devices. Twenty minutes after cross-clamping of the abdominal aorta, ST-segment elevation on the lead III of electrocardiogram (ECG) and dyskinesis in the inferior wall shown by transesophageal echocardiography (TEE) were noted. Coronary spasm was suspected, and isosorbide dinitrate was administered intravenously without delay, leading to prompt reversal of ischemic changes. A number of reports have suggested that care should be taken against coronary spasm in non-cardiac surgery as well as cardiac surgery, especially in patients with coronary risk factors. Monitoring by multi-lead ECG and TEE is a powerful method by which to detect and evaluate intraoperative myocardial ischemia.

Background The P2X7 receptor is a member of the P2X family of adenosine 5′-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery. Results We first conducted linkage disequilibrium (LD) analyses for 55 reported single-nucleotide polymorphisms (SNPs) in the region within and around the P2RX7 gene using genomic samples from 100 patients. In our samples, 42 SNPs were polymorphic, and a total of five LD blocks with six Tag SNPs (rs2708092, rs1180012, rs1718125, rs208293, rs1718136, and rs7132846) were observed. Thus, we further analyzed associations between genotypes/haplotypes of these Tag SNPs and clinical data using a total of 355 samples. In the genotype-based association study, only the rs1718125 G > A SNP tended to be associated with higher pain scores on a visual analog scale 24 h after surgery (VAS24). The haplotype-based association study showed that subjects with homozygous haplotype No.3 (GTAAAC; estimated frequency: 15.0%) exhibited significantly higher cold pain sensitivity and lower analgesic effects of fentanyl for acute cold pain in the cold pressor test. Conversely, subjects who carried haplotype No.1 (ACGGAC; estimated frequency: 24.5%) tended to exhibit lower cold pain sensitivity and higher analgesic effects of fentanyl. Furthermore, subjects with homozygous haplotype No.2 (GCGGAC; estimated frequency: 22.9%) exhibited significantly lower VAS24 scores. Conclusions Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5′-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl. Electronic supplementary material The online version of this article (doi:10.1186/1744-8069-10-75) contains supplementary material, which is available to authorized users.

UNLABELLED The role of lactate in liver ischemia-reperfusion injury in cirrhosis has not been clarified. Fifty patients with hepatocellular carcinoma who underwent partial liver resection under Pringle's maneuver were included in this study. We performed the indocyanine green clearance test before the operation and three times during the surgery to calculate its elimination rate. Blood lactate and base excess were measured at the corresponding times. Systolic and diastolic systemic arterial pressure, heart rate, cardiac index, and esophageal temperature were monitored. Aminotransferase levels were recorded the day before the operation, 1 h after the operation, and on the first and third postoperative days. We calculated the increase or decrease in lactate levels during the preischemic, ischemic, and postischemic phases, and examined the correlation between these results and the changes in indocyanine green elimination rate and some clinical factors. The lactate levels increased before reperfusion and began to decrease after reperfusion. The lactate increase and decrease during the ischemic and postischemic phases correlated with the change in indocyanine green elimination rate (P < 0.0001 and P = 0.02 for the respective phases). The lactate increase during the preischemic phase correlated with the duration of the preischemic phase (P < 0.0001). In cirrhotic patients who undergo liver resection with Pringle's maneuver and who do not show postoperative liver failure, the blood lactate profile might be a reliable indicator of liver metabolic capacity during surgery. IMPLICATIONS In cirrhotic patients who underwent liver resection with Pringle's maneuver, the lactate increase and decrease during the ischemic and postischemic phases correlated with the change in the indocyanine green elimination rate. The blood lactate profile might be a reliable indicator of liver metabolic capacity during surgery.

The Starfish heart positioning device allows excellent cardiac positioning and hemodynamic stability during off-pump coronary artery bypass graft surgery. Herein, we present a patient in whom the use of this device caused epicardial hematoma as the result of an injured epicardial vein, an uncommon complication of this device. In this patient, regional left ventricular wall motion abnormality on transesophageal echocardiography and a ST-T change on electrocardiogram occurred secondary to the development of the epicardial hematoma. These signs completely disappeared upon removal of the hematoma. These findings suggested that the hematoma resulted in reversible myocardial ischemia.

The effects of amrinone, a selective phosphodiesterase III inhibitor, on liver ischaemia reperfusion injury have not yet been clarified. Forty-five patients with hepatocellular carcinoma who underwent partial liver resection using Pringle's manoeuvre were studied. Patients were divided into three groups: those given amrinone, those given prostaglandin E1 (PGE1) and those not treated (controls). An indocyanine green (ICG) clearance test was performed before the operation and three times during surgery: just before induction of liver ischaemia, just after liver resection and 60 min after reperfusion. Blood lactate and base excess were measured at the same times. Systolic and diastolic arterial pressure, heart rate, cardiac index and oesophageal temperature were monitored. Aminotransferase levels were recorded the day before surgery, 1 h after operation and on the first and third postoperative days. These data were compared between groups. The ICG elimination rate, lactate and base excess in the amrinone group differed significantly from those in controls during the observation period (P = 0.03, P = 0.04 and P = 0.03, respectively). The differences between the PGE1 and control groups were not significant. There were no significant differences between the groups in perioperative vital signs, cardiac index or postoperative aminotransferase. Amrinone enhanced intraoperative ICG elimination in cirrhotic patients who underwent liver resection.

To the Editor: Discrete subaortic stenosis (DSS) is an uncommon form of left ventricular outflow tract (LVOT) obstruction characterized by a discrete subaortic membrane (DSM) [1]. We report a case of DSS that was misdiagnosed as valvular aortic stenosis (AS) preoperatively with transthoracic echocardiography (TTE) or cardiac catheterization and correctly diagnosed intraoperatively by careful examination with transesophageal echocardiography (TEE). A 5-year-old boy, who had undergone corrective surgery for coarctation complex in the neonatal period, was scheduled to undergo aortic valve replacement or aortic valve plasty for severe AS. The preoperative diagnosis made by TTE and cardiac catheterization was valvular AS with the peak pressure gradient of 92 mmHg resulting from limited opening of the right coronary cusp (RCC) and moderate aortic regurgitation (AR). Our initial findings with intraoperative TEE after induction of anesthesia were the same (Online Resources 1A–D, 2A). By closer observation, however, we noticed that the tip of the RCC opened almost fully (Online Resource 1B). Because it was difficult to identify the morphological structure causing AS because of the rapid movement of the valve structures, we froze the moving image and reviewed it carefully by frame-by-frame advance. By means of this procedure, we could identify a DSM just below the RCC that obstructed the LVOT (Online Resources 3A,B) and thus could establish the diagnosis of DSS. Resection of the DSM was performed on mild hypothermic cardiopulmonary bypass (CPB). After ending CPB, we confirmed that the DSM was successfully resected (Online Resource 4A), the LVOT obstruction was released (Online Resource 4B), and the grade of AR was reduced from moderate to mild (Online Resource 2B). Continuous-wave Doppler recordings showed that the peak flow rate in the aorta decreased from 4.0 m/s before CPB to 2.6 m/s after CPB (Online Resources 5A,B). Our experience indicates that although TEE is superior to TTE in evaluating morphological features of DSS [1], careful examination is required to identify this structure even when using TEE in some patients with DSS.

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 Ca(2+) channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Ca(v)2.3 (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.

In the near future, the population of elderly people will increase tremendously. Therefore, in the 21st century, pain control for elderly patients who have chronic and intractable pain is one of the most important medical fields. In this round table discussion, pain clinicians from Japan, Taiwan, China, Korea, and Philippines discussed the problems and useful methods for pain control of chronic and intractable pain in patients in Asia. We were able to understand the differences of pain control among the Asian countries, and also, we introduced the classification of pain patient's sex, age, chronic non-cancer pain, and treatments of non-cancer pain patients in the Department of Anesthesiology and Pain Relief Center, University of Tokyo Hospital. This round table discussion gave us valuable hints for the application to chronic pain patients.