Background The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain. Methods Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain-related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months. Polymorphisms identified were validated in a matched cohort of 103 patients with chronic postsurgical pain and 103 patients who were pain free. The functions of targeted polymorphisms were tested in an experimental plantar incisional nociception model using knock-in mice. Results At 12 months after surgery, 246 (21.4%) patients reported chronic postsurgical pain. Forty-two polymorphisms were found to be associated with chronic postsurgical pain, 19 decreased the risk of pain, and 23 increased the risk of pain. Patients carrying allele A of rs6265 polymorphism in brain-derived neurotrophic factor (BDNF) had a lower risk of chronic postsurgical pain in the discovery and validation cohorts, with an adjusted odds ratio (95% CI) of 0.62 (0.43 to 0.90) and 0.57 (0.39 to 0.85), respectively. Age less than 65 yr, male sex, and prior history of pain syndrome were associated with an increased risk of pain. Genetic polymorphisms had higher population attributable risk (7.36 to 11.7%) compared with clinical risk factors (2.90 to 5.93%). Importantly, rs6265 is a substitution of valine by methionine at amino acid residue 66 (Val66Met) and was associated with less mechanical allodynia in BDNF Met/Met mice compared with BDNF Val/Val group after plantar incision. Conclusions This study demonstrated that genetic variant of BDNF rs6265G>A is associated with decreased risk of chronic postsurgical pain.

Background: Proteases have been shown to modulate pain signaling in the spinal cord and may contribute to the development of chronic postsurgical pain. By using peripheral inflammation in rats as a chronic pain model, the authors identified the deregulation of proteases and their inhibitors as a hallmark of chronic pain development using a genome-wide screening approach. Methods: A microarray analysis was performed and identified spinal cathepsin G ( CTSG ) as the most up-regulated gene in rats with persistent hyperalgesia after intraplantar injection of complete Freund’s adjuvant (n = 4). Further experiments were performed to elucidate the mechanisms of CTSG-induced hyperalgesia by intrathecally applying specific CTSG inhibitor (n = 10). The authors also evaluated the association between CTSG gene polymorphisms and the risk of chronic postsurgical pain in 1,152 surgical patients. Results: CTSG blockade reduced heat hyperalgesia, accompanied by a reduction in neutrophil infiltration and interleukin 1β levels in the dorsal horns. In the gene association study, 246 patients (21.4%) reported chronic postsurgical pain at 12-month follow-up. Patients with AA genotypes at polymorphisms rs2070697 (AA-15.3%, GA-24.1%, and GG-22.3%) or rs2236742 (AA-6.4%, GA-20.4%, and GG-22.6%) in the CTSG gene had lower risk for chronic postsurgical pain compared with wild-types. The adjusted odds ratios were 0.67 (95% CI, 0.26 to 0.99) and 0.34 (95% CI, 0.21 to 0.98), respectively. Conclusions: This study demonstrated that CTSG is a pronociceptive mediator in both animal model and human study. CTSG represents a new target for pain control and a potential marker to predict patients who are prone to develop chronic pain after surgery. Abstract Cathepsin G blockade reduced inflammation in the spinal cord and reduced pain behavior in rodents. In humans, two specific polymorphisms were associated with a lower risk for the development of chronic postsurgical pain. The data suggest that cathepsin G in a pronociceptive mediator in experimental subjects and humans; as such, it offers a potential therapeutic target for prevention of chronic postsurgical pain. Supplemental Digital Content is available in the text.

Background: Nitrous oxide inactivates methionine synthase and may lead to DNA damage and wound infection. By using single-cell gel electrophoresis (comet assay), the authors determined the effect of nitrous oxide on DNA damage in circulating leukocytes. Methods: In this double-blind, randomized controlled trial, 91 patients undergoing major colorectal surgery were randomized to receive 70% nitrous oxide ( n = 31) or nitrous oxide-free anesthesia using 30 ( n = 30) or 80% ( n = 30) oxygen. Venous blood was collected before and 24 h after surgery. The primary outcome was extent of DNA damage, quantified as the percentage of DNA staining intensity in the comet tail using digital fluorescence microscopy. Incidence of postoperative wound infection was also recorded. Results: Nitrous oxide exposure was associated with a two-fold increase in the percentage of DNA intensity in tail ( P = 0.0003), but not in the 30 ( P = 0.181) or 80% oxygen groups ( P = 0.419). There was a positive correlation between the duration of nitrous oxide exposure and extent of DNA damage, r = 0.33, P = 0.029. However, no correlation was observed in nitrous oxide-free patients. The proportions of postoperative wound infection, using the Centers for Disease Control and Prevention criteria, were 19.4% (6 of 31) in the 70% nitrous oxide group and 6.7% (2 of 30) in both the 30 and 80% oxygen groups, P = 0.21. An increase in DNA damage was associated with a higher risk of wound infection, adjusted odds ratio (95% CIs): 1.19 (1.07–1.34), P = 0.003. Conclusions: Nitrous oxide increased DNA damage compared with nitrous oxide-free anesthesia and was associated with postoperative wound infection.

Background The potencies of bupivacaine and ropivacaine have been compared using up-and-down methodology, but their complete dose-response curves have not been compared. The authors performed a random allocation-graded dose-response study of epidural bupivacaine and ropivacaine given epidurally for labor analgesia. Methods Three hundred laboring nulliparous patients were randomly given epidural bupivacaine (5, 10, 15, 20, 30, or 40 mg) or ropivacaine (7, 15, 20, 30, 45, or 60 mg) in 20 ml of saline. Visual Analog Scale pain scores were recorded for 30 min. Response was defined by the percentage decrease in pain score from baseline at 30 min, and dose-response data were analyzed by using nonlinear regression. Results Sigmoidal Emax model dose-response curves were fitted to the datasets for bupivacaine (R = 0.53) and ropivacaine (R = 0.59). The curves had similar steepness (Hill coefficient 2.02 [95% CI, 1.55-2.50] vs. 2.25 [1.70-2.79], P = 0.55). The ED50 (dose of the drug that reduces pain score to 50% of baseline at 30 min, also known as D50) of ropivacaine was greater than that of bupivacaine (15.3 [95% CI 13.7-17.1] mg vs. 11.3 [10.0-12.7] mg, P = 0.0003), but ED90 (D90) was similar (40.6 [32.4-51.1] mg vs. 33.4 [26.2-42.7] mg, P = 0.29). The potency ratio at ED50 for ropivacaine:bupivacaine was 0.75 (95% CI, 0.65-0.88). Conclusions Ropivacaine is less potent than bupivacaine, but otherwise they have similar dose-response characteristics. The difference in potency is not statistically significant at ED90 doses.

Background The purpose of this study was to determine an optimum dose of alfentanil, coadministered with 2.5 mg/kg propofol, when inserting a classic laryngeal mask airway. Methods Seventy-five adult ethnic Chinese patients with an American Society of Anesthesiologists physiologic status classification I or II and requiring anesthesia for minor surgery with a laryngeal mask were recruited. They were randomly assigned to five dosage groups: placebo or 5, 10, 15, or 20 microg/kg. The study drug plus propofol were administered, and 90 s later, insertion conditions were assessed using a six-category score. The duration of apnea was recorded. A probit analysis was performed and used to estimate the ED50 and ED95 with 95% confidence intervals for each assessment. Results Twenty-five male and 50 female patients, aged 18-59 yr, were studied. The five groups were similar. Laryngeal mask insertion was successful in all but one alfentanil patient. Duration of apnea increased with increasing dosage of alfentanil to over 5 min (P < 0.001). Dose-responses could not be predicted for categories of resistance to mouth opening and to insertion. For the other four categories, swallowing, gagging, movement, and laryngospasm, ED50 and ED95 with confidence intervals for alfentanil could be determined. Conclusion The optimum dose for alfentanil, when coadministered with 2.5 mg/kg propofol, was 10 microg/kg.

Background The use of traditional Chinese herbal medicines (TCHMs) among the presurgical population is widespread, but their impact on perioperative patient care is unclear. The authors estimated the incidence and risk of TCHM-related perioperative events. Methods In a Hong Kong cohort study, 601 patients undergoing major elective surgery were asked about their Western medicine and TCHM use in the 2 weeks before surgery. Unanticipated perioperative events were noted by attending anesthesiologists, blinded to patients' use of specific TCHMs. Modified Poisson regression models were used to obtain the relative risk of combined endpoints of perioperative events associated with TCHM use. Results Of the 601 patients, 483 patients (80%) took self-prescribed TCHM, and 47 (8%) took TCHM by prescription (with or without self-prescribed TCHM) in the 2 weeks before surgery. The crude incidences of any combined endpoints of preoperative, intraoperative, and postoperative events were 23% (95% confidence interval, 19-26%), 74% (95% confidence interval, 71-78%), and 63% (95% confidence interval, 59-66%), respectively. Compared with nonusers, patients who took TCHM by prescription were more likely to have a preoperative event (adjusted relative risk, 2.21; 95% confidence interval, 1.14-4.29). The authors present four case reports to highlight the effect of TCHM by prescription on prolonged activated partial thromboplastin time and hypokalemia in the preoperative period. In contrast, there was no significant association between the use of any type of TCHM and the occurrence of either intraoperative or postoperative events. Conclusions The use of TCHM by prescription near the time of surgery should be discouraged because of the increased risk of adverse events in the preoperative period.

Background Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was designed to describe the pharmacokinetics of ropivacaine after thoracic paravertebral block. Methods Twenty female patients undergoing elective unilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine, with or without 5 mug/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay. Data were analyzed with NONMEM, using two possible absorption models: conventional first-order absorption and absorption following the inverse gaussian density function. Results Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absorption times were 7.8 min for the rapid absorption phase and 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of arterial-venous equilibration was 1.5 min. Conclusion The absorption of ropivacaine after thoracic paravertebral block is described by rapid and slow absorption phases. The rapid phase approximates the speed of intravenous administration and accounts for nearly half of ropivacaine absorption. The addition of 5 mug/ml epinephrine to ropivacaine significantly delays its systemic absorption and reduces the peak plasma concentration.

Background The anesthetic requirement is decreased in animals with head injury, but there are no data regarding the effect of intracranial tumor on the potency for intravenous anesthetics. The authors compared the quantal dose-response curves for propofol in patients having large (> or = 30 mm, mass effect) brain tumor with those having smaller (< 30 mm) lesions and with control patients undergoing noncranial surgery. Methods Sixty patients in each group were randomly assigned to receive one of the six doses of propofol (0.5, 0.7, 1.0, 1.3, 1.8, or 2.5 mg/kg) over 10 s. Two minutes after drug administration, patients were asked to open their eyes as a test for response to verbal command. Patients who failed to respond were given a 10-s, 50-Hz, 80-mA transcutaneous tetanic electrical current to the ulnar nerve as a test for response to painful stimulus. Purposeful movement indicated positive response. Log dose-response curves for loss of response to verbal command and tetanic stimulus were calculated after logit transformation. Results The median effective doses (ED50s; 95% confidence interval) for suppressing response to verbal command and tetanic stimulus were 0.75 (0.65-0.86) mg/kg and 1.28 (1.11-1.49) mg/kg, respectively, in patients with large brain tumor. These values were significantly less than the corresponding ED50s in patients with small tumor, 1.01 (0.88-1.15) mg/kg and 1.76 (1.51-2.07) mg/kg, or healthy control subjects, 0.98 (0.86-1.12) mg/kg and 1.89 (1.62-2.23) mg/kg. Conclusions The doses of propofol required to suppress response to verbal command and tetanic stimulus were 23% less and 32% less in patients with large brain tumor compared with control subjects. Small tumor did not affect potency of propofol.

Background Anesthetic requirements for inhalational agents are decreased during pregnancy, but there are no data regarding requirements for intravenous agents. The quantal dose-response curves for thiopental were calculated for 70 nonpregnant women having gynecologic surgery and for 70 pregnant women of 7-13 weeks' gestation having elective abortions. Methods Groups of 10 patients were given 2, 2.4, 2.8, 3.3, 3.8, 4.5, or 5.3 mg/kg thiopental as a bolus dose during a period of 10 s. Two minutes later, patients were asked to open their eyes as a test for hypnosis. Patients who did not open their eyes were given a 10-s, 50-Hz, 80-mA transcutaneous tetanic electrical stimulus to the ulnar nerve as a test for anesthesia. Purposeful movement indicated that there was no anesthesia. Log dose-response curves for hypnosis and anesthesia were calculated after logit transformation. Results In the nonpregnant women, the median effective doses (ED50s) (95% confidence interval) for hypnosis and anesthesia were 3.1 (2.8-3.4) mg/kg and 4.9 (4.5-5.4) mg/kg, whereas in the pregnant women the corresponding ED50s were 2.6 (2.3-2.8) mg/kg and 4 (3.7-4.4) mg/kg. In the non-pregnant women, the ED95s (95% CI) for hypnosis and anesthesia were 4.4 (3.9-5.4) mg/kg and 6.4 (5.7-7.9) mg/kg, whereas in the pregnant women the corresponding ED95s were 3.7 (3.3-4.5) mg/kg and 5.2 (4.7-6.3) mg/kg. The pregnant to nonpregnant relative median potency (95% CI) ratio for hypnosis was 0.83 (0.67-0.96) and for anesthesia it was 0.82 (0.62-0.94). Conclusions The dose of thiopental for hypnosis was 17% less and that for anesthesia was 18% less in pregnant women of 7-13 weeks' gestation compared with that in nonpregnant women.

Background Minimum alveolar concentration (MAC) of isoflurane is decreased in early pregnancy but it is not known whether this occurs to the same extent with other inhalational anesthetics. The MAC of halothane and enflurane were compared in pregnant women undergoing elective termination of pregnancy and in nonpregnant women. Methods We studied 16 pregnant women scheduled for termination of pregnancy at 8 to 13 weeks gestation and 16 non-pregnant patients undergoing laparoscopic sterilization. Eight patients in each group received halothane and the others received enflurane. After inhalational induction of anesthesia and tracheal intubation, MAC was determined in each patient by observing the motor response to a 10-s, 50-Hz, 80-mA transcutaneous electric tetanic stimulus to the ulnar nerve at varying concentrations of either halothane or enflurane. The end-tidal concentration of inhalational anesthetic was kept constant for at least 15 min before each stimulus and the concentration was varied ultimately in steps of 0.05 vol% (halothane) or 0.10 vol% (enflurane) until a sequence of three alternate responses (move, not move, move) or (not move, move, not move) was obtained. Minimum alveolar concentration for each person was taken as the mean of the two concentrations just permitting and just preventing movement, and MAC for the group was the median of individual MAC values. Confidence intervals were calculated for the percentage decrease in MAC for pregnant women compared with nonpregnant women. Results The median (range) MAC of halothane, 0.58 vol% (0.53 to 0.58), and enflurane, 1.15 vol% (0.95-1.25), in the pregnant women were less than those in the nonpregnant women, 0.75 vol% (0.70 to 0.78), P = 0.0005 and 1.65 vol% (1.45 to 1.75), P = 0.0007, respectively. The percentage decrease (95% CI) in MAC for pregnant women was 27% (20 to 27%) for halothane and 30% (24 to 36%) for enflurane. Conclusions The MAC of halothane and enflurane were reduced by a similar degree in pregnant women at 8 to 13 weeks gestation compared with nonpregnant women.

Background Epidural meperidine is effective for postoperative analgesia, but the optimum dose has not been evaluated. Methods Five doses of epidural meperidine (12.5, 25, 50, 75, and 100 mg) given at the first request for analgesia after cesarean section were compared. Visual analog pain scores, duration of analgesia as defined by time to first patient-controlled epidural analgesia demand, plasma concentrations of meperidine, side effects, and subsequent 24-h consumption of meperidine were evaluated. Results All doses were effective, but patients took longer to become pain-free after 12.5 mg (median 30 min) compared with 25 mg (median 12 min, P = 0.038), and duration of analgesia was shorter after 12.5 mg (median 83 min) compared with 25 mg (median 165 min, P = 0.0005). Increasing dose to more than 25 mg did not improve onset or duration of analgesia. Plasma concentrations of meperidine were less than minimum effective analgesia concentration for all doses except 100 mg. There was more frequent nausea (P = 0.004) and dizziness (P = 0.0002) after 100 mg compared with smaller doses. Conclusions Epidural meperidine provides effective postoperative analgesia, although of relatively short duration. A single dose of 25 mg is superior to 12.5 mg, but there is no benefit from increasing the dose to 50 mg or greater.

Background Minimum alveolar concentration (MAC) is decreased in pregnancy, but it is not known how quickly after delivery MAC returns to normal. We measured the MAC of isoflurane in a group of women undergoing elective tubal ligation after delivery. Methods After delivery, 20 patients underwent inhalational induction of anesthesia with isoflurane and tracheal intubation. MAC was determined in each patient by observing the response to a 10-s, 50-Hz, 80-mA transcutaneous tetanic electric stimulus to the ulnar nerve at various concentrations of isoflurane. The end-tidal concentration of isoflurane was kept constant for at least 10 min before each stimulus, and the concentration of isoflurane was ultimately varied in steps of 0.05 vol% until we obtained a sequence of three alternate responses: move-not move-move or not move-move-not move. The MAC for each subject was taken as the mean of the two concentrations just permitting and just preventing movement. A venous blood sample was taken immediately before induction of anesthesia for measurement of progesterone concentration. MAC was compared with time after delivery and plasma progesterone concentrations by Kendall's rank correlation. Results There was a positive correlation between MAC and the time after delivery (P < 0.001). The median MAC of isoflurane was 0.775 vol% (range 0.675-0.775 vol%) in five women 24-36 h postpartum. MAC was more variable, 0.825 vol% (0.675-0.975 vol%) in nine women 36-72 h postpartum, whereas six patients more than 72 h postpartum had a MAC of 1.125 vol% (1.025-1.175 vol%). The correlation between MAC and plasma progesterone concentration was almost statistically significant (P = 0.060). Conclusions The MAC of isoflurane was reduced in women 24-36 h postpartum and gradually increased to normal values by 72 h postpartum.