8. Tambahan Arsip Neuro

ORIGINAL ARTICLE

4218T/C polymorphism associations with post-cesarean patientcontrolled epidural fentanyl consumption and pain perception W. Xie1,†, W. Zhuang2,†, L. Chen2

, W. Xie1, C. Jiang1 and N. Liu1

1

Department of Anesthesiology, Quanzhou First Hospital, Quanzhou, China Department of Anesthesiology, Huian Hospital, Quanzhou, China

2

Correspondence L. Chen, Department of Anesthesiology, Huian Hospital, Quanzhou, China E-mail: [email protected] and W. Xie, Department of Anesthesiology, Quanzhou First Hospital, Quanzhou, China E-mail: [email protected] †

Contributed equally.

Conflict of interest The authors report no conflict of interest. Submitted 3 October 2017; accepted 29 October 2017; submission 23 June 2017. Citation Xie W, Zhuang W, Chen L, Xie W, Jiang C, Liu N. 4218T/C polymorphism associations with post-cesarean patient-controlled epidural fentanyl consumption and pain perception. Acta Anaesthesiologica Scandinavica 2017 doi: 10.1111/aas.13040

Background: The utilization of intrathecal opioids is an efficacious component of post-cesarean section pain management. Given that growing evidence indicates that calcitonin gene-related peptide (CGRP) plays a key role in the development of peripheral sensitization and is associated with enhanced pain, we hypothesized that CGRP 4218T/C polymorphism is associated with the variability in fentanyl consumption for post-cesarean analgesia. Methods: We recruited 548 patients who presented for elective cesarean delivery, and used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze CGRP 4218T/C polymorphism. We examined the association of CGRP 4218T/C polymorphism and post-operative fentanyl consumption for analgesia as well as adverse reactions to fentanyl in those patients who received cesarean section surgeries. Results: We found that the CGRP 4218T/C polymorphism has a significant effect on pain perception, analgesic requirement, and nausea and vomiting for the first 24 h after cesarean delivery in patients who received PCEA fentanyl. Individuals with the C/C genotype had more pain, required more PCEA fentanyl, and experienced a lower incidence of nausea and vomiting. Conclusion: These results indicated that patients with C/C genotype may have reduced sensitivity to fentanyl analgesia and/or increased pain perception, and were more willing to use PCEA fentanyl to manage their pain.

Editorial comment

In this cohort undergoing cesarean section, polymorphism for the specific calcitonin gene-related peptide (CGRP 4218T/C) was determined, along with reported post-operative pain and epidural fentanyl consumption. Those with the C/C genotype appeared to have more pain and opioid consumption compared to those with the T/T or T/C genotype. Adequate interaction between mother and infant during the early post-delivery period is psychologically important to the new mother and is substantially involved in the development of the infant.1 Thus, post-cesarean section analgesia needs to provide effective pain control while allowing the mother to remain active

and available for the needs of infant. However, with the rising rate of cesarean section in China, effective pain management after cesarean section is still a great challenge, with the respective of accelerated post-operative recovery and rapid discharge, as well as patient satisfaction.2,3

Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

An international journal of anaesthesiology, intensive care, pain, and critical emergency medicine

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The utilization of intrathecal opioids is an efficacious component of post-cesarean section pain management.4–6 While low-dose morphine has been the gold standard in post-cesarean section pain management,7–9 it suffers from late onset of action10,11 and high frequency of side effects.12,13 In contrast, fentanyl is one of the most commonly used intrathecal lipophilic opioids. It exhibits a rapid onset and relatively short duration of action10 and has become a well-accepted practice in the management of labor analgesia. However, numerous studies have shown that poor analgesic effects of opioid drugs are attributed to certain genetic polymorphisms.14–16 Similarly, significant differences in the sensitivity to fentanyl among patients are a major issue in clinical therapy. While recent studies have shown that CYP3A4*1G genetic polymorphism contributes to the variability in CYP3A activity and response to fentanyl,17,18 it is still unclear whether other human genetic polymorphisms contribute to the clinical effectiveness of fentanyl. One that deserves investigation is the genetic polymorphism of calcitonin gene-related peptide (CGRP). Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Ad sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system.19–21 Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and is associated with enhanced pain.22,23 Recent studies showed that blocking the function of CGRP can alleviate migraine. Furthermore, CGRP 4218T/C contributes to post-operative fentanyl consumption in cancer patients as well as adverse reactions to fentanyl. However, whether CGRP 4218T/C is involved in the analgesic effects of post-cesarean section fentanyl is still not fully understood. Thus, the present study examined the hypothesis that CGRP 4218T/C polymorphism is associated with the variability in fentanyl consumption for postcesarean analgesia. To this end, we recruited patient who presented for elective cesarean delivery, and used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze CGRP 4218T/C polymorphism. We examined the association of CGRP 4218T/C

polymorphism and post-operative fentanyl consumption for analgesia as well as adverse reactions to fentanyl in those patients who received cesarean section surgeries. Materials and Methods Participants A total of 548 patients were recruited in our study. Patients were recruited from Quanzhou First Hospital during a period from January 2015 to December 2016. Enrolled patients were all American Society of Anesthesiologists physical status I, Han Chinese women who presented for elective cesarean delivery at ≥37 weeks of gestation. The inclusion criteria were: age 25– 35 years; ability to comprehend and operate the patient-controlled analgesia (PCA) pump; ability to comprehend and describe pain score by the 0–10 verbal/visual analog scales; no history of drug dependence or recreational drug use. The exclusion criteria were: have at least one medical condition (e.g. diabetes mellitus, hypertension, etc.); contraindication to spinal anesthesia and/or allergy to opioids or any of the drugs to be given intraoperatively. This study was approved by the ethics committee of Quanzhou First Hospital. All patients received consent form and signed it before enrollment. Anesthetic procedure Before the initiation of anesthesia, we collected baseline noninvasive blood pressure, heart rate, respiratory rate, and oxygen saturation using pulse oximetry. Mandatory intravenous access was established before surgery. Venous blood (3 ml) was then collected and stored. Before the induction of anesthesia, all patients were given 0.5 l lactated Ringer’s solution for pre-hydration. Spinal anesthesia was induced with a 27gauge Whitacre spinal needle inserted at the L3–L4 level in the right lateral position of patients. After free flow of cerebrospinal fluid was achieved, 0.5% hyperbaric bupivacaine (2 ml) was injected intrathecally, supplemented with fentanyl (25 lg). The patients, surgeons, anesthetists, or other medical staff who participated in the study were all blind to the genotypes of the patients. Sensory block was Acta Anaesthesiologica Scandinavica (2017)

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assessed bilaterally by loss of cold sensation. The surgery was initiated when the block was detected at T4 level. Hypotension was treated with 5–10 mg of intravenous ephedrine. Intravenous ondansetron (4 mg), metoclopramide (10 mg), and dexamethasone (4 mg) were routinely given before the end of surgery. The duration of surgery was recorded. Post-operative analgesia After surgery, all patients were treated with patient controlled epidural analgesia (PCEA) using the Wechsler electronic pump. The regimen was set as follows: 2.5 lg/ml fentanyl; demand dose = 2 ml, lockout interval = 10 min, background infusion = 2 ml/h. The concentration of fentanyl ranging 2–3 lg/ml is routinely used for pain management after surgery.24,25 During the first 24 h post-operatively (the time of arrival at recovery was defined as time 0), no other supplemental analgesics were given. Data related to patients’ age, weight, height, body mass index, history of previous cesarean delivery, duration of surgery, and pain scores (0–10 visual analog scale) at time 0, 4, 8, 12, 16, 20, and 24 h were recorded. The total amount of fentanyl over the first 24 post-operative hours was recorded; requests and boluses received served as a surrogate to the overall pain experience. The side effects were also recorded at time 0, 4, 8, 12, 16, 20, and 24 h, including nausea (severity scale of 0–3: 0 = none, 1 = mild, 2 = moderate, 3 = severe), vomiting (the number of episodes of retching with or without expulsion of fluids from the stomach), pruritus (severity scale of 0–3: 0 = none, 1 = mild, 2 = moderate, 3 = severe), central nervous system depression (asleep and difficult to rouse with a moderately loud auditory stimulus (i.e., calling out patients’ names) or glabellar tap), and respiratory depression (a rate of less than 8 and/or shallow breathing and/or oxygen saturation of <90% on room air as indicated by pulse oximetry). Women with more than mild nausea and/or vomiting were treated with 10 mg intravenous metoclopramide and 4 mg intravenous ondansetron. Women with severe pruritus were offered intravenous naloxone (0.04–0.1 mg). Intravenous naloxone (0.04– 0.1 mg) and supplemental oxygen by mask were

available for women with signs of central nervous system or respiratory system depression. Genotyping method Venous blood was collected with heparin anticoagulant. Conventional phenol/chloroform method was used to extract DNA. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to analyze CGRP 4218T/C polymorphism. We used Premier 5.0 to design primers, the sequences of which were shown as follows: F: 5-GGA AGAAGCAAA GACCAGGA-3; R: 5-CTGCAAG AACAATTCCCACA-3. PCR products were then digested with Alu I enzyme. For the wild homozygote (T/T), three bands of 202 bp, 169 bp, and 106 bp were presented. For the heterozygote (T/C), four bands of 371 bp, 202 bp, 169 bp, and 106 bp were presented. For the mutant homozygote (C/C), two bands of 371 bp and 106 bp were presented. Statistical analysis We excluded data from patients when there was a failure to establish a free flow of cerebrospinal fluid after three attempts or failure to establish a complete block of T4 after 30 min. Data from patients with complications such as hemorrhage necessitating additional procedures or surgery necessitating more than 120 min of operating time were also excluded from analysis. In this study, we first treated genotypes including homozygous (T/T), heterozygous (T/C), and homozygous (C/C) as independent variables. The sample size (521 subjects) exhibits a power of 82% to detect an additive genetic effect corresponding to a 10% change in total fentanyl intake of the baseline genotype T/T at a 5% level of significance. The normality of numerical variables were assessed within each genotype group using Shapiro-Wilk test, and expressed using the mean and standard deviation (SD). The significant differences between the three genotypes for numerical variables were then assessed using one-way analysis of variance (ANOVA) when they were normally distributed. For numerical variables with skewed distributions, the Kruskal–Wallis rank sum test was then used. To assess the association between the genotypes and

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the categorical variables, the Pearson chi-square test was used. The genotypes for the CGRP 4218T/C polymorphism were tested for departures from Hardy–Weinberg equilibrium using a likelihood ratio test. The call rate of the polymorphism was used as a measure of genotyping performance. An ANOVA with repeated measures was used for pain scores and fentanyl consumption with genotypes as between-subjects factor, and time as within-subjects factor. For the analysis of side effects, the area under curve described by the severity scores was used to analyze the overall severity of these side effects over the whole duration of study. To compare total fentanyl consumption among genotypes, the Wilcoxon rank sum test was performed. To explore the variables that were associated with total fentanyl consumption, a multivariate regression analysis with a stepwise model-selection procedure using the Akaike information criterion was used.26 All analyses were performed with SPSS 18.0. The differences were statistically significant only when P < 0.05. Results Demographic and clinical Characteristic The demographic and clinical Characteristic results were summarized in Table 1. Generally, a total of 548 women patients were enrolled in the present study. Two patients encountered technical failure. Five patients had complete block failure, and 14 patients encountered partial block failure. Intraoperative complications such as hemorrhage were developed in six patients. As a result, these patients required more than 120 min of operating time. Therefore,

data from these 27 patients were excluded. Data from the remaining 521 patients were included and analyzed in this study. We found that there are 351 (67.3%) patients carrying the wild homozygote (T/T), 128 (24.5%) patients carrying the mutant heterozygote (T/C), and 42 (8.0%) patients carrying the mutant homozygote (C/C). The call rate of genotyping was 99.4% (518 of 521). The allelic frequencies for the T and C alleles were 79.6% and 20.4%, respectively. We did not find any significant differences in the demographic and baseline clinical parameters between the three genotypic groups. In addition, there was also no difference in the duration of surgery among the three genotypic groups. Fentanyl consumption We found that there was a significant difference in the total consumption of PCEA fentanyl among the three genotypic groups (P = 0.016; Fig. 1A). Furthermore, all three genotypic groups exhibited a similar pattern of consumption, with the lowest average doses at 12–16 h. However, at the 4, 8, and 12 h after the surgery, the consumption of PCEA fentanyl in the C/C group was significantly higher than the T/T group (Tukey test, P < 0.05; Fig. 1B). No failed PCEA demands were reported throughout the study. Pain scores In general, pain scores remained low in all three genotypic groups. However, there was a significant difference in the total pain scores among the three genotypic groups (P = 0.041; Fig. 2A).

Table 1 Clinical characteristics of the study population.

Age (years) Weight (kg) Height (cm) BMI (kg/m²) Previous C-sec, 0 : >1 Surgery Duration (min)

TT (n = 351)

TC (n = 128)

CC (n = 42)

P value

26.8  3.8 64.2  7.8 156.1  4.8 27.4  3.5 311 : 40 51.2  13.5

27.1  3.8 64.5  8.1 155.8  4.9 27.2  2.9 111 : 17 53.5  18.8

26.9  3.6 64.4  8.2 155.9  5.2 27.6  2.8 37 : 5 52.7  16.9

0.86 0.78 0.69 0.77 0.15 0.22

Data are expressed as mean  SD. Acta Anaesthesiologica Scandinavica (2017)

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Fig. 1. Patient-controlled epidural analgesia (PCEA) fentanyl (mean  SD) consumption (lg/kg) (A) in total and (B) across time after surgery in each genotype. *Significant difference between CC and TT (P < 0.05). No difference between TC and TT.

Fig. 2. Pain perception in patients. (A) Pain severity and (B) pain scores (mean  SD) across time after surgery in each genotype. *Significant difference between CC and TT (P < 0.05). No difference between TC and TT.

Furthermore, similar with the pattern of sumption of PCEA fentanyl, at the 4, 8, 12 h after the surgery, pain scores in the group was significantly higher than the group (Tukey test, P < 0.05; Fig. 2B).

conand C/C T/T

Side effects The results of side effects were summarized in Table 2. We found that the overall incidence of nausea was low. The C/C group exhibited significantly lower incidence of nausea compared to the other two groups. There was no significant difference between the T/T and T/C groups. The C/C group also experienced the lowest severity scores for nausea over the first 24 h. Also, there was no significant difference between the T/T and T/C groups in severity scores for nausea. Similar to nausea, the overall incidence of vomiting remained low in the

present study. The C/C group exhibited significantly lower incidence of vomiting compared to the other two groups. There was no significant difference between the T/T and T/C groups. We found that a total of 188 patients (36.1%) developed pruritus. Additionally, there was no difference among the three genotypic groups. Furthermore, there was no difference in the severity scores for pruritus over the first 24 h among the three genotypic groups. In the present study, no women needed intravenous naloxone treatment for pruritus. We also did not find any patients with respiratory or central nervous system depression. Risk factors of the consumption of PCEA fentanyl We next conducted multivariate regression to evaluate the risk factors that were related to the

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Table 2 Summary of side effects

Nausea (n) Vomiting (n) Pruritus (n) Nausea Score over 24 h Medium (Min–Max) Pruritus Score over 24 h Medium (Min–Max)

TT (n = 351)

TC (n = 128)

CC (n = 42)

P value

25 17 105 0.03 (0–5)

6 3 19 0.01 (0–3.5)

1 1 6 0.01 (0–0.9)

0.02 0.02 0.01 0.03

0.5 (0–10)

0.27 (0–10)

0.01 (0–5)

0.04

consumption of PCEA fentanyl (Table 3). With adjustments for age, height, weight, duration of the operation, and previous cesarean delivery, we found that C-allele-containing genotypes was associated with a significantly high consumption of PCEA fentanyl (OR = 2.29, 95% CI: 1.66–5.77, P = 0.031; Table 3). Discussion The present study was designed to exam the role of CGRP 4218T/C in post-operative fentanyl consumption and pain perception as well as adverse reactions in patients who received cesarean section surgeries. We reported that CGRP 4218T/C polymorphism was associated with the variability in fentanyl consumption for post-cesarean analgesia. Specifically, we reported that women with the C/C genotype consumed higher amount of PCEA fentanyl and exhibited higher pain scores than other genotypic groups. With adjustments for age, height, weight, duration of the operation, and previous cesarean delivery, we reported that C-allele-containing genotype was associated with a significantly high consumption of PCEA fentanyl. These results suggested that Table 3 Risk factors of the consumption of PCEA fentanyl.

Clinical characteristics

PCEA fentanyl OR (95% CIs)

P

TC/CC vs. TT Age Weight Height BMI percentiles Previous C-sec Surgery duration

2.29 1.75 0.74 0.99 1.00 1.32 1.68

0.031 0.019 0.285 0.921 0.650 0.491 0.135

(1.66–5.77) (1.14–2.57) (0.38–1.43) (0.57–1.68) (0.99–1.05) (0.67–2.66) (0.84–3.32)

C/C genotype exhibits low sensitivity to the analgesic effect of PCEA fentanyl. Our findings seem consistent with previous clinical studies in the patients after cancer surgeries. Additionally, our results indicated that physiologic changes during pregnancy did not alter the association of the genotype with pain perception and analgesic consumption. Calcitonin gene-related peptide is a type of neuropeptide widely distributed in both the peripheral and central nervous system. Studies have shown that CGRP plays a critical role in nociceptive information transmission, generation of hyperalgesia in the spinal cord, and pain modulation.27,28 A recent study has reported the effects of CGRP 4218T/C polymorphism on the analgesic effects of intravenous fentanyl in the patients after cancer surgeries.29 Adding to this literature, the results of our study indicated that the CGRP 4218T/C polymorphism had a significant influence on post-cesarean section epidural fentanyl consumption for analgesia and pain perception. These studies together suggested that CGRP 4218T/C polymorphism may be involved in modulation of fentanyl analgesia regardless of administration regimen. Multiple factors may influence the post-operative analgesic effects of opioids in clinical settings. These factors include individual differences in the sensitivity to pain, the metabolism rate of analgesics, and specific opioid drug mechanisms.8,9 Furthermore, multiple genetic factors may together have influences on the post-operative analgesic effects of opioids. For example, previous studies have shown that A118G single nucleotide polymorphism of human l-opioid receptor gene plays a critical role in pain perception and patient-controlled intravenous morphine consumption for Acta Anaesthesiologica Scandinavica (2017)

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post-cesarean analgesia.30 However, others have reported that the analgesic requirements of patients receiving sufentanil and ropivacaine through PCEA after cesarean section were not associated with A118G polymorphism of lopioid receptor gene.31 These results suggested that the role of genetic factors in post-operative analgesic effects of opioids may depend on specific opioid drug mechanisms. Adding to this line of research, we reported that CGRP 4218T/C polymorphism is also critical for the post-operative analgesic effects of fentanyl. However, future studies will be necessary to exam whether CGRP 4218T/C polymorphism is significantly involved in modulation of the post-operative analgesic effects of other opioids. Additionally, our study investigated the association of CGRP 4218T/C polymorphism with PCEA fentanyl-induced adverse reactions. Our results demonstrated that CGRP 4218T/C polymorphism had significant influence on the incidence of adverse effects of fentanyl, including nausea and vomiting. Based on the results of our study, it is unlikely that the incidence of nausea caused by PCEA fentanyl had discouraged patients in the C/C genotypic group from self-administration, because there were correspondingly higher consumptions of PCEA fentanyl and low incidence of nausea in patients of the C/C genotype. Also, the total amount of PCEA fentanyl was not likely to be a significant factor in inducing nausea since the C/C genotypic group used the highest amount of fentanyl and exhibited the lowest nausea scores. In conclusion, our results indicated that the CGRP 4218T/C polymorphism has a significant effect on pain perception, analgesic requirement, and nausea and vomiting for the first 24 h after cesarean delivery for patients who received PCEA fentanyl. Individuals with the C/C genotype had more pain, required more PCEA fentanyl, and experienced a lower incidence of nausea and vomiting. It is also possible that patients with C/C genotype may have greater pain scores after surgery. Therefore, patients with C/C genotype may be willing to use more PCEA fentanyl initially. These results indicated that patients with C/C genotype may have reduced sensitivity to fentanyl analgesia and/or increased pain perception, and were more willing to use PCEA fentanyl to manage their pain.

However, the clinical impact contributed by this genetic variation in acute post-operative pain management and in the prevention of the development of chronic pain is still not clear. Therefore, future studies would be necessary to examine it. This line of research will not only be important for investigating the role of genetic polymorphisms in the influence of effects of opioids, but also for the development of effective post-operative pain management strategies. Acknowledgments None. References 1. Rowe-Murray HJ, Fisher JR. Operative intervention in delivery is associated with compromised early mother-infant interaction. BJOG 2001; 108: 1068– 75. 2. Sufang G, Padmadas SS, Fengmin Z, Brown JJ, Stones RW. Delivery settings and cesarean section rates in China. Bull World Health Organ 2007; 85: 733–820. 3. Feng XL, Xu L, Guo Y, Ronsmans C. Factors influencing rising caesarean section rates in China between 1988 and 2008. Bull World Health Organ 2012; 90: 30–39A. 4. Imani F. Postoperative pain management. Anesth Pain Med 2011; 1: 6–7. 5. Walder B, Schafer M, Henzi I, Tramer M. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. Acta Anaesthesiol Scand 2001; 45: 795–804. 6. Eisenach JC, Grice SC, Dewan DM. Patientcontrolled analgesia following cesarean section: a comparison with epidural and intramuscular narcotics. Obstet Anesth Digest 1988; 8: 135. 7. Argoff CE. Clinical implications of opioid pharmacogenetics. Clin J Pain 2010; 26: S16–20. 8. Sadhasivam S, Chidambaran V. Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics 2012; 13: 1719–40. 9. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007; 81: 429–44. 10. Hamber EA, Viscomi CM. Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia. Reg Anesth Pain Med 1999; 24: 255–63. 11. Weigl W, Bieryło A, Krzemie
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21. Ma W, Zheng W-H, Kar S, Quirion R. Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. Neuroscience 2000; 99: 529–39. 22. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006; 46: S3– 8. 23. Russell F, King R, Smillie S-J, Kodji X, Brain S. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 2014; 94: 1099–142. 24. Matsota P, Batistaki C, Apostolaki S, Kostopanagiotou G. Patient-controlled epidural analgesia after Caesarean section: levobupivacaine 0.15% versus ropivacaine 0.15% alone or combined with fentanyl 2 lg/ml: a comparative study. Arch Med Sci 2011; 7: 685. 25. Gambling DR, Huber CJ, Berkowitz J, Howell P, Swenerton JE, Ross PL, Crocheti ere CT, Pavy TJ. Patient-controlled epidural analgesia in labour: varying bolus dose and lockout interval. Can J Anaesth 1993; 40: 211–7. 26. Akaike H. A new look at the statistical model identification. IEEE Trans Autom Control 1974; 19: 716–23. 27. Piehl F, Hammarberg H, Tabar G, H€ okfelt T, Cullheim S. Changes in the mRNA expression pattern, with special reference to calcitonin generelated peptide, after axonal injuries in rat motoneurons depends on age and type of injury. Exp Brain Res 1998; 119: 191–204. 28. Borke R, Curtis M, Ginsberg C. Choline acetyltransferase and calcitonin gene-related peptide immunoreactivity in motoneurons after different types of nerve injury. J Neurocytol 1993; 22: 141–53. 29. Yi Y, Zhao M, Xu F, Liu C, Yin Y, Yu J. CGRP 4218T/C polymorphism correlated with postoperative analgesic effect of fentanyl. Int J Clin Exp Pathol 2015; 8: 5761. 30. Sia AT, Lim Y, Lim EC, Goh RW, Law HY, Landau R, Teo Y-y, Tan EC. A118G single nucleotide polymorphism of human l-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. J Am Soc Anesth 2008; 109: 520–6. 31. Xu G-H, Gao M, Sheng Q-Y, Liu X-S, Gu E-W. Opioid receptor A118G polymorphism does not affect the consumption of sufentanil and ropivacaine by patient-controlled epidural analgesia after cesarean section. Ther Drug Monit 2015; 37: 53–7. Acta Anaesthesiologica Scandinavica (2017)

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