GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 17, Number 10, 2013 ª Mary Ann Liebert, Inc. Pp. 743–749 DOI: 10.1089/gtmb.2013.0282
Effects of OPRM1 A118G Polymorphism on Epidural Analgesia with Fentanyl During Labor: A Meta-Analysis Zheming Song,1,* Boxiang Du,1,* Kai Wang,2 and Xueyin Shi1
Background: Emerging evidence has shown that the most common polymorphism (A118G; rs1799971 A > G) in the m-opioid receptor (OPRM1) gene may influence the response to labor analgesia, but individually published studies showed inconclusive results. Objective: This meta-analysis aimed to derive a more precise estimation of the effects of the OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. Methods: A literature search was conducted on PubMed, Embase, Web of Science, and China BioMedicine databases before April 1st, 2013. The crude standardized mean difference (SMD) or odds ratio (OR) with 95% confidence interval (CI) was calculated. Results: Six clinical studies were included with a total 838 women who received epidural analgesia with fentanyl during labor. The meta-analysis results indicated that women carrying the G allele (AG + GG) of the OPRM1 A118G polymorphism required less fentanyl doses to achieve adequate pain relief compared with those with the AA homozygote (SMD = - 0.24, 95% CI [ - 0.44, - 0.03], p = 0.022). The 118G variant was associated with a decreased ED50 of fentanyl for labor analgesia (SMD = - 1.56, 95% CI [ - 1.97, - 1.15], p < 0.001). The analgesia satisfaction in women carrying the G allele (AG + GG) was higher than those with the AA homozygote (SMD = 0.22, 95% CI [0.05, 0.39], p = 0.012). However, there were no statistically significant differences between an AA homozygote and a G carrier (AG + GG) in the incidence of nausea and vomiting (OR = 1.99, 95% CI [0.88, 4.52], p = 0.101). Conclusion: In conclusion, the current meta-analysis indicates that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism may have a good response to epidural analgesia with fentanyl during labor. The OPRM1 A118G polymorphism may help predict individuals’ response to epidural labor analgesia and so optimize postoperative pain control.
Introduction
L
abor pain has been described as one of the most intense pains that a woman can experience in her lifetime (Lowe, 2002). Pain intensity and analgesic requests during labor and delivery are variable and unpredictable (Gambling et al., 2013), however, multiple factors have an impact on labor pain sensitivity, such as age, ethnicity, anxiety, type of labor and delivery, and preoperative pain (Orejuela et al., 2012). Although some women want to undergo labor without pain medications, most women receive epidural analgesia, which provides relatively consistent pain relief for labor analgesia (Agaram et al., 2009). Nowadays, epidural opioids, including morphine, meperidine, sufentanil, and fentanyl, have become increasingly popular as an option for labor analgesia (Hawkins, 2010). However, a large interindividual variability has been observed in analgesic efficacy, incidence and severity of side effects, and tolerance profiles (Bauchat et al., 2012). Recent
advances in genetic research have indicated that genetic polymorphisms may contribute to individuals’ variability in response to opioid treatment. Emerging evidence indicates that genetic variations in opioid receptor genes may influence the response to epidural opioid analgesia during labor (Oertel et al., 2006; Wong et al., 2010; Pettersson et al., 2012). The m-opioid receptor (OPRM1), which is encoded by the OPRM1 gene, is the primary receptor mediating the analgesic and euphoric effects of opioid drugs (Deb et al., 2010). The human OPRM1 gene is located on chromosome 6q24-q25, spanning *1.9 kb, and it contains two exons (Kleinjan et al., 2012). More than 100 single-nucleotide polymorphisms (SNPs) in the OPRM1 gene have been identified (Pettersson et al., 2012). The most widely studied one is A118G (rs1799971 A > G), which encodes an Asn40Asp amino substitution and may increase the binding affinity and potency of b-endorphin (Rhodin et al., 2013). In recent years, the influence of the most common polymorphism OPRM1 A118G on the analgesic
1
Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, China. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. *These two authors contributed equally to the manuscript and are cofirst authors. 2
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SONG ET AL.
FIG. 1. Flowchart of literature search and study selection.
conflicting results from previous studies, we performed a meta-analysis of all available data to evaluate the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor.
response to various opioids in different routes of administration and clinical settings has been evaluated (Chou et al., 2006a, 2006b; Hayashida et al., 2008; Sia et al., 2008; Liao et al., 2013). Hypothetically, individuals carrying the OPRM1 gene variant may show differences in OPRM1 functions, resulting in interindividual differences in the clinical response to opioid analgesics (Deb et al., 2010). Several recent studies have indicated that the OPRM1 A118G polymorphism might play a critical role in the response to epidural analgesia with fentanyl during labor (Landau et al., 2008; Zhang et al., 2010; De Capraris et al., 2011; Zhang et al., 2011; Camorcia et al., 2012; Zhang et al., 2013). However, some other studies exist, which suggest that OPRM1 A118G polymorphism has no influence on the efficacy and safety of epidural fentanyl for labor analgesia (Wong et al., 2010; Landau et al., 2013). In view of the
Materials and Methods Literature search strategy Relevant articles published before April 1st, 2013 were identified through a search on PubMed, Embase, Web of Science, and China BioMedicine databases using the following terms: (‘‘genetic polymorphism’’ or ‘‘polymorphism’’ or ‘‘SNP’’ or ‘‘single nucleotide polymorphism’’ or ‘‘gene mutation’’ or ‘‘genetic variants’’) and (‘‘Receptors, Opioid, mu’’ or ‘‘mu Opioid Receptors’’ or ‘‘Morphine Receptor’’ or ‘‘mu
Table 1. Characteristics of Included Studies in This Meta-Analysis
First author Year Landau et al. Zhang et al. Camorcia et al. Zhang et al. Wong et al. Landau et al.
Country
Genotype Case Ethnicity number AA AG GG AG + GG Genotype method
2013 USA
Caucasian
98
59 34
5
39
2013 China 2012 Italy
Asian Caucasian
96 57
35 45 16 33 23 1
61 24
2011 China Asian 2010 USA Caucasian 2008 Switzerland Caucasian
174 190 223
80 63 22 144 34 12 150 62 11
85 46 73
PCR-SSP/ Pyrosequencing Direct sequencing PCR-SSP/ Pyrosequencing Direct sequencing Direct sequencing PCR-SSP/ Pyrosequencing
SNP ID
Evaluating indicators
NOS score
rs1799971
¡
14/16
rs1799971 rs1799971
¨¡ ¡Æ
11/16 12/16
rs1799971 rs1799971 rs1799971
¨¡Ø ¨¡Ø Æ
10/16 13/16 10/16
¨: Fentanyl consumption; ¡: analgesia satisfaction; Æ: ED50; Ø: postoperative nausea and vomiting. PCR-SSP, polymerase chain reaction with sequence-specific primer; SNP, single-nucleotide polymorphism; NOS, Newcastle–Ottawa score.
OPRM1 A118G POLYMORPHISM AND LABOR ANALGESIA
745
Fentanyl consumption Weight %
Study ID
SMD (95% CI)
Zhang et al (2013)
−1.61 (−2.08, −1.13)
18.31
Zhang et al (2011)
0.15 (−0.16, 0.46)
44.20
Wong et al (2010)
−0.03 (−0.36, 0.31)
37.49
−0.24 (−0.44, −0.03)
100.0
2
Overall (I = 95.0%, P < 0.001)
0
−2.08
FIG. 2. Forest plot for the effects of m-opioid receptor (OPRM1) A118G polymorphism on the fentanyl consumption for labor analgesia.
2.08
lected: the first author, year of publication, country, language, study design, ethnicity of subjects, numbers of subjects, mean age, analgesia type, genotype method, genotype frequencies, and clinical indicators (¨ fentanyl consumption; ¡ analgesia satisfaction; Æ median effective dose [ED50]; Ø postoperative nausea and vomiting). In case of conflicting evaluations, an agreement was reached following a discussion with a third reviewer.
Receptors’’ or ‘‘OPRM1’’) and (‘‘Fentanyl’’ or ‘‘Fentora’’ or ‘‘Phentanyl’’ or ‘‘Fentanest’’ or ‘‘Sublimaze’’ or ‘‘R-4263’’ or ‘‘Duragesic’’). The references from the eligible articles or textbooks were also reviewed to find other potential sources. Disagreements were resolved through discussions among the authors. Inclusion and exclusion criteria Studies included in our meta-analysis had to meet the following criteria: (1) clinical studies focused on the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor; (2) all women received epidural analgesia with fentanyl for labor pain relief; (3) published data about the efficacy and safety of epidural analgesia with fentanyl were sufficient. Studies were excluded when they were (1) not a clinical study on OPRM1 A118G polymorphism and labor analgesia; (2) duplicates of previous publications; (3) publications with incomplete data; (4) meta-analyses, letters, reviews, or editorial articles. If more than one study by the same author using the same case series was published, either the study with the largest sample size or the most recently published study was included.
Two authors independently assessed the quality of included articles according to the modified Newcastle–Ottawa quality assessment scale (Stang, 2010; Oremus et al., 2012). The scale uses a score system based on three criteria: selection of participants, comparability of study groups, and assessment of exposure. Eight assessment items related to the quality appraisal were used in this meta-analysis with scores ranging from 0 to 16. Scores of 0–8, 9–12, and 13–16 were defined as low, moderate, and high quality, respectively. Disagreement between the two reviewing authors was resolved by consensus. If consensus could not be reached, a third author was deferred to arbitration and consensus.
Data extraction
Statistical analysis
Data from the published studies were extracted independently by two authors into a standardized form. For each study, the following characteristics and numbers were col-
The crude standardized mean difference (SMD) or odds ratio (OR) with 95% confidence interval (CI) were calculated. The statistical significance of the pooled estimate was
Quality assessment of included studies
Analgesia satisfaction Study ID
SMD (95% CI) Weight %
Landau et al (2013)
0.24 (−0.16, 0.65)
17.41
Zhang et al (2013)
0.47 (0.05, 0.89)
16.19
Camorcia et al (2012)
0.30 (−0.23, 0.83)
10.26
Zhang et al (2011)
−0.18 (−0.49, 0.12) 30.66
Wong et al (2010)
0.49 (0.15, 0.83)
25.48
Overall (I2 = 42.1%, P = 0.052)
0.22 (0.05, 0.39)
100.00
−0.889
0
0.889
FIG. 3. Forest plot for the effects of OPRM1 A118G polymorphism on analgesia satisfaction of epidural analgesia with fentanyl during labor.
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SONG ET AL. ED50
FIG. 4. Forest plot for the effects of OPRM1 A118G polymorphism on the ED50 of epidural analgesia with fentanyl during labor.
Study ID
SMD (95% CI)
Camorcia et al (2012)
−0.71 (−1.25, −0.17)
56.77
Landau et al (2008)
−2.67 (−3.29, −2.05)
43.23
−1.56 (−1.97, −1.15)
100.00
2
Overall (I = 6.4%, P = 0.172)
−3.29
examined using the Z test. Between-study variations and heterogeneities were estimated using Cochran’s Q-statistic with a p-value < 0.05 as statistically significant heterogeneity ( Jackson et al., 2012). We also quantified the effects of heterogeneity by using the I2 test (ranges from 0% to 100%), which represents the proportion of interstudy variability that can be contributed to heterogeneity rather than to chance (Peters et al., 2006). When a significant Q-test with p < 0.05 or I2 > 50% indicated that heterogeneity among studies existed, the random effects model (DerSimonian Laird method) was conducted for the meta-analysis; otherwise, the fixed effects model (MantelHaenszel method) was used. Sensitivity analysis was performed by omitting each study in turn to assess the quality and consistency of the results. Begger’s funnel plots and Egger’s linear regression tests were also used to evaluate the publication biases (Zintzaras and Ioannidis, 2005). All the p values were two-sided. All analyses were calculated using the STATA Version 12.0 software (Stata Corp., College Station, TX). Results Characteristics of included studies In accordance with the inclusion criteria, six clinical studies were included in this meta-analysis and 153 were excluded (Landau et al., 2008; Wong et al., 2010; Zhang et al., 2011; Camorcia et al., 2012; Landau et al., 2013; Zhang et al., 2013). The flow chart of the study selection process is shown in Figure 1. The publication years of the involved studies ranged from 2008 to 2013. Four studies were conducted among Caucasian
0
Weight %
3.29
populations, while the other two studies were conducted among Asian populations. A combination of sequencespecific primer polymerase chain reaction (PCR) and automatic DNA pyrosequencing (PCR sequence-specific primer/ Pyrosequencing) methods was performed in three studies, and the other study used direct sequencing. All quality scores of included studies were higher than 8 (moderate high quality). The characteristics and methodological quality of the included studies are summarized in Table 1. Quantitative data synthesis The effect of OPRM1 A118G polymorphism on the fentanyl consumption for labor analgesia is discussed in three studies. Since obvious heterogeneity existed, the random effects model was used. The meta-analysis results showed that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism required less fentanyl to achieve adequate pain relief compared with those who were AA homozygous (SMD = - 0.24, 95% CI [ - 0.44, - 0.03], p = 0.022) (Fig. 2). Analgesia satisfaction of epidural analgesia with fentanyl during labor was investigated in five studies. No heterogeneity was observed, so the fixed effects model was used. The results showed that there was a statistically significant difference between the G allele carrier (AG + GG) and the AA homozygote on analgesia satisfaction (SMD = 0.22, 95% CI [0.05, 0.39], p = 0.012) (Fig. 3). Only two studies referred to the effect of OPRM1 A118G polymorphism on the ED50 of epidural analgesia with
Incidence of postoperative nausea and vomiting
FIG. 5. Forest plot for the effect of OPRM1 A118G polymorphism on the incidence of postoperative nausea and vomiting.
Study ID
SMD (95% CI )
Zhang et al (2011)
2.02 (0.87, 4.73)
Wong et al (2010)
1.63 (0.08, 34.60) 8.86
2
Overall (I = 0.0%, P = 0.894)
0.0289
1.99 (0.88, 4.52)
1
34.3
Weight %
91.14
100.00
OPRM1 A118G POLYMORPHISM AND LABOR ANALGESIA Lower CI Limit
Estimate
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Upper CI Limit
Landau et al (2013)
Zhang et al (2013)
FIG. 6. Sensitivity analysis for the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia.
Camorcia et al (2012)
Zhang et al (2011)
Wong et al (2010) −0.07
0.05
0.22
0.39
fentanyl during labor. Since no heterogeneity existed, the fixed effects model was used. Meta-analysis of these studies indicated that the 118G variant was associated with decreased IV fentanyl ED50 for labor analgesia (SMD = - 1.56, 95% CI [ - 1.97, - 1.15], p < 0.001) (Fig. 4). There were also only two studies that reported results on the effect of OPRM1 A118G polymorphism on the incidence of postoperative nausea and vomiting. Heterogeneity was not obvious; so, the fixed effects model was used. No significant difference was found in the incidence of postoperative nausea and vomiting between the G allele carrier (AG + GG) and the AA homozygote for labor analgesia (OR = 1.99, 95% CI [0.88, 4.52], p = 0.101) (Fig. 5). Sensitivity analysis and publication bias Sensitivity analysis was performed to assess the influence of each individual study on the pooled SMD of analgesia satisfaction by omission of individual studies. The analysis
0.60
results suggested that no individual studies significantly affected the pooled SMD of the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia, indicating a statistically robust result (Fig. 6). The Begger’s funnel plot and Egger’s linear regression test were performed to assess publication biases in the included studies. The shapes of the funnel plots of the effect of OPRM1 A118G polymorphism on analgesia satisfaction for labor analgesia did not reveal any evidence of obvious asymmetry (Fig. 7). The Egger’s test also did not indicate any strong statistical evidence of publication bias (t = - 0.84, p = 0.488). Discussion The OPRM1, a member of the G-protein coupled receptor superfamily, mediates the analgesic and euphoric effects of opioid drugs (Fredriksson et al., 2003). A number of SNPs have been identified in the OPRM1 gene, which have been largely limited to the DNA sequence and short intron 2 so far
Log[SMD]
−0.5
FIG. 7. Begger’s funnel plot for the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia.
−1.0
−1.5 0
0.1
0.2 SE(Log[SMD])
0.3
748 (Deb et al., 2010). The most widely studied is A118G (rs1799971 A > G) polymorphism, which leads to a substitution of Asn/Asp within exon 1 and may increase the binding affinity and potency of b-endorphin, which mediates analgesia and pain threshold (Rhodin et al., 2013). Therefore, it is biologically plausible that genetic variations of OPRM1 A118G polymorphism may modulate an individual’s response to epidural analgesia with fentanyl during labor (Camorcia et al., 2012). Several studies have investigated the functional effects of OPRM1 A118G polymorphism, but their findings have been inconclusive. This meta-analysis aimed to derive a more precise estimation of the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. In this meta-analysis, six clinical studies were included with a total of 838 women who received epidural analgesia with fentanyl during labor. When all the eligible studies were pooled into the meta-analysis, we demonstrated that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism had a dramatically decreased fentanyl dose for labor analgesia, suggesting that the 118G variant might be associated with an increased sensitivity to epidural opioid analgesia. One explanation for a significant increase in pain tolerance and decreased fentanyl consumption in 118G carriers could be the change of quantity and binding affinity of OPRM1 due to genetic variability at the OPRM1. These results provide support for the potential use of genetic data in predicting the fentanyl dosage for postoperative labor pain control. The present results also suggested that the analgesia satisfaction in women carrying the G allele (AG + GG) was higher than those who are AA, which is consistent with previous studies. A major goal of labor analgesia is minimal motor impairment, emphasizing the need to minimize local anesthetic use. Similarly, there is a need to reduce opioid doses to minimize opioid-related side effects such as pruritus and fetal bradycardia. Our findings indicated that women carrying the 118G variant had a lower ED50 with a 1.15- to 1.97-fold decrease in fentanyl dose for labor analgesia. One explanation for decreased ED50 of fentanyl analgesia in 118G carriers would be that the 118G variant might enhance b-endorphins binding and thereby increase the response to fentanyl. Postoperative nausea and vomiting are common side effects of labor analgesis. Theoretically, with a decrease in fentanyl dosage, side effects may correspondingly decrease during labor analgesia. However, no statistically significant differences were found between the AA homozygote and the G carrier (AG + GG) in the incidence of nausea and vomiting, suggesting that OPRM1 A118G polymorphism does not explain the nausea and vomiting caused by fentanyl. Similar to other meta-analyses, our study also bears some limitations and shortages. First, the sample size is relatively small and may not provide sufficient power to estimate the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. Therefore, more research with a larger sample size is needed to accurately provide a more representative statistical analysis. Second, as a retrospective study, a meta-analysis may encounter recall or selection bias, possibly influencing the reliability of our study results (Camorcia et al., 2012). Third, our lack of access to the original data from the studies limited further evaluation of potential effects of epidural analgesia with fentanyl on analgesia success, VAS score, VPS score, and other side effects (van Melle et al., 2004). In
SONG ET AL. spite of these limitations, however, this is the first meta-analysis on the influences of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. It is also worthwhile to mention that we established an efficient searching strategy based on computer-assisted programs, as well as manual searches, which allowed us to include as many as possible. According to our selection criteria, the quality of studies included in this meta-analysis is sufficient. Nonetheless, explicit methods for study selection, data extraction, and data analysis were well designed before initiating. Finally, there was no evidence of publication bias in this meta-analysis and the sensitivity analysis indicated that our results are statistically robust. In conclusion, our meta-analysis suggests that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism may have a good response to epidural analgesia with fentanyl during labor. The OPRM1 A118G polymorphism may help predict individuals’ response to epidural labor analgesia, and thus optimize postoperative pain control. Based on the limitations mentioned earlier, detailed studies are needed to confirm our findings. Further studies are still needed to warrant and validate the effects of OPRM1 A118G polymorphism on epidural labor analgesia. Acknowledgment We thank all our colleagues working in the Department of Anesthesiology, Changzheng Hospital, Second Military Medical University. Author Disclosure Statement No competing financial interests exist. References Agaram R, Douglas MJ, McTaggart RA, et al. (2009) Inadequate pain relief with labor epidurals: a multivariate analysis of associated factors. Int J Obstet Anesth 18:10–14. Bauchat JR, McCarthy RJ, Koski TR, et al. (2012) Prior lumbar discectomy surgery does not alter the efficacy of neuraxial labor analgesia. Anesth Analg 115:348–353. Camorcia M, Capogna G, Stirparo S, et al. (2012) Effect of muopioid receptor A118G polymorphism on the ED50 of epidural sufentanil for labor analgesia. Int J Obstet Anesth 21:40–44. Chou WY, Wang CH, Liu PH, et al. (2006a) Human opioid receptor A118G polymorphism affects intravenous patientcontrolled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105:334–337. Chou WY, Yang LC, Lu HF, et al. (2006b) Association of muopioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–792. De Capraris A, Cinnella G, Marolla A, et al. (2011) Micro opioid receptor A118G polymorphism and post-operative pain: opioids’ effects on heterozygous patients. Int J Immunopathol Pharmacol 24:993–1004. Deb I, Chakraborty J, Gangopadhyay PK, et al. (2010) Singlenucleotide polymorphism (A118G) in exon 1 of OPRM1 gene causes alteration in downstream signaling by mu-opioid receptor and may contribute to the genetic risk for addiction. J Neurochem 112:486–496. Fredriksson R, Lagerstrom MC, Lundin LG, et al. (2003) The Gprotein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272.
OPRM1 A118G POLYMORPHISM AND LABOR ANALGESIA Gambling D, Berkowitz J, Farrell TR, et al. (2013) A randomized controlled comparison of epidural analgesia and combined spinal-epidural analgesia in a private practice setting: pain scores during first and second stages of labor and at delivery. Anesth Analg 116:636–643. Hawkins JL (2010) Epidural analgesia for labor and delivery. N Engl J Med 362:1503–1510. Hayashida M, Nagashima M, Satoh Y, et al. (2008) Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype. Pharmacogenomics 9:1605–1616. Jackson D, White IR, Riley RD (2012) Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 31:3805–3820. Kleinjan M, Poelen EA, Engels RC, et al. (2012) Dual growth of adolescent smoking and drinking: evidence for an interaction between the mu-opioid receptor (OPRM1) A118G polymorphism and sex. Addict Biol [Epub ahead of print]; DOI: 10.1111/j.1369-1600.2011.00422.x. Landau R, Kern C, Columb MO, et al. (2008) Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain 139:5–14. Landau R, Liu SK, Blouin JL, et al. (2013) The effect of OPRM1 and COMT genotypes on the analgesic response to intravenous fentanyl labor analgesia. Anesth Analg 116:386–391. Liao Q, Chen DJ, Zhang F, et al. (2013) Effect of CYP3A4*18B polymorphisms and interactions with OPRM1 A118G on postoperative fentanyl requirements in patients undergoing radical gastrectomy. Mol Med Rep 7:901–908. Lowe NK (2002) The nature of labor pain. Am J Obstet Gynecol 186:S16–S24. Oertel BG, Schmidt R, Schneider A, et al. (2006) The mu-opioid receptor gene polymorphism 118A > G depletes alfentanilinduced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics 16: 625–636. Orejuela FJ, Garcia T, Green C, et al. (2012) Exploring factors influencing patient request for epidural analgesia on admission to labor and delivery in a predominantly Latino population. J Immigr Minor Health 14:287–291. Oremus M, Oremus C, Hall GB, et al. (2012) Inter-rater and testretest reliability of quality assessments by novice student raters using the Jadad and Newcastle-Ottawa Scales. BMJ Open 2:pii: e001368. Peters JL, Sutton AJ, Jones DR, et al. (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295:676–680. Pettersson FD, Gronbladh A, Nyberg F, et al. (2012) The A118G single-nucleotide polymorphism of human mu-
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opioid receptor gene and use of labor analgesia. Reprod Sci 19:962–967. Rhodin A, Gronbladh A, Ginya H, et al. (2013) Combined analysis of circulating beta-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects. Mol Brain 6:8. Sia AT, Lim Y, Lim EC, et al. (2008) A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 109:520–526. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605. van Melle JP, de Jonge P, Spijkerman TA, et al. (2004) Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 66:814–822. Wong CA, McCarthy RJ, Blouin J, et al. (2010) Observational study of the effect of mu-opioid receptor genetic polymorphism on intrathecal opioid labor analgesia and post-cesarean delivery analgesia. Int J Obstet Anesth 19:246–253. Zhang SQ, Li SY, Tan XH (2013) [Human m-opioid receptor A118G polymorphism affects epidural patient-controlled analgesia with fentanyl]. Nan Fang Yi Ke Da Xue Xue Bao 33:309–311 [In Chinese]. Zhang W, Chang YZ, Kan QC, et al. (2010) Association of human micro-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia 65:130–135. Zhang W, Yuan JJ, Kan QC, et al. (2011) Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia. Minerva Anestesiol 77:33–39. Zintzaras E, Ioannidis JP (2005) HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics 21: 3672–3673.
Address correspondence to: Xueyin Shi, MD Department of Anesthesiology Changzheng Hospital Second Military Medical University Fengyang Road No. 415 Shanghai 200003 China E-mail: [email protected]
Effects of OPRM1 A118G Polymorphism on Epidural Analgesia with Fentanyl During Labor: A Meta-Analysis Zheming Song,1,* Boxiang Du,1,* Kai Wang,2 and Xueyin Shi1
Background: Emerging evidence has shown that the most common polymorphism (A118G; rs1799971 A > G) in the m-opioid receptor (OPRM1) gene may influence the response to labor analgesia, but individually published studies showed inconclusive results. Objective: This meta-analysis aimed to derive a more precise estimation of the effects of the OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. Methods: A literature search was conducted on PubMed, Embase, Web of Science, and China BioMedicine databases before April 1st, 2013. The crude standardized mean difference (SMD) or odds ratio (OR) with 95% confidence interval (CI) was calculated. Results: Six clinical studies were included with a total 838 women who received epidural analgesia with fentanyl during labor. The meta-analysis results indicated that women carrying the G allele (AG + GG) of the OPRM1 A118G polymorphism required less fentanyl doses to achieve adequate pain relief compared with those with the AA homozygote (SMD = - 0.24, 95% CI [ - 0.44, - 0.03], p = 0.022). The 118G variant was associated with a decreased ED50 of fentanyl for labor analgesia (SMD = - 1.56, 95% CI [ - 1.97, - 1.15], p < 0.001). The analgesia satisfaction in women carrying the G allele (AG + GG) was higher than those with the AA homozygote (SMD = 0.22, 95% CI [0.05, 0.39], p = 0.012). However, there were no statistically significant differences between an AA homozygote and a G carrier (AG + GG) in the incidence of nausea and vomiting (OR = 1.99, 95% CI [0.88, 4.52], p = 0.101). Conclusion: In conclusion, the current meta-analysis indicates that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism may have a good response to epidural analgesia with fentanyl during labor. The OPRM1 A118G polymorphism may help predict individuals’ response to epidural labor analgesia and so optimize postoperative pain control.
Introduction
L
abor pain has been described as one of the most intense pains that a woman can experience in her lifetime (Lowe, 2002). Pain intensity and analgesic requests during labor and delivery are variable and unpredictable (Gambling et al., 2013), however, multiple factors have an impact on labor pain sensitivity, such as age, ethnicity, anxiety, type of labor and delivery, and preoperative pain (Orejuela et al., 2012). Although some women want to undergo labor without pain medications, most women receive epidural analgesia, which provides relatively consistent pain relief for labor analgesia (Agaram et al., 2009). Nowadays, epidural opioids, including morphine, meperidine, sufentanil, and fentanyl, have become increasingly popular as an option for labor analgesia (Hawkins, 2010). However, a large interindividual variability has been observed in analgesic efficacy, incidence and severity of side effects, and tolerance profiles (Bauchat et al., 2012). Recent
advances in genetic research have indicated that genetic polymorphisms may contribute to individuals’ variability in response to opioid treatment. Emerging evidence indicates that genetic variations in opioid receptor genes may influence the response to epidural opioid analgesia during labor (Oertel et al., 2006; Wong et al., 2010; Pettersson et al., 2012). The m-opioid receptor (OPRM1), which is encoded by the OPRM1 gene, is the primary receptor mediating the analgesic and euphoric effects of opioid drugs (Deb et al., 2010). The human OPRM1 gene is located on chromosome 6q24-q25, spanning *1.9 kb, and it contains two exons (Kleinjan et al., 2012). More than 100 single-nucleotide polymorphisms (SNPs) in the OPRM1 gene have been identified (Pettersson et al., 2012). The most widely studied one is A118G (rs1799971 A > G), which encodes an Asn40Asp amino substitution and may increase the binding affinity and potency of b-endorphin (Rhodin et al., 2013). In recent years, the influence of the most common polymorphism OPRM1 A118G on the analgesic
1
Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, China. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. *These two authors contributed equally to the manuscript and are cofirst authors. 2
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SONG ET AL.
FIG. 1. Flowchart of literature search and study selection.
conflicting results from previous studies, we performed a meta-analysis of all available data to evaluate the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor.
response to various opioids in different routes of administration and clinical settings has been evaluated (Chou et al., 2006a, 2006b; Hayashida et al., 2008; Sia et al., 2008; Liao et al., 2013). Hypothetically, individuals carrying the OPRM1 gene variant may show differences in OPRM1 functions, resulting in interindividual differences in the clinical response to opioid analgesics (Deb et al., 2010). Several recent studies have indicated that the OPRM1 A118G polymorphism might play a critical role in the response to epidural analgesia with fentanyl during labor (Landau et al., 2008; Zhang et al., 2010; De Capraris et al., 2011; Zhang et al., 2011; Camorcia et al., 2012; Zhang et al., 2013). However, some other studies exist, which suggest that OPRM1 A118G polymorphism has no influence on the efficacy and safety of epidural fentanyl for labor analgesia (Wong et al., 2010; Landau et al., 2013). In view of the
Materials and Methods Literature search strategy Relevant articles published before April 1st, 2013 were identified through a search on PubMed, Embase, Web of Science, and China BioMedicine databases using the following terms: (‘‘genetic polymorphism’’ or ‘‘polymorphism’’ or ‘‘SNP’’ or ‘‘single nucleotide polymorphism’’ or ‘‘gene mutation’’ or ‘‘genetic variants’’) and (‘‘Receptors, Opioid, mu’’ or ‘‘mu Opioid Receptors’’ or ‘‘Morphine Receptor’’ or ‘‘mu
Table 1. Characteristics of Included Studies in This Meta-Analysis
First author Year Landau et al. Zhang et al. Camorcia et al. Zhang et al. Wong et al. Landau et al.
Country
Genotype Case Ethnicity number AA AG GG AG + GG Genotype method
2013 USA
Caucasian
98
59 34
5
39
2013 China 2012 Italy
Asian Caucasian
96 57
35 45 16 33 23 1
61 24
2011 China Asian 2010 USA Caucasian 2008 Switzerland Caucasian
174 190 223
80 63 22 144 34 12 150 62 11
85 46 73
PCR-SSP/ Pyrosequencing Direct sequencing PCR-SSP/ Pyrosequencing Direct sequencing Direct sequencing PCR-SSP/ Pyrosequencing
SNP ID
Evaluating indicators
NOS score
rs1799971
¡
14/16
rs1799971 rs1799971
¨¡ ¡Æ
11/16 12/16
rs1799971 rs1799971 rs1799971
¨¡Ø ¨¡Ø Æ
10/16 13/16 10/16
¨: Fentanyl consumption; ¡: analgesia satisfaction; Æ: ED50; Ø: postoperative nausea and vomiting. PCR-SSP, polymerase chain reaction with sequence-specific primer; SNP, single-nucleotide polymorphism; NOS, Newcastle–Ottawa score.
OPRM1 A118G POLYMORPHISM AND LABOR ANALGESIA
745
Fentanyl consumption Weight %
Study ID
SMD (95% CI)
Zhang et al (2013)
−1.61 (−2.08, −1.13)
18.31
Zhang et al (2011)
0.15 (−0.16, 0.46)
44.20
Wong et al (2010)
−0.03 (−0.36, 0.31)
37.49
−0.24 (−0.44, −0.03)
100.0
2
Overall (I = 95.0%, P < 0.001)
0
−2.08
FIG. 2. Forest plot for the effects of m-opioid receptor (OPRM1) A118G polymorphism on the fentanyl consumption for labor analgesia.
2.08
lected: the first author, year of publication, country, language, study design, ethnicity of subjects, numbers of subjects, mean age, analgesia type, genotype method, genotype frequencies, and clinical indicators (¨ fentanyl consumption; ¡ analgesia satisfaction; Æ median effective dose [ED50]; Ø postoperative nausea and vomiting). In case of conflicting evaluations, an agreement was reached following a discussion with a third reviewer.
Receptors’’ or ‘‘OPRM1’’) and (‘‘Fentanyl’’ or ‘‘Fentora’’ or ‘‘Phentanyl’’ or ‘‘Fentanest’’ or ‘‘Sublimaze’’ or ‘‘R-4263’’ or ‘‘Duragesic’’). The references from the eligible articles or textbooks were also reviewed to find other potential sources. Disagreements were resolved through discussions among the authors. Inclusion and exclusion criteria Studies included in our meta-analysis had to meet the following criteria: (1) clinical studies focused on the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor; (2) all women received epidural analgesia with fentanyl for labor pain relief; (3) published data about the efficacy and safety of epidural analgesia with fentanyl were sufficient. Studies were excluded when they were (1) not a clinical study on OPRM1 A118G polymorphism and labor analgesia; (2) duplicates of previous publications; (3) publications with incomplete data; (4) meta-analyses, letters, reviews, or editorial articles. If more than one study by the same author using the same case series was published, either the study with the largest sample size or the most recently published study was included.
Two authors independently assessed the quality of included articles according to the modified Newcastle–Ottawa quality assessment scale (Stang, 2010; Oremus et al., 2012). The scale uses a score system based on three criteria: selection of participants, comparability of study groups, and assessment of exposure. Eight assessment items related to the quality appraisal were used in this meta-analysis with scores ranging from 0 to 16. Scores of 0–8, 9–12, and 13–16 were defined as low, moderate, and high quality, respectively. Disagreement between the two reviewing authors was resolved by consensus. If consensus could not be reached, a third author was deferred to arbitration and consensus.
Data extraction
Statistical analysis
Data from the published studies were extracted independently by two authors into a standardized form. For each study, the following characteristics and numbers were col-
The crude standardized mean difference (SMD) or odds ratio (OR) with 95% confidence interval (CI) were calculated. The statistical significance of the pooled estimate was
Quality assessment of included studies
Analgesia satisfaction Study ID
SMD (95% CI) Weight %
Landau et al (2013)
0.24 (−0.16, 0.65)
17.41
Zhang et al (2013)
0.47 (0.05, 0.89)
16.19
Camorcia et al (2012)
0.30 (−0.23, 0.83)
10.26
Zhang et al (2011)
−0.18 (−0.49, 0.12) 30.66
Wong et al (2010)
0.49 (0.15, 0.83)
25.48
Overall (I2 = 42.1%, P = 0.052)
0.22 (0.05, 0.39)
100.00
−0.889
0
0.889
FIG. 3. Forest plot for the effects of OPRM1 A118G polymorphism on analgesia satisfaction of epidural analgesia with fentanyl during labor.
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SONG ET AL. ED50
FIG. 4. Forest plot for the effects of OPRM1 A118G polymorphism on the ED50 of epidural analgesia with fentanyl during labor.
Study ID
SMD (95% CI)
Camorcia et al (2012)
−0.71 (−1.25, −0.17)
56.77
Landau et al (2008)
−2.67 (−3.29, −2.05)
43.23
−1.56 (−1.97, −1.15)
100.00
2
Overall (I = 6.4%, P = 0.172)
−3.29
examined using the Z test. Between-study variations and heterogeneities were estimated using Cochran’s Q-statistic with a p-value < 0.05 as statistically significant heterogeneity ( Jackson et al., 2012). We also quantified the effects of heterogeneity by using the I2 test (ranges from 0% to 100%), which represents the proportion of interstudy variability that can be contributed to heterogeneity rather than to chance (Peters et al., 2006). When a significant Q-test with p < 0.05 or I2 > 50% indicated that heterogeneity among studies existed, the random effects model (DerSimonian Laird method) was conducted for the meta-analysis; otherwise, the fixed effects model (MantelHaenszel method) was used. Sensitivity analysis was performed by omitting each study in turn to assess the quality and consistency of the results. Begger’s funnel plots and Egger’s linear regression tests were also used to evaluate the publication biases (Zintzaras and Ioannidis, 2005). All the p values were two-sided. All analyses were calculated using the STATA Version 12.0 software (Stata Corp., College Station, TX). Results Characteristics of included studies In accordance with the inclusion criteria, six clinical studies were included in this meta-analysis and 153 were excluded (Landau et al., 2008; Wong et al., 2010; Zhang et al., 2011; Camorcia et al., 2012; Landau et al., 2013; Zhang et al., 2013). The flow chart of the study selection process is shown in Figure 1. The publication years of the involved studies ranged from 2008 to 2013. Four studies were conducted among Caucasian
0
Weight %
3.29
populations, while the other two studies were conducted among Asian populations. A combination of sequencespecific primer polymerase chain reaction (PCR) and automatic DNA pyrosequencing (PCR sequence-specific primer/ Pyrosequencing) methods was performed in three studies, and the other study used direct sequencing. All quality scores of included studies were higher than 8 (moderate high quality). The characteristics and methodological quality of the included studies are summarized in Table 1. Quantitative data synthesis The effect of OPRM1 A118G polymorphism on the fentanyl consumption for labor analgesia is discussed in three studies. Since obvious heterogeneity existed, the random effects model was used. The meta-analysis results showed that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism required less fentanyl to achieve adequate pain relief compared with those who were AA homozygous (SMD = - 0.24, 95% CI [ - 0.44, - 0.03], p = 0.022) (Fig. 2). Analgesia satisfaction of epidural analgesia with fentanyl during labor was investigated in five studies. No heterogeneity was observed, so the fixed effects model was used. The results showed that there was a statistically significant difference between the G allele carrier (AG + GG) and the AA homozygote on analgesia satisfaction (SMD = 0.22, 95% CI [0.05, 0.39], p = 0.012) (Fig. 3). Only two studies referred to the effect of OPRM1 A118G polymorphism on the ED50 of epidural analgesia with
Incidence of postoperative nausea and vomiting
FIG. 5. Forest plot for the effect of OPRM1 A118G polymorphism on the incidence of postoperative nausea and vomiting.
Study ID
SMD (95% CI )
Zhang et al (2011)
2.02 (0.87, 4.73)
Wong et al (2010)
1.63 (0.08, 34.60) 8.86
2
Overall (I = 0.0%, P = 0.894)
0.0289
1.99 (0.88, 4.52)
1
34.3
Weight %
91.14
100.00
OPRM1 A118G POLYMORPHISM AND LABOR ANALGESIA Lower CI Limit
Estimate
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Upper CI Limit
Landau et al (2013)
Zhang et al (2013)
FIG. 6. Sensitivity analysis for the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia.
Camorcia et al (2012)
Zhang et al (2011)
Wong et al (2010) −0.07
0.05
0.22
0.39
fentanyl during labor. Since no heterogeneity existed, the fixed effects model was used. Meta-analysis of these studies indicated that the 118G variant was associated with decreased IV fentanyl ED50 for labor analgesia (SMD = - 1.56, 95% CI [ - 1.97, - 1.15], p < 0.001) (Fig. 4). There were also only two studies that reported results on the effect of OPRM1 A118G polymorphism on the incidence of postoperative nausea and vomiting. Heterogeneity was not obvious; so, the fixed effects model was used. No significant difference was found in the incidence of postoperative nausea and vomiting between the G allele carrier (AG + GG) and the AA homozygote for labor analgesia (OR = 1.99, 95% CI [0.88, 4.52], p = 0.101) (Fig. 5). Sensitivity analysis and publication bias Sensitivity analysis was performed to assess the influence of each individual study on the pooled SMD of analgesia satisfaction by omission of individual studies. The analysis
0.60
results suggested that no individual studies significantly affected the pooled SMD of the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia, indicating a statistically robust result (Fig. 6). The Begger’s funnel plot and Egger’s linear regression test were performed to assess publication biases in the included studies. The shapes of the funnel plots of the effect of OPRM1 A118G polymorphism on analgesia satisfaction for labor analgesia did not reveal any evidence of obvious asymmetry (Fig. 7). The Egger’s test also did not indicate any strong statistical evidence of publication bias (t = - 0.84, p = 0.488). Discussion The OPRM1, a member of the G-protein coupled receptor superfamily, mediates the analgesic and euphoric effects of opioid drugs (Fredriksson et al., 2003). A number of SNPs have been identified in the OPRM1 gene, which have been largely limited to the DNA sequence and short intron 2 so far
Log[SMD]
−0.5
FIG. 7. Begger’s funnel plot for the effect of OPRM1 A118G polymorphism on the analgesia satisfaction for labor analgesia.
−1.0
−1.5 0
0.1
0.2 SE(Log[SMD])
0.3
748 (Deb et al., 2010). The most widely studied is A118G (rs1799971 A > G) polymorphism, which leads to a substitution of Asn/Asp within exon 1 and may increase the binding affinity and potency of b-endorphin, which mediates analgesia and pain threshold (Rhodin et al., 2013). Therefore, it is biologically plausible that genetic variations of OPRM1 A118G polymorphism may modulate an individual’s response to epidural analgesia with fentanyl during labor (Camorcia et al., 2012). Several studies have investigated the functional effects of OPRM1 A118G polymorphism, but their findings have been inconclusive. This meta-analysis aimed to derive a more precise estimation of the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. In this meta-analysis, six clinical studies were included with a total of 838 women who received epidural analgesia with fentanyl during labor. When all the eligible studies were pooled into the meta-analysis, we demonstrated that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism had a dramatically decreased fentanyl dose for labor analgesia, suggesting that the 118G variant might be associated with an increased sensitivity to epidural opioid analgesia. One explanation for a significant increase in pain tolerance and decreased fentanyl consumption in 118G carriers could be the change of quantity and binding affinity of OPRM1 due to genetic variability at the OPRM1. These results provide support for the potential use of genetic data in predicting the fentanyl dosage for postoperative labor pain control. The present results also suggested that the analgesia satisfaction in women carrying the G allele (AG + GG) was higher than those who are AA, which is consistent with previous studies. A major goal of labor analgesia is minimal motor impairment, emphasizing the need to minimize local anesthetic use. Similarly, there is a need to reduce opioid doses to minimize opioid-related side effects such as pruritus and fetal bradycardia. Our findings indicated that women carrying the 118G variant had a lower ED50 with a 1.15- to 1.97-fold decrease in fentanyl dose for labor analgesia. One explanation for decreased ED50 of fentanyl analgesia in 118G carriers would be that the 118G variant might enhance b-endorphins binding and thereby increase the response to fentanyl. Postoperative nausea and vomiting are common side effects of labor analgesis. Theoretically, with a decrease in fentanyl dosage, side effects may correspondingly decrease during labor analgesia. However, no statistically significant differences were found between the AA homozygote and the G carrier (AG + GG) in the incidence of nausea and vomiting, suggesting that OPRM1 A118G polymorphism does not explain the nausea and vomiting caused by fentanyl. Similar to other meta-analyses, our study also bears some limitations and shortages. First, the sample size is relatively small and may not provide sufficient power to estimate the effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. Therefore, more research with a larger sample size is needed to accurately provide a more representative statistical analysis. Second, as a retrospective study, a meta-analysis may encounter recall or selection bias, possibly influencing the reliability of our study results (Camorcia et al., 2012). Third, our lack of access to the original data from the studies limited further evaluation of potential effects of epidural analgesia with fentanyl on analgesia success, VAS score, VPS score, and other side effects (van Melle et al., 2004). In
SONG ET AL. spite of these limitations, however, this is the first meta-analysis on the influences of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. It is also worthwhile to mention that we established an efficient searching strategy based on computer-assisted programs, as well as manual searches, which allowed us to include as many as possible. According to our selection criteria, the quality of studies included in this meta-analysis is sufficient. Nonetheless, explicit methods for study selection, data extraction, and data analysis were well designed before initiating. Finally, there was no evidence of publication bias in this meta-analysis and the sensitivity analysis indicated that our results are statistically robust. In conclusion, our meta-analysis suggests that women carrying the G allele (AG + GG) of OPRM1 A118G polymorphism may have a good response to epidural analgesia with fentanyl during labor. The OPRM1 A118G polymorphism may help predict individuals’ response to epidural labor analgesia, and thus optimize postoperative pain control. Based on the limitations mentioned earlier, detailed studies are needed to confirm our findings. Further studies are still needed to warrant and validate the effects of OPRM1 A118G polymorphism on epidural labor analgesia. Acknowledgment We thank all our colleagues working in the Department of Anesthesiology, Changzheng Hospital, Second Military Medical University. Author Disclosure Statement No competing financial interests exist. References Agaram R, Douglas MJ, McTaggart RA, et al. (2009) Inadequate pain relief with labor epidurals: a multivariate analysis of associated factors. Int J Obstet Anesth 18:10–14. Bauchat JR, McCarthy RJ, Koski TR, et al. (2012) Prior lumbar discectomy surgery does not alter the efficacy of neuraxial labor analgesia. Anesth Analg 115:348–353. Camorcia M, Capogna G, Stirparo S, et al. (2012) Effect of muopioid receptor A118G polymorphism on the ED50 of epidural sufentanil for labor analgesia. Int J Obstet Anesth 21:40–44. Chou WY, Wang CH, Liu PH, et al. (2006a) Human opioid receptor A118G polymorphism affects intravenous patientcontrolled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105:334–337. Chou WY, Yang LC, Lu HF, et al. (2006b) Association of muopioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–792. De Capraris A, Cinnella G, Marolla A, et al. (2011) Micro opioid receptor A118G polymorphism and post-operative pain: opioids’ effects on heterozygous patients. Int J Immunopathol Pharmacol 24:993–1004. Deb I, Chakraborty J, Gangopadhyay PK, et al. (2010) Singlenucleotide polymorphism (A118G) in exon 1 of OPRM1 gene causes alteration in downstream signaling by mu-opioid receptor and may contribute to the genetic risk for addiction. J Neurochem 112:486–496. Fredriksson R, Lagerstrom MC, Lundin LG, et al. (2003) The Gprotein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272.
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Address correspondence to: Xueyin Shi, MD Department of Anesthesiology Changzheng Hospital Second Military Medical University Fengyang Road No. 415 Shanghai 200003 China E-mail: [email protected]
