clinical study polymorphism of -opioid receptor gene g...

Hindawi Publishing CorporationPain Research and TreatmentVolume 2013 Article ID 259306 7 pageshttpdxdoiorg1011552013259306

Clinical StudyPolymorphism of 120583-Opioid Receptor Gene(OPRM1c118AgtG) Might Not Protect against or EnhanceMorphine-Induced Nausea or Vomiting

Li-Kuei Chen1 2 Shiou-Sheng Chen3 4 Chi-Hsiang Huang1 Hong-Jyh Yang5

Chen-Jung Lin1 Kuo-Liong Chien6 and Shou-Zen Fan1

1 Department of Anesthesiology National Taiwan University Hospital National Taiwan University College of MedicineTaipei 10048 Taiwan

2Department of Anesthesiology National Taiwan University Hospital Hsin-Chu Branch Hsinchu City 30059 Taiwan3Department of Urology School of Medicine National Yang-Ming University Taipei 112 Taiwan4Department of Surgery Taipei City Hospital Renai Branch Taipei 103 Taiwan5Department of Internal Medicine National Taiwan University Hospital Hsin-Chu Branch Hsinchu City 30059 Taiwan6College of Public Health National Taiwan University Taipei 10020 Taiwan

Correspondence should be addressed to Shou-Zen Fan chenlk12gmailcom

Received 20 September 2012 Revised 9 December 2012 Accepted 11 December 2012

Academic Editor Michael G Irwin

Copyright copy 2013 Li-Kuei Chen et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A cohort double blind and randomized study was conducted to investigate the effect of a single nucleotide polymorphism of the120583-opioid receptor at nucleotide position 118 (OPRM1c118AgtG) on the association with the most common side effects (nausea orvomiting) induced by intravenous patient control analgesia (IVPCA) with morphine including incidence and severity analysisA total of 129 Taiwanese women undergoing gynecology surgery received IVPCA with pure morphine for postoperative painrelief Blood samples were collected and sequenced with high resolution melting analysis to detect three different genotypes ofOPRM1 (AA AG and GG) All candidates 24 h postoperatively will be interviewed to record the clinical phenotype with subjectivecomplaints and objective observations The genotyping after laboratory analysis showed that 56 women (434) were AA 57(442) were AG and 16 (124) were GG The distribution of genotype did not violate Hardy-Weinberg equilibrium test Therewas no significant difference neither between the severity and incidence of IVPCAmorphine-induced side effects and genotype norbetween the association between morphine consumption versus genotype However there was significant difference of the relationbetween morphine consumption and the severity and incidence of IVPCA morphine-induced nausea and vomiting The geneticanalysis for the severity and incidence of IVPCAmorphine-induced nausea or vomiting showed no association between phenotypeand genotype It might imply that OPRM1c118AgtG does not protect against IVPCA morphine-induced nausea or vomiting

1 Introduction

IVPCA with pure morphine at present clinical practice wasstill widely used for postoperative pain management byproviding excellent analgesic effect [1 2] however the highincidence of some annoying side effects especially nauseaor vomiting induced by IVPCA morphine may limit itsclinical implicationThemost common side effects of IVPCAmorphine are nausea or vomiting with some other lesscommon like pruritus (2 to 10) [3] urinary retention and

respiration depression [4 5] The incidence of postoperativenausea or vomiting has been reported from 20 to 30and the incidence of severe nausea and vomiting around01 [6ndash8] The prophylactic protocol or treatment regimenfor opioid-induced nausea or vomiting had been elucidatedand studied recently with many publications [9ndash19] Pre-vious studies investigating the association between IVPCAmorphine and the genetic variability of human 120583-opioidreceptor gene had focused on the difference of morphineconsumption or analgesic effects [20ndash26] Nevertheless the

2 Pain Research and Treatment

association between the side effects induced by IVPCAmorphine (especially nausea or vomiting) and the geneticvariability of human 120583-opioid receptor gene had never beenelucidated thoroughly and specifically We designed andconducted this cohort double blind randomized study toinvestigate the effect of OPRM1c118AgtG on the nauseaor vomiting induced by IVPCA morphine following totalabdominal hysterectomy analgesia including incidence andseverity analysis

2 Materials and Methods

21 Patient Profile and Anesthetic Procedure This studywas approved by the Ethic Institute Review Board of theNational TaiwanUniversity Hospital after obtaining a writteninformed consent This was a population-based prospectiveobservational study with the double blind designed in dataanalysis A total of 129 American Society of Anesthesiologistsphysical status I or II Taiwanese women who underwenttotal abdominal hysterectomy (TAH) and received IVPCAmorphine for postoperative pain control were recruited intothis study in the 12-month period from August 1 2007to July 31 2008 All the recruited women could under-stand and describe the pain score Those women wereexcluded for any of the following reasons contraindicationsfor IVPCA morphine complaint of nausea or vomitingbefore the operation a history of significant cardiovasculardisease renal disease diabetes hepatic disease or chronicpain with taking pain medication A standardized gen-eral anesthesia technique was used for all patients Forinduction of anesthesia 2120583gkg fentanyl 2mgkg propofoland 015mgkg cisatracurium were used For maintenanceof anesthesia during operation cisatracurium and inhaledanesthetic desflurane at a low flow rate of 05 Lmin wereapplied Residual neuromuscular block was antagonized with25mg neostigmine and 10mg atropine and patients wereextubated at the end of surgery After extubation patientswere transferred to the postanesthesia care unit for obser-vation at least 1 hour and then transferred back to wardAll of the recruited women attending anesthesiologists forpracticing anesthesia and analgesia and the well-trainedinvestigator were blinded to the genotype at time of surgerybecause genotyping was determined only later in the labora-tory

22 Postoperative Pain Management Assessment and DataCollection At the postanesthesia care unit patients wereasked every 15min whether pain medication indicated toreduce their 10 cm VAS pain score lt3 until they becamealert enough to use the IVPCA pumpThemorphine solutionprovided in the PCA pump contained 250mL normal salineand 100mg pure morphine The pump was set to deliver a1mg bolus of morphine solution with a lockout time of 5minand a maximum dose of 15mg within a 4 h limit without abackground Overdose was prevented by limiting the totaldose administrated within a given period of time The totalamount of consumed morphine for 72 h after the operation

was recorded by the PCA device and was recorded usingan Abbott TRW printer model TP 40 (Abbott Life CareInfuser Chicago IL USA) PCA was started immediatelyafter patients were alert to control the PCA machine inthe postanesthesia care unit and was stopped 72 h after theoperation A trained investigator would interview the patientone time per day during the first 72 h postoperatively Ifpatients still felt wound pain (10 cm VAS pain score over 3)even after we gave the loading dose as 3mg of morphineand doubled the bolus dose as 2mg those cases wouldbe excluded This investigator would also explain thosepossible side effects induced by IVPCAmorphine to patientsand record those side effects (especially focus on nauseaand vomiting) as mild or severe For those patients withsevere side effects this investigator would conduct effec-tive management immediately following anesthesiologistrsquosorder

Data related to patientsrsquo age weight height history ofprevious operation ASA class and wound pain score werecollected Itching is defined as the sensation that provokesdesire to scratch the skin over the whole body Nausea isdefined as the sensation of having an urge to vomit andvomiting was defined by the number of episodes of retchingwith orwithout expulsion of fluids from the stomachUrinaryretention is defined as patients could not void by themselvesand urinal catheterization is indicated Dizziness is definedas having a whirling sensation and a tendency to fall andlethargy is defined as a state of sluggishness inactivityand apathy All of the above side effects (including nauseavomiting itching dizziness) were scored on a severity scaleas the following severe = the number of episodes gt 3and medical treatment is indicated mild = the number ofepisodes 3 and medical treatment is not indicated andnone as the number of episodes = 0 The incidence of theabove side effects is defined as the number of episodestaking place during the observation period Patients whohad severe nausea or vomiting or dizziness were treatedwith prochlorperazine 5mg patients with severe itchingweretreated with diphenhydramine HCL 4mg

23 Laboratory Analysis Genomic DNA was extractedfrom 3 mL of peripheral blood cell samples with a PuregeneDNA Isolation Kit (Gentra Systems Minneapolis MNUSA) according to the manufacturerrsquos instructionsReal-time PCR and data analysis were performed ina LightCycler 480 Real-Time PCR System and withLightCycler 480 software using LightCycler FastStart DNAMaster HybProbe Kit The reactions in a final volumeof 10120583L consisted of 025 120583M concentrations of eachprimer (forward 51015840-GTAGAGGGCCATGATCGTGAT-31015840and reverse 51015840-GCTTGGAACCCGAAAAGTCT-31015840)025 120583M concentrations of each probe (forward 51015840-CCCGGTTCCTGGGTCAACTTGTCC-31015840 and reverse51015840-CTTAGATGGCAACCTGTCCGACC-31015840) 1 120583L of FastStart DNA master hybridization probe reaction mixture(Roche) 5mM MgCl

2 and 1 120583L of genomic DNA Pipet

10 120583L PCR products into each well of the LightCycler 480(Roche Applied Science) Multiwell Plate Load the multiwall

Pain Research and Treatment 3

Melting peaks

0082

0072

0062

0052

0042

0032

0022

0012

0002

minus0008

minus0018

42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74Temperature (C)

minus(ddT

)fl

uor

esce

nce

(48

3ndash64

0) GG

AA

AG

c11

8 G

G

c11

8 A

A

c11

8 A

G

Figure 1 The figure from high resolution melting analysis to detect three different genotypes (AA AG and GG) by using the LightCycler480 Gene Scanning Software

Plate in LightCycler 480 instrument and start the meltingprogram High resolution melting was performed at 95∘Cfor 1min 40∘C for 1min 65∘C for 1 s and acquisitions at95∘C The data was evaluated using the LightCycler 480Gene Scanning Software (Figure 1) The blood samples weresequenced for genotypes wild-type A118 homozygous (AA)mutant heterozygous (AG) and mutant G118 homozygous(GG) which were first treated as individual variables

24 Statistical Analysis The nonnormal distributed vari-able morphine consumptions were summarized by medianand interquartile range (IQR) Morphine consumptions invarious genotypes or side effects with two categories werecompared by the nonparametric Mann-Whiney test mor-phine consumptions in various genotypes or side effectswith three categories were compared by the nonparametricKruskal-Wallis test with Bonferroni correction for post-hoccomparisons The categorical variables were summarized bycount and percentages and the associations between themwere tested by Fisherrsquos exact test The genetic frequency wasanalyzed with using 10000 permutations to approximate andexact 119875 value for the HWE (Hardy-Weinberg equilibrium)test as well as 1000 bootstrap samples to obtain the confi-dence interval for the allele frequencies and one-locusHardy-Weinberg disequilibrium (HWD) coefficients The goodnessof fit in Hardy-Weinberg equilibrium was tested with chi-square test Statistical significance was set at 005 Statisticalanalyses were performed with the SPSS 150 software package(SPSS Inc Chicago IL USA)

3 Results

A total of 132 women were enrolled in this study and dueto incomplete analgesia (VAS gt 3) the 3 were excludedremaining 129 women were analyzed in this study Thegenotyping after laboratory analysis showed that 56 women(434) were AA 57 (442) were AG and 16 (124) wereGG This sample size has a power greater than 80 to detecta 10 difference in those side effects among three differentgenotype groups The allelic frequencies for the A and Galleles were 655 and 345 respectively The distributionof genotypes and allelic frequencies did not violate Hardy-Weinberg equilibrium (Table 5 119875 = 0969)

31 Side Effects versus Genotype The association between theseverity of IVPCA-morphine-induced side effects and threegenotypes was shown in Table 1 with all the 119875 value gt 05The association between the incidences of IVPCA-morphine-induced side effects and three genotypes was shown inTable 2 with all the119875 valuegt 05 In the analysis of the severityand incidence no significant association was found betweenIVPCA morphine-induced side effects and three genotypes(Tables 1 and 2)

32 Morphine Consumption versus Genotype The geneticanalysis using autosomal dominant autosomal recessive andcodominant model of inheritance to evaluate the differencesbetween genotypes and morphine consumptions was shown


Table 1 The association between the severity of IVPCA morphine-induced side effects and genotype

Total (119899 = 129) Genotype P valueAA (119899 = 56) AG (119899 = 57) GG (119899 = 16)

NauseaSevere 36 (279) 15 (268) 16 (281) 5 (313)

0987Mild 45 (349) 19 (339) 21 (368) 5 (313)None 48 (372) 22 (393) 20 (351) 6 (375)

VomitingSevere 28 (217) 11 (196) 14 (246) 3 (188)

0910Mild 30 (233) 13 (232) 12 (211) 5 (313)None 71 (550) 32 (571) 31 (544) 8 (500)

ItchingSevere 3 (23) 2 (36) 1 (18) 0 (00)

0976Mild 11 (85) 5 (89) 5 (88) 1 (63)None 115 (891) 49 (875) 51 (895) 15 (938)

DizzinessSevere 10 (78) 5 (89) 4 (70) 1 (63)

0672Mild 51 (395) 20 (357) 22 (386) 9 (563)None 68 (527) 31 (554) 31 (544) 6 (375)

Table 2 The association between the incidences of IVPCA morphine-induced side effects and genotype

Total Genotype P valueAA (119899 = 56) AG (119899 = 57) GG (119899 = 16)

Nausea Yes 81 (628) 34 (607) 37 (649) 10 (625) 0935No 48 (372) 22 (393) 20 (351) 6 (375)

Vomiting Yes 58 (450) 24 (429) 26 (456) 8 (500) 0882No 71 (550) 32 (571) 31 (544) 8 (500)

Nausea or Vomiting Yes 82 (636) 35 (625) 37 (649) 10 (625) 0967No 47 (364) 21 (375) 20 (351) 6 (375)

Itching Yes 14 (109) 7 (125) 6 (105) 1 (63) 0857No 115 (891) 49 (875) 51 (895) 15 (938)

Dizziness Yes 61 (473) 25 (446) 26 (456) 10 (625) 0469No 68 (527) 31 (554) 31 (544) 6 (375)

Lethargy Yes 12 (93) 7 (125) 4 (70) 1 (63) 0579No 117 (907) 49 (875) 53 (930) 15 (938)

in Table 3 without significant difference found betweenIVPCA morphine consumption and genotypes

33 Morphine Consumption versus Side Effects The relationbetween morphine consumption and the side effects wassummarized in Table 4 Patients with the side effect of nauseahad significantly less morphine consumptions than thosewithout occurring nausea (210mg (160 331) versus 290mg(210 390) 119875 = 0010) A similar result was observedin the side effect of vomiting patients with the side effectof vomiting had significantly less morphine consumptionsthan those without occurring vomiting (191mg (150 290)versus 295mg (200 371) 119875 = 0004) In the compar-isons for morphine consumption between various degreesof vomiting patients with severe vomiting had significantlyless morphine consumptions than those without occurringvomiting (191mg (111 231) versus 295mg (200 371))

4 Discussion

Previous pharmacogenetic studies for morphine have beenfocused on the investigation of morphine consumption vari-ety between the different genotypes [20 23 25 27] Howeverthe specific genetic study for those side effects induced bymorphine was limited except Romberg et al group reportingthe association between respiratory depression induced byopioid with OPRM1c118AgtG [21] Nausea or vomiting themost common side effect induced by intravenous morphinefor postoperative analgesia was observed with different phe-notypes in incidence and severity among different patientsPrevious studies have supplementary mentioned about theassociation between OPRM1c118AgtG with nausea or vom-iting induced by morphine without definite or with defectconclusion [20 23 25 27]

The possible mechanisms of opiates inducing nausea orvomiting might be attributed as follows direct activation of


Table 3 Tests for the relations between morphine consumptionversus genotype

Morphine consumption (mg) P value

GenotypeAA 226 (145 341)

0430AG 231 (190 401)GG 261 (200 356)

Genotype AA 226 (145 341) 0203AG or GG 240 (190 381)

Genotype AA or AG 230 (160 367) 0499GG 261 (200 356)

Table 4 Tests for the relations between morphine consumptionversus side effects


NauseaSevere 205 (136 351)

0033lowastMild 210 (160 321)None 290 (210 390)

Nausea Yes 210 (160 331) 0010lowastNo 290 (210 390)

VomitingSevere 191 (111 231)dagger

0014lowastMild 206 (155 321)None 295 (200 371)

Vomiting Yes 191 (150 290) 0004lowastNo 295 (200 371)

Nausea or vomiting Yes 210 (160 340) 0018lowastNo 286 (210 392)

lowastIndicated that there is significant difference in morphine consumptionbetween various categories in the corresponding side effectdaggerIndicated that there is significant difference in morphine consumptionbetween those with severe vomiting and without vomiting

Table 5 Test for Hardy-Weinberg equilibrium

Theobservedfrequency

The expected frequency in a stateof Hardy-Weinberg equilibrium P value

GenotypeAA 56 (434) 554 (429)

0969AG 57 (442) 583 (452)GG 16 (124) 154 (119)

the chemoreceptor trigger zone (CTZ) in the area postremaof the medulla with the action conveyed to the vomit-ing center increased sensitivity of vestibular function andindirect stimulation of the CTZ with action conveyed tothe vomiting center decreased stomach motility prolon-gation of gastric emptying time and increased possibilityof esophageal reflux However the incidence and sever-ity of nausea or vomiting induced by intravenous mor-phine had been reported differently according to previouspapers [7 8] The differences might be attributed to theroute of administrating the opioids [28] the gender factor

(the incidence higher in female patients [28]) the differentethnics [11 29] and so on Especially the study by Hirayamaet al clearly indicated that postoperative nausea and vomiting(PONV)withmorphine therapy developed inmore than 60of Japanese patients after surgery [11] We may reasonablyhypothesize that OPRM1c118AgtG could have played a rolein protecting against or increasing the severity and incidenceof nausea or vomiting induced by IVPCA morphine

Reviewing previous published papers we found theremight be too many confounding factors affecting the diversi-fied incidence and severity of PONV Patient-related factorsmight be attributed to the following age gender obesepatients history of motion sickness andor previous postop-erative nausea anxiety gastroparesis and different operativeprocedures Anesthetic-related factors associated with emesismight be attributed to those confounding factors preanes-thetic medication gastric distension and suctions differentanesthetic techniques (general anesthesia regional anesthe-sia or monitored anesthesia care) and postoperative factors(including painful sensation dizziness feeling ambulationoral intake and PCA device with opioids) Most previousstudies had been focused on evaluating the relationshipbetween morphine consumption and genetic variations byusing IVPCA morphine for different operations with thesubsidiary conclusion that there was no association betweenside effects and genotype polymorphism [20 23 25 27] Atpresent there is not yet a complete and well-designed geneticassociation study to particularly evaluate those most com-mon side effects induced by epidural morphine Howeverpharmacogenetic studies for nausea or vomiting specificallyinduced by IVPCA morphine should exclude those con-founding factors with definite confirmation that nausea orvomiting should be induced by morphine only The resultsfrom previous pharmacogenetic studies [20 23 25 27] fornausea or vomiting induced by morphine have the followingdefects due to not excluding those confounding factorsMost of studies [20 23 25 27] recorded their data for sideeffects since patients were sent to postanesthesia care unitand started to use IVPCA morphine Therefore it could beimpossible to get the reliable and true data for the incidenceand severity of nausea or vomiting induced by IVPCAmorphine without excluding the confounding factors (suchas preanesthetic medication gastric distension and suctionsand different anesthetic techniques) In one study [23]they analyzed the genetic association between the IVPCAmorphine consumption after intrathecal morphine withOPRM1c118AgtG They concluded that OPRM1c118AgtGhad a significant effect on pain perception analgesic require-ment and nauseavomiting for patient who received PCAintravenous morphine after intrathecal morphine Howeverapparently there were some confounding factors with inad-equate study design in patient selection to influence thegenetic variation analysis for the severity and incidence ofthose side effects induced by morphine since those patientsin the study received intrathecal 01mg morphine duringspinal anesthesia first then followed by IVPCA morphinefor postoperative pain management The underlying mech-anisms for the incidence and severity of those side effectsinduced by neuroaxial or parenteral morphine were different


and those side effects did not have distinct proportional rela-tionshipwith opioid dosage neither [30ndash33] For example themost common and severe side effect induced by intrathecalmorphine could be pruritus and the most common andsevere side effect induced by intravenous morphine couldbe nausea or vomiting It might be inferred importantly andreasonably that the study design and patient selection of thegenetic variation evaluation for those side effects inducedby morphine should be homogenous unitary such as thesingle intervention design by only parenteral or neuroaxialmorphine for postoperative analgesia alone

In our study design for recording those side effectsinduced by IVPCA morphine and patient selection wehave tried our best to exclude those confounding factorsthat would have the high possibility to affect the resultswe collected for the analysis We recruited more homoge-nous criteria with Taiwanese female who received the sameoperation (TAH) with the same general anesthesia protocoland used IVPCA morphine only for postoperative analgesiaIn the recruiting criteria we excluded those patients withany systemic disease or medication associated with nau-sea or vomiting with the history of PONV after surgeryand complaints of nausea or vomiting before surgery Westarted to record those side effects (including the severityand incidence analysis) induced by IVPCA morphine onetime per day 24 hours after surgery to exclude those con-founding factors (such as preanesthetic medication gastricdistension and suctions and different anesthetic techniques)Furthermore we excluded those patients with inadequateanalgesia (VAS gt 3) medications related to PONV dizzinessfeeling or ambulation influence to exclude those postop-erative confounding factors At the meantime the samewell-trained nursing observer who was blind to the geneticanalysis data visited all the patients one time per day andrecorded all the data Under this selection criteria and studydesign we might reasonably confirm that those side effectswere definitely and purely induced by IVPCA morphineCompared with previous similar pharmacogenetic studies[20 23 25 27] for morphine with lower incidence (around15) and less severe of nausea or vomiting the overallincidence of nausea (81129 628) vomiting (58129 45)and nausea or vomiting (82129 636) induced by IVPCAin our study was much more compatible with and similarto previous published papers [11 34ndash39] and our previousexperience During the data analysis accidently we foundthat patients with the episode of nausea andor vomitinghad significantly less morphine consumptions (Table 4) andpatients with severe nausea or vomiting had significantly lessmorphine consumptions (Table 4) although therewas no sig-nificant difference between IVPCA morphine consumptionand genotypes (Table 3) However we still need more clinicalinformation to detect if there was any relationship amongthe three dimensions total morphine consumption differentgenotypes and incidence and severity of nausea or vomitinginduced by IVPCA morphine

In summary our study might be the most integrated andthorough investigation on the genetic relationship betweenOPRM1c118AgtG and nausea or vomiting induced by mor-phine The major finding of our study is that not only

the incidence of nausea or vomiting induced by IVPCAmor-phine following TAH analgesia but also the severity was notassociatedwithA118GpolymorphismofOPRM1c118AgtG inTaiwanesewomenwith definite and clear conclusion Itmightimply that OPRM1c118AgtG does not protect against norenhance nausea or vomiting induced by IVPCAmorphine inseverity and incidence

Acknowledgments

This work was supported by Grant no 96-2314-B-002-122from the National Science Council Taiwan This paper waspresented as the poster at the 2009 American Society ofAnesthesiology October New Orleans LA USA

References

[1] Y Lim S Jha A T Sia and N Rawal ldquoMorphine for post-caesarean section analgesia intrathecal epidural or intra-venousrdquo Singapore Medical Journal vol 46 no 8 pp 392ndash3962005

[2] R S Sinatra K Lodge K Silbert et al ldquoA comparisonof morphine meperidine and oxymorphone as utilized inpatient-controlled analgesia following cesarean deliveryrdquo Anes-thesiology vol 70 no 4 pp 585ndash590 1989

[3] N Cherny C Ripamonti J Pereira et al ldquoStrategies to managethe adverse effects of oral morphine an evidence-based reportrdquoJournal of Clinical Oncology vol 19 no 9 pp 2542ndash2554 2001

[4] M S Cepeda J T Farrar M Baumgarten R Boston D BCarr and B L Strom ldquoSide effects of opioids during short-term administration effect of age gender and racerdquo ClinicalPharmacology andTherapeutics vol 74 no 2 pp 102ndash112 2003

[5] M F Watcha and P F White ldquoPostoperative nausea and vomit-ing its etiology treatment and preventionrdquoAnesthesiology vol77 no 1 pp 162ndash184 1992

[6] A Borgeat and H R Stirnemann ldquoOndansetron is effective totreat spinal or epidural morphine-induced pruritusrdquo Anesthesi-ology vol 90 no 2 pp 432ndash436 1999

[7] J Leeser and H Lip ldquoPrevention of postoperative nausea andvomiting using ondansetron a new selective 5-HT3 receptorantagonistrdquoAnesthesia and Analgesia vol 72 no 6 pp 751ndash7551991

[8] E Campora L Merlini M Pace et al ldquoThe incidence ofnarcotic-induced emesisrdquo Journal of Pain and Symptom Man-agement vol 6 no 7 pp 428ndash430 1991

[9] G Sussman J Shurman M R Creed et al ldquoIntravenousondansetron for the control of opioid-induced nausea andvomiting International S3AA3013 study grouprdquo Clinical Ther-apeutics vol 21 no 7 pp 1216ndash1227 1999

[10] P IWilliams andM Smith ldquoAn assessment of prochlorperazinebuccal for the prevention of nausea and vomiting during intra-venous patient-controlled analgesia with morphine followingabdominal hysterectomyrdquo European Journal of Anaesthesiologyvol 16 no 9 pp 638ndash645 1999

[11] T Hirayama F Ishii K Yago and H Ogata ldquoEvaluation ofthe effective drugs for the prevention of nausea and vomitinginduced bymorphine used for postoperative pain a quantitativesystematic reviewrdquo Yakugaku Zasshi vol 121 no 2 pp 179ndash1852001


[12] G W Rung L Claybon A Hord et al ldquoIntravenous ondan-setron for postsurgical opioid-induced nausea and vomitingrdquoAnesthesia and Analgesia vol 84 no 4 pp 832ndash838 1997

[13] M Dresner S Dean A Lumb and M Bellamy ldquoHigh-doseondansetron regimen vs droperidol for morphine patient-controlled analgesiardquo British Journal of Anaesthesia vol 81 no3 pp 384ndash386 1998

[14] A S Habib and T J Gan ldquoThe effectiveness of rescue antiemet-ics after failure of prophylaxis with ondansetron or droperidola preliminary reportrdquo Journal of Clinical Anesthesia vol 17 no1 pp 62ndash65 2005

[15] L H J Eberhart A M Morin U Bothner and M Georgi-eff ldquoDroperidol and 5-HT3-receptor antagonists alone orin combination for prophylaxis of postoperative nausea andvomiting ameta-analysis of randomised controlled trialsrdquoActaAnaesthesiologica Scandinavica vol 44 no 10 pp 1252ndash12572000

[16] P S Loewen C A Marra and P J Zed ldquo5-HT3 receptor antag-onists vs traditional agents for the prophylaxis of postoperativenausea and vomitingrdquo Canadian Journal of Anesthesia vol 47no 10 pp 1008ndash1018 2000

[17] E Figueredo and L Canosa ldquoProphylactic ondansetron forpost-operative emesis meta-analysis of its effectiveness inpatients with and without a previous history of motion sick-nessrdquo European Journal of Anaesthesiology vol 16 no 8 pp556ndash564 1999

[18] E Figueredo and L Canosa ldquoProphylactic ondansetron forpostoperative emesis Meta-analysis of its effectiveness inpatients with previous history of postoperative nausea andvomitingrdquo Acta Anaesthesiologica Scandinavica vol 43 no 6pp 637ndash644 1999

[19] C C Apfel K Korttila M Abdalla et al ldquoA factorial trial ofsix interventions for the prevention of postoperative nausea andvomitingrdquoNewEngland Journal ofMedicine vol 350 no 24 pp2441ndash2451 2004

[20] W Y Chou L C Yang H F Lu et al ldquoAssociation of 120583-opioidreceptor gene polymorphism (A118G) with variations in mor-phine consumption for analgesia after total knee arthroplastyrdquoActa Anaesthesiologica Scandinavica vol 50 no 7 pp 787ndash7922006

[21] R R Romberg E Olofsen H Bijl et al ldquoPolymorphism of120583-opioid receptor gene (OPRM1c118AgtG) does not protectagainst opioid-induced respiratory depression despite reducedanalgesic responserdquo Anesthesiology vol 102 no 3 pp 522ndash5302005

[22] J Lotsch and G Geisslinger ldquoAre 120583-opioid receptor poly-morphisms important for clinical opioid therapyrdquo Trends inMolecular Medicine vol 11 no 2 pp 82ndash89 2005

[23] A T Sia Y Lim E C P Lim et al ldquoA118G single nucleotidepolymorphism of human 120583-opioid receptor gene influencespain perception and patient-controlled intravenous morphineconsumption after intrathecal morphine for postcesarean anal-gesiardquo Anesthesiology vol 109 no 3 pp 520ndash526 2008

[24] C Bond K S Laforge M Tian et al ldquoSingle-nucleotidepolymorphism in the human mu opioid receptor gene alters 120573-endorphin binding and activity possible implications for opiateaddictionrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 95 no 16 pp 9608ndash9613 1998

[25] W Y Chou C H Wang P H Liu C C Liu C C Tsengand B Jawan ldquoHuman opioid receptor A118G polymorphism

affects intravenous patient-controlled analgesia morphine con-sumption after total abdominal hysterectomyrdquo Anesthesiologyvol 105 no 2 pp 334ndash337 2006

[26] E C Tan E C P Lim Y Y Teo Y Lim H Y Law andA T Sia ldquoEthnicity and OPRM variant independently predictpain perception and patient-controlled analgesia usage for post-operative painrdquoMolecular Pain vol 5 article 32 2009

[27] D Campa A Gioia A Tomei P Poli and R Barale ldquoAssoci-ation of ABCB1MDR1 and OPRM1 gene polymorphisms withmorphine pain reliefrdquo Clinical Pharmacology and Therapeuticsvol 83 no 4 pp 559ndash566 2008

[28] L S Zun L V A Downey W Gossman J Rosenbaum and GSussman ldquoGender differences in narcotic-induced emesis in theEDrdquoAmerican Journal of EmergencyMedicine vol 20 no 3 pp151ndash154 2002

[29] E M M Quigley W L Hasler and H P Parkman ldquoAGAtechnical review on nausea and vomitingrdquo Gastroenterologyvol 120 no 1 pp 263ndash286 2001

[30] S Z Zhao F Chung D B Hanna A L Raymundo R YCheung and C Chen ldquoDose-response relationship betweenopioid use and adverse effects after ambulatory surgeryrdquo Journalof Pain and Symptom Management vol 28 no 1 pp 35ndash462004

[31] M A Chaney ldquoSide effects of intrathecal and epidural opioidsrdquoCanadian Journal of Anaesthesia vol 42 no 10 pp 891ndash9031995

[32] P R Bromage E M Camporesi A C Durant and C HNielsen ldquoNonrespiratory side effects of epidural morphinerdquoAnesthesia and Analgesia vol 61 no 6 pp 490ndash495 1982

[33] R D Vincent Jr D H Chesnut W W Choi P L G Ostmanand J N Bates ldquoDoes epidural fentanyl decrease the efficacyof epidural morphine after cesarean deliveryrdquo Anesthesia andAnalgesia vol 74 no 5 pp 658ndash663 1992

[34] K A Loper and L B Ready ldquoEpidural morphine after anteriorcruciate ligament repair a comparison with patient-controlledintravenous morphinerdquoAnesthesia and Analgesia vol 68 no 3pp 350ndash352 1989

[35] R Weller M Rosenblum P Conard et al ldquoComparison ofepidural and patient-controlled intravenous morphine follow-ing joint replacement surgeryrdquoCanadian Journal of Anaesthesiavol 38 no 5 pp 582ndash586 1991

[36] S E Rapp L B Ready and B E Greer ldquoPostoperativepain management in gynecologic oncology patients utilizingepidural opiate analgesia and patient-controlled analgesiardquoGynecologic Oncology vol 35 no 3 pp 341ndash344 1989

[37] D M Harrison R Sinatra L Morgese and J H ChungldquoEpidural narcotic and patient-controlled analgesia for post-cesarean section pain reliefrdquo Anesthesiology vol 68 no 3 pp454ndash457 1988

[38] S J Mather and J M Peutrell ldquoPostoperative morphinerequirements nausea and vomiting following anaesthesia fortonsillectomy Comparison of intravenous morphine and non-opioid analgesic techniquesrdquo Paediatric Anaesthesia vol 5 no3 pp 185ndash188 1995

[39] S A Nortcliffe J Shah and D J Buggy ldquoPrevention ofpostoperative nausea and vomiting after spinal morphine forCaesarean section comparison of cyclizine dexamethasoneand placebordquo British Journal of Anaesthesia vol 90 no 5 pp665ndash670 2003

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


association between the side effects induced by IVPCAmorphine (especially nausea or vomiting) and the geneticvariability of human 120583-opioid receptor gene had never beenelucidated thoroughly and specifically We designed andconducted this cohort double blind randomized study toinvestigate the effect of OPRM1c118AgtG on the nauseaor vomiting induced by IVPCA morphine following totalabdominal hysterectomy analgesia including incidence andseverity analysis

2 Materials and Methods

21 Patient Profile and Anesthetic Procedure This studywas approved by the Ethic Institute Review Board of theNational TaiwanUniversity Hospital after obtaining a writteninformed consent This was a population-based prospectiveobservational study with the double blind designed in dataanalysis A total of 129 American Society of Anesthesiologistsphysical status I or II Taiwanese women who underwenttotal abdominal hysterectomy (TAH) and received IVPCAmorphine for postoperative pain control were recruited intothis study in the 12-month period from August 1 2007to July 31 2008 All the recruited women could under-stand and describe the pain score Those women wereexcluded for any of the following reasons contraindicationsfor IVPCA morphine complaint of nausea or vomitingbefore the operation a history of significant cardiovasculardisease renal disease diabetes hepatic disease or chronicpain with taking pain medication A standardized gen-eral anesthesia technique was used for all patients Forinduction of anesthesia 2120583gkg fentanyl 2mgkg propofoland 015mgkg cisatracurium were used For maintenanceof anesthesia during operation cisatracurium and inhaledanesthetic desflurane at a low flow rate of 05 Lmin wereapplied Residual neuromuscular block was antagonized with25mg neostigmine and 10mg atropine and patients wereextubated at the end of surgery After extubation patientswere transferred to the postanesthesia care unit for obser-vation at least 1 hour and then transferred back to wardAll of the recruited women attending anesthesiologists forpracticing anesthesia and analgesia and the well-trainedinvestigator were blinded to the genotype at time of surgerybecause genotyping was determined only later in the labora-tory

22 Postoperative Pain Management Assessment and DataCollection At the postanesthesia care unit patients wereasked every 15min whether pain medication indicated toreduce their 10 cm VAS pain score lt3 until they becamealert enough to use the IVPCA pumpThemorphine solutionprovided in the PCA pump contained 250mL normal salineand 100mg pure morphine The pump was set to deliver a1mg bolus of morphine solution with a lockout time of 5minand a maximum dose of 15mg within a 4 h limit without abackground Overdose was prevented by limiting the totaldose administrated within a given period of time The totalamount of consumed morphine for 72 h after the operation

was recorded by the PCA device and was recorded usingan Abbott TRW printer model TP 40 (Abbott Life CareInfuser Chicago IL USA) PCA was started immediatelyafter patients were alert to control the PCA machine inthe postanesthesia care unit and was stopped 72 h after theoperation A trained investigator would interview the patientone time per day during the first 72 h postoperatively Ifpatients still felt wound pain (10 cm VAS pain score over 3)even after we gave the loading dose as 3mg of morphineand doubled the bolus dose as 2mg those cases wouldbe excluded This investigator would also explain thosepossible side effects induced by IVPCAmorphine to patientsand record those side effects (especially focus on nauseaand vomiting) as mild or severe For those patients withsevere side effects this investigator would conduct effec-tive management immediately following anesthesiologistrsquosorder

Data related to patientsrsquo age weight height history ofprevious operation ASA class and wound pain score werecollected Itching is defined as the sensation that provokesdesire to scratch the skin over the whole body Nausea isdefined as the sensation of having an urge to vomit andvomiting was defined by the number of episodes of retchingwith orwithout expulsion of fluids from the stomachUrinaryretention is defined as patients could not void by themselvesand urinal catheterization is indicated Dizziness is definedas having a whirling sensation and a tendency to fall andlethargy is defined as a state of sluggishness inactivityand apathy All of the above side effects (including nauseavomiting itching dizziness) were scored on a severity scaleas the following severe = the number of episodes gt 3and medical treatment is indicated mild = the number ofepisodes 3 and medical treatment is not indicated andnone as the number of episodes = 0 The incidence of theabove side effects is defined as the number of episodestaking place during the observation period Patients whohad severe nausea or vomiting or dizziness were treatedwith prochlorperazine 5mg patients with severe itchingweretreated with diphenhydramine HCL 4mg

23 Laboratory Analysis Genomic DNA was extractedfrom 3 mL of peripheral blood cell samples with a PuregeneDNA Isolation Kit (Gentra Systems Minneapolis MNUSA) according to the manufacturerrsquos instructionsReal-time PCR and data analysis were performed ina LightCycler 480 Real-Time PCR System and withLightCycler 480 software using LightCycler FastStart DNAMaster HybProbe Kit The reactions in a final volumeof 10120583L consisted of 025 120583M concentrations of eachprimer (forward 51015840-GTAGAGGGCCATGATCGTGAT-31015840and reverse 51015840-GCTTGGAACCCGAAAAGTCT-31015840)025 120583M concentrations of each probe (forward 51015840-CCCGGTTCCTGGGTCAACTTGTCC-31015840 and reverse51015840-CTTAGATGGCAACCTGTCCGACC-31015840) 1 120583L of FastStart DNA master hybridization probe reaction mixture(Roche) 5mM MgCl

2 and 1 120583L of genomic DNA Pipet

10 120583L PCR products into each well of the LightCycler 480(Roche Applied Science) Multiwell Plate Load the multiwall


Melting peaks

0082

0072

0062

0052

0042

0032

0022

0012

0002

minus0008

minus0018

42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74Temperature (C)

minus(ddT

)fl

uor

esce

nce

(48

3ndash64

0) GG

AA

AG

c11

8 G

G

c11

8 A

A

c11

8 A

G




3 Results







NauseaSevere 36 (279) 15 (268) 16 (281) 5 (313)

0987Mild 45 (349) 19 (339) 21 (368) 5 (313)None 48 (372) 22 (393) 20 (351) 6 (375)

VomitingSevere 28 (217) 11 (196) 14 (246) 3 (188)

0910Mild 30 (233) 13 (232) 12 (211) 5 (313)None 71 (550) 32 (571) 31 (544) 8 (500)

ItchingSevere 3 (23) 2 (36) 1 (18) 0 (00)

0976Mild 11 (85) 5 (89) 5 (88) 1 (63)None 115 (891) 49 (875) 51 (895) 15 (938)


0672Mild 51 (395) 20 (357) 22 (386) 9 (563)None 68 (527) 31 (554) 31 (544) 6 (375)



Nausea Yes 81 (628) 34 (607) 37 (649) 10 (625) 0935No 48 (372) 22 (393) 20 (351) 6 (375)

Vomiting Yes 58 (450) 24 (429) 26 (456) 8 (500) 0882No 71 (550) 32 (571) 31 (544) 8 (500)


Itching Yes 14 (109) 7 (125) 6 (105) 1 (63) 0857No 115 (891) 49 (875) 51 (895) 15 (938)

Dizziness Yes 61 (473) 25 (446) 26 (456) 10 (625) 0469No 68 (527) 31 (554) 31 (544) 6 (375)

Lethargy Yes 12 (93) 7 (125) 4 (70) 1 (63) 0579No 117 (907) 49 (875) 53 (930) 15 (938)



4 Discussion







0430AG 231 (190 401)GG 261 (200 356)






0033lowastMild 210 (160 321)None 290 (210 390)



0014lowastMild 206 (155 321)None 295 (200 371)







GenotypeAA 56 (434) 554 (429)

0969AG 57 (442) 583 (452)GG 16 (124) 154 (119)









Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Melting peaks

0082

0072

0062

0052

0042

0032

0022

0012

0002

minus0008

minus0018

42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74Temperature (C)

minus(ddT

)fl

uor

esce

nce

(48

3ndash64

0) GG

AA

AG

c11

8 G

G

c11

8 A

A

c11

8 A

G




3 Results







NauseaSevere 36 (279) 15 (268) 16 (281) 5 (313)

0987Mild 45 (349) 19 (339) 21 (368) 5 (313)None 48 (372) 22 (393) 20 (351) 6 (375)

VomitingSevere 28 (217) 11 (196) 14 (246) 3 (188)

0910Mild 30 (233) 13 (232) 12 (211) 5 (313)None 71 (550) 32 (571) 31 (544) 8 (500)

ItchingSevere 3 (23) 2 (36) 1 (18) 0 (00)

0976Mild 11 (85) 5 (89) 5 (88) 1 (63)None 115 (891) 49 (875) 51 (895) 15 (938)


0672Mild 51 (395) 20 (357) 22 (386) 9 (563)None 68 (527) 31 (554) 31 (544) 6 (375)



Nausea Yes 81 (628) 34 (607) 37 (649) 10 (625) 0935No 48 (372) 22 (393) 20 (351) 6 (375)

Vomiting Yes 58 (450) 24 (429) 26 (456) 8 (500) 0882No 71 (550) 32 (571) 31 (544) 8 (500)


Itching Yes 14 (109) 7 (125) 6 (105) 1 (63) 0857No 115 (891) 49 (875) 51 (895) 15 (938)

Dizziness Yes 61 (473) 25 (446) 26 (456) 10 (625) 0469No 68 (527) 31 (554) 31 (544) 6 (375)

Lethargy Yes 12 (93) 7 (125) 4 (70) 1 (63) 0579No 117 (907) 49 (875) 53 (930) 15 (938)



4 Discussion







0430AG 231 (190 401)GG 261 (200 356)






0033lowastMild 210 (160 321)None 290 (210 390)



0014lowastMild 206 (155 321)None 295 (200 371)







GenotypeAA 56 (434) 554 (429)

0969AG 57 (442) 583 (452)GG 16 (124) 154 (119)









Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















NauseaSevere 36 (279) 15 (268) 16 (281) 5 (313)

0987Mild 45 (349) 19 (339) 21 (368) 5 (313)None 48 (372) 22 (393) 20 (351) 6 (375)

VomitingSevere 28 (217) 11 (196) 14 (246) 3 (188)

0910Mild 30 (233) 13 (232) 12 (211) 5 (313)None 71 (550) 32 (571) 31 (544) 8 (500)

ItchingSevere 3 (23) 2 (36) 1 (18) 0 (00)

0976Mild 11 (85) 5 (89) 5 (88) 1 (63)None 115 (891) 49 (875) 51 (895) 15 (938)


0672Mild 51 (395) 20 (357) 22 (386) 9 (563)None 68 (527) 31 (554) 31 (544) 6 (375)



Nausea Yes 81 (628) 34 (607) 37 (649) 10 (625) 0935No 48 (372) 22 (393) 20 (351) 6 (375)

Vomiting Yes 58 (450) 24 (429) 26 (456) 8 (500) 0882No 71 (550) 32 (571) 31 (544) 8 (500)


Itching Yes 14 (109) 7 (125) 6 (105) 1 (63) 0857No 115 (891) 49 (875) 51 (895) 15 (938)

Dizziness Yes 61 (473) 25 (446) 26 (456) 10 (625) 0469No 68 (527) 31 (554) 31 (544) 6 (375)

Lethargy Yes 12 (93) 7 (125) 4 (70) 1 (63) 0579No 117 (907) 49 (875) 53 (930) 15 (938)



4 Discussion







0430AG 231 (190 401)GG 261 (200 356)






0033lowastMild 210 (160 321)None 290 (210 390)



0014lowastMild 206 (155 321)None 295 (200 371)







GenotypeAA 56 (434) 554 (429)

0969AG 57 (442) 583 (452)GG 16 (124) 154 (119)









Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















0430AG 231 (190 401)GG 261 (200 356)






0033lowastMild 210 (160 321)None 290 (210 390)



0014lowastMild 206 (155 321)None 295 (200 371)







GenotypeAA 56 (434) 554 (429)

0969AG 57 (442) 583 (452)GG 16 (124) 154 (119)









Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















clinical study polymorphism of -opioid receptor gene g...

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