<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01731873</url>
  </required_header>
  <id_info>
    <org_study_id>2010-2268</org_study_id>
    <nct_id>NCT01731873</nct_id>
  </id_info>
  <brief_title>Patient Controlled Analgesia Pharmacogenetic Study</brief_title>
  <official_title>Non-Interventional Pharmacogenetic Study of Patient / Proxy Controlled Analgesia in Children Undergoing Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital Medical Center, Cincinnati</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to identify factors and genes (the nucleic acid&#xD;
      material that determines the makeup of the human body) that may be associated with acute and&#xD;
      chronic post-surgical pain as well as develop pharmacometric models for response to opioids,&#xD;
      like morphine and hydromorphone. While children undergioing different surgeries will be&#xD;
      recruited for acute outcomes, children undergoing spine fusion will be followed for 10-12&#xD;
      months for evaluation of psychological and genomic factors affecting chronic post-surgical&#xD;
      pain, with a goal of identifying genetic and epigenetic risk models for prediction of acute&#xD;
      and chronic post-surgical pain. Although opioids are used every day, some children have bad&#xD;
      reactions from their use, like breathing problems, sedation, etc. The investigators want to&#xD;
      study factors that may be associated with pain sensitivity, opioid requirements after&#xD;
      surgery, their metabolism, efficacy and their side-effects. The investigators expect that the&#xD;
      information obtained in this research study will help to develop effective, safer, and&#xD;
      tailored treatment options in the future.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pain management after surgery is not optimal partly due to great interindividual variability&#xD;
      in pain perception and coping. This also can lead to persistent pain beyond the healing&#xD;
      period and disability. Up to two-thirds of the inter-individual variability result from&#xD;
      genetic variations in pain perception as well as response to the pain medicine. The&#xD;
      investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles&#xD;
      contributing to this variability. Opioids are the mainstay for treatment of postoperative&#xD;
      pain in children. Experience dictates that opioids have narrow therapeutic indices and large&#xD;
      inter-patient variability in response. This leads to serious side effects like respiratory&#xD;
      depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is&#xD;
      evident that there are particular children who are more susceptible to suffering side effects&#xD;
      and having inadequate pain relief from opioids.&#xD;
&#xD;
      It is hypothesized that much of the genetic variability can be explained by gene function&#xD;
      which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins&#xD;
      involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid&#xD;
      receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without&#xD;
      structural changes to the DNA, and c) genes that influence psychological factors.&#xD;
&#xD;
      Identifying genetic and non-genetic predictors for this susceptibility is vital for safe and&#xD;
      effective analgesia in children. This is a critical knowledge gap in medical literature that&#xD;
      significantly impacts pediatric pain management. The investigators' central hypothesis is&#xD;
      that specific genetic polymorphisms in genes involved in pain perception, opioid transport,&#xD;
      and opioid receptor signaling pathways contribute significantly to pain sensitivity, opioid&#xD;
      side-effects, and analgesic efficacy in children.&#xD;
&#xD;
      The choice and dosing of opioids and pain management approaches have thus far been largely&#xD;
      empirical, with a frequent need to switch medications, strategies and alter doses due to&#xD;
      inherent differences in individuals. By this study, the investigators hope to develop&#xD;
      preemptive approaches and drug targets that can be targeted to individual risk and&#xD;
      genomic-psychosocial profiles. The study will help determine the 'right' doses of the 'right'&#xD;
      opioids for optimized and safe postoperative analgesia in children. This will be done by&#xD;
      first building population pharmacokinetic and pharmacodynamic models for opioid&#xD;
      concentration-exposure and then investigating covariates.&#xD;
&#xD;
      Given the unexplored nature of this complex phenomenon, The investigators propose a&#xD;
      comprehensive study to evaluate gene, drug, and surgical interactions, in a large sample of&#xD;
      650 children undergoing different surgeries, requiring patient controlled analgesia with&#xD;
      opioids.&#xD;
&#xD;
      The investigators' long term goal is to develop more effective, safer, and tailored pediatric&#xD;
      opioid analgesia, by contributing to better understanding of the underlying genetic basis for&#xD;
      variations in the sensitivity to pain, pain relief, and development of adverse effects from&#xD;
      the extended use of postoperative intravenous opioids in children.&#xD;
&#xD;
      The data collected will include acute and long-term pain data, opioid doses, incidence of&#xD;
      side-effects of opioids - including respiratory depression, sedation, vomiting, and itching,&#xD;
      and blood samples for genetic and pharmacometric analyses. Data analysis will use advanced&#xD;
      logistic regression techniques to uncover the association between the SNP variants and the&#xD;
      response to specific opioids following various surgeries.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 17, 2012</start_date>
  <completion_date type="Actual">April 30, 2019</completion_date>
  <primary_completion_date type="Actual">April 30, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Post-operative pain</measure>
    <time_frame>48 hours post-operatively</time_frame>
    <description>Post-surgical pain scores at rest and on mobilization, opioid requirements/48 hours</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Chronic post-surgical pain</measure>
    <time_frame>6-12 months after surgery</time_frame>
    <description>Pain scores several months after surgery</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Opioid pharmacometrics</measure>
    <time_frame>24-48 hours postoperatively</time_frame>
    <description>Drug Concentration-Exposure curves</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic post-surgical disability</measure>
    <time_frame>6-12 months after surgery</time_frame>
    <description>Functional disability scores</description>
  </secondary_outcome>
  <enrollment type="Actual">182</enrollment>
  <condition>Pain</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      A database/ repository will be constructed for future research, analysis, and recruitment.&#xD;
      De-identified study participants' genetic information, their responses to pain and pain&#xD;
      medications, and side-effects will be included in a study database. Blood specimens will be&#xD;
      included in the repository for exploring potentially important SNPs and biomarkers. No&#xD;
      patient identifiers will be included in the database, and there will be a confidential&#xD;
      (access limited to investigators only) code or link between the database and other&#xD;
      information about the participant. Repeat timed blood samples will be collected and analyzed&#xD;
      for opioid concentrations and metabolite concentrations (morphine, hydromorphone, fentanyl).&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Children (weighing at least 5 kg, and up to and including 18 year olds) undergoing surgery&#xD;
        requiring postoperative Patient Controlled Analgesia (PCA) or PCA by Proxy with opioids&#xD;
        (P/NCA), shall be eligible for the study, if inclusion/exclusion criteria are met.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria include:&#xD;
&#xD;
          1. Children up to and including the age of 18 years;&#xD;
&#xD;
          2. Children weighing at least 5kg at time of surgery; and&#xD;
&#xD;
          3. Children scheduled for surgery requiring opioids PCA or PCA by proxy for postoperative&#xD;
             pain relief.&#xD;
&#xD;
        Exclusion criteria include:&#xD;
&#xD;
          1. Children with a history of active liver or renal dysfunction (generally indicated by&#xD;
             current abnormal lab results);&#xD;
&#xD;
          2. Patients with severe respiratory problems (indicated by an ASA rating &gt; 4, or&#xD;
             oxygen/CPAP/BiPAP dependence);&#xD;
&#xD;
          3. Children with recent chronic preoperative pain, especially those requiring opioids or&#xD;
             nerve pain medications within the last 6 months prior to surgery;&#xD;
&#xD;
          4. Children who are anticipated to receive ketamine (i.e., injection, infusion, IM) or&#xD;
             dexmedetomidine/sufentanil/lidocaine infusions perioperatively;&#xD;
&#xD;
          5. Children with BMI &gt; 35;&#xD;
&#xD;
          6. Children with certain genetic diseases or chromosomal abnormalities known to affect&#xD;
             pain perception and/or breathing; and&#xD;
&#xD;
          7. Non-English speaking patients.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vidya Chidambaran, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cincinnati Childrens Hospital Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cincinnati Childrens Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Sadhasivam S, Boat A, Mahmoud M. Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children. J Clin Anesth. 2009 Nov;21(7):493-501. doi: 10.1016/j.jclinane.2008.12.017.</citation>
    <PMID>20006257</PMID>
  </reference>
  <reference>
    <citation>Voepel-Lewis T, Marinkovic A, Kostrzewa A, Tait AR, Malviya S. The prevalence of and risk factors for adverse events in children receiving patient-controlled analgesia by proxy or patient-controlled analgesia after surgery. Anesth Analg. 2008 Jul;107(1):70-5. doi: 10.1213/ane.0b013e318172fa9e.</citation>
    <PMID>18635469</PMID>
  </reference>
  <reference>
    <citation>Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative titration of intravenous morphine. Eur J Anaesthesiol. 2001 Mar;18(3):159-65. doi: 10.1046/j.0265-0215.2000.00796.x.</citation>
    <PMID>11298174</PMID>
  </reference>
  <reference>
    <citation>Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU, Du Bois R, Riley J. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5(5):324-36. doi: 10.1038/sj.tpj.6500327.</citation>
    <PMID>16103897</PMID>
  </reference>
  <reference>
    <citation>Ikeda K, Ide S, Han W, Hayashida M, Uhl GR, Sora I. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci. 2005 Jun;26(6):311-7. doi: 10.1016/j.tips.2005.04.001.</citation>
    <PMID>15925706</PMID>
  </reference>
  <reference>
    <citation>White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology. 2010 Jan;112(1):220-5. doi: 10.1097/ALN.0b013e3181c6316e. No abstract available.</citation>
    <PMID>20010418</PMID>
  </reference>
  <reference>
    <citation>Silverstein JH, Rieders MF, McMullin M, Schulman S, Zahl K. An analysis of the duration of fentanyl and its metabolites in urine and saliva. Anesth Analg. 1993 Mar;76(3):618-21. doi: 10.1213/00000539-199303000-00030.</citation>
    <PMID>8452277</PMID>
  </reference>
  <reference>
    <citation>Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos. 1996 Sep;24(9):932-9.</citation>
    <PMID>8886601</PMID>
  </reference>
  <reference>
    <citation>Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10.</citation>
    <PMID>18695978</PMID>
  </reference>
  <reference>
    <citation>Zhang W, Chang YZ, Kan QC, Zhang LR, Li ZS, Lu H, Wang ZY, Chu QJ, Zhang J. CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol. 2010 Jan;66(1):61-6. doi: 10.1007/s00228-009-0726-4. Epub 2009 Sep 26.</citation>
    <PMID>19784640</PMID>
  </reference>
  <reference>
    <citation>D'Arcy Y. One opioid does not fit all. Nurse Pract. 2007 Nov;32(11):7-8. doi: 10.1097/01.NPR.0000298262.47655.14. No abstract available.</citation>
    <PMID>18075450</PMID>
  </reference>
  <reference>
    <citation>Hirota T, Ieiri I, Takane H, Sano H, Kawamoto K, Aono H, Yamasaki A, Takeuchi H, Masada M, Shimizu E, Higuchi S, Otsubo K. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos. 2003 May;31(5):677-80. doi: 10.1124/dmd.31.5.677.</citation>
    <PMID>12695358</PMID>
  </reference>
  <reference>
    <citation>Sadhasivam S, Cohen LL, Szabova A, Varughese A, Kurth CD, Willging P, Wang Y, Nick TG, Gunter J. Real-time assessment of perioperative behaviors and prediction of perioperative outcomes. Anesth Analg. 2009 Mar;108(3):822-6. doi: 10.1213/ane.0b013e318195c115.</citation>
    <PMID>19224789</PMID>
  </reference>
  <reference>
    <citation>Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther. 2003 Jun;73(6):566-74. doi: 10.1016/S0009-9236(03)00053-5.</citation>
    <PMID>12811366</PMID>
  </reference>
  <reference>
    <citation>Takeda S, Ishii Y, Iwanaga M, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H. Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4. Mol Pharmacol. 2005 Mar;67(3):665-72. doi: 10.1124/mol.104.007641. Epub 2004 Dec 20.</citation>
    <PMID>15611481</PMID>
  </reference>
  <reference>
    <citation>Beaulieu P, Cyrenne L, Mathews S, Villeneuve E, Vischoff D. Patient-controlled analgesia after spinal fusion for idiopathic scoliosis. Int Orthop. 1996;20(5):295-9. doi: 10.1007/s002640050081.</citation>
    <PMID>8930721</PMID>
  </reference>
  <reference>
    <citation>Duguay Y, Baar C, Skorpen F, Guillemette C. A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther. 2004 Mar;75(3):223-33. doi: 10.1016/j.clpt.2003.10.006.</citation>
    <PMID>15001974</PMID>
  </reference>
  <reference>
    <citation>Benetton SA, Borges VM, Chang TK, McErlane KM. Role of individual human cytochrome P450 enzymes in the in vitro metabolism of hydromorphone. Xenobiotica. 2004 Apr;34(4):335-44. doi: 10.1080/00498250310001657559.</citation>
    <PMID>15268978</PMID>
  </reference>
  <reference>
    <citation>Hanna MH, Elliott KM, Fung M. Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery. Anesthesiology. 2005 Apr;102(4):815-21. doi: 10.1097/00000542-200504000-00018.</citation>
    <PMID>15791112</PMID>
  </reference>
  <reference>
    <citation>Smith HS. Opioid metabolism. Mayo Clin Proc. 2009 Jul;84(7):613-24. doi: 10.1016/S0025-6196(11)60750-7.</citation>
    <PMID>19567715</PMID>
  </reference>
  <reference>
    <citation>Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994 Jul;270(1):414-23.</citation>
    <PMID>8035341</PMID>
  </reference>
  <reference>
    <citation>Dahan A, Aarts L, Smith TW. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology. 2010 Jan;112(1):226-38. doi: 10.1097/ALN.0b013e3181c38c25.</citation>
    <PMID>20010421</PMID>
  </reference>
  <reference>
    <citation>Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997 May-Jun;23(3):293-7.</citation>
    <PMID>9220806</PMID>
  </reference>
  <reference>
    <citation>von Baeyer CL, Spagrud LJ, McCormick JC, Choo E, Neville K, Connelly MA. Three new datasets supporting use of the Numerical Rating Scale (NRS-11) for children's self-reports of pain intensity. Pain. 2009 Jun;143(3):223-227. doi: 10.1016/j.pain.2009.03.002. Epub 2009 Apr 8.</citation>
    <PMID>19359097</PMID>
  </reference>
  <reference>
    <citation>Duedahl TH, Hansen EH. A qualitative systematic review of morphine treatment in children with postoperative pain. Paediatr Anaesth. 2007 Aug;17(8):756-74. doi: 10.1111/j.1460-9592.2007.02213.x.</citation>
    <PMID>17596221</PMID>
  </reference>
  <reference>
    <citation>Bulloch B, Tenenbein M. Validation of 2 pain scales for use in the pediatric emergency department. Pediatrics. 2002 Sep;110(3):e33. doi: 10.1542/peds.110.3.e33.</citation>
    <PMID>12205283</PMID>
  </reference>
  <reference>
    <citation>Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974 Jun 22;2(5920):656-9. doi: 10.1136/bmj.2.5920.656.</citation>
    <PMID>4835444</PMID>
  </reference>
  <reference>
    <citation>Ramsay MA. Anesthesia and pain management at Baylor University Medical Center. Proc (Bayl Univ Med Cent). 2000 Apr;13(2):151-65. doi: 10.1080/08998280.2000.11927660. No abstract available.</citation>
    <PMID>16389370</PMID>
  </reference>
  <reference>
    <citation>Paqueron X, Lumbroso A, Mergoni P, Aubrun F, Langeron O, Coriat P, Riou B. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? Br J Anaesth. 2002 Nov;89(5):697-701.</citation>
    <PMID>12393765</PMID>
  </reference>
  <reference>
    <citation>Gramke HF, de Rijke JM, van Kleef M, Raps F, Kessels AG, Peters ML, Sommer M, Marcus MA. The prevalence of postoperative pain in a cross-sectional group of patients after day-case surgery in a university hospital. Clin J Pain. 2007 Jul-Aug;23(6):543-8. doi: 10.1097/AJP.0b013e318074c970.</citation>
    <PMID>17575496</PMID>
  </reference>
  <reference>
    <citation>Sommer M, de Rijke JM, van Kleef M, Kessels AG, Peters ML, Geurts JW, Gramke HF, Marcus MA. The prevalence of postoperative pain in a sample of 1490 surgical inpatients. Eur J Anaesthesiol. 2008 Apr;25(4):267-74. doi: 10.1017/S0265021507003031. Epub 2007 Dec 6.</citation>
    <PMID>18053314</PMID>
  </reference>
  <reference>
    <citation>Fletcher D, Fermanian C, Mardaye A, Aegerter P; Pain and regional anesthesia committee of the French Anesthesia and Intensive Care Society (SFAR). A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges. Pain. 2008 Jul 15;137(2):441-451. doi: 10.1016/j.pain.2008.02.026. Epub 2008 Apr 15.</citation>
    <PMID>18417292</PMID>
  </reference>
  <reference>
    <citation>Brennan F, Carr DB, Cousins M. Pain management: a fundamental human right. Anesth Analg. 2007 Jul;105(1):205-21. doi: 10.1213/01.ane.0000268145.52345.55.</citation>
    <PMID>17578977</PMID>
  </reference>
  <reference>
    <citation>Joshi GP, Kehlet H, Rawal N; PROSPECT Working Group. Evidence-based guidelines for postoperative pain management. Reg Anesth Pain Med. 2007 Mar-Apr;32(2):173. doi: 10.1016/j.rapm.2006.11.002. No abstract available.</citation>
    <PMID>17350537</PMID>
  </reference>
  <reference>
    <citation>Kain ZN, Mayes LC, Caldwell-Andrews AA, Karas DE, McClain BC. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery. Pediatrics. 2006 Aug;118(2):651-8. doi: 10.1542/peds.2005-2920.</citation>
    <PMID>16882820</PMID>
  </reference>
  <reference>
    <citation>Bringuier S, Dadure C, Raux O, Dubois A, Picot MC, Capdevila X. The perioperative validity of the visual analog anxiety scale in children: a discriminant and useful instrument in routine clinical practice to optimize postoperative pain management. Anesth Analg. 2009 Sep;109(3):737-44. doi: 10.1213/ane.0b013e3181af00e4.</citation>
    <PMID>19690240</PMID>
  </reference>
  <reference>
    <citation>Chen E, Zeltzer LK, Craske MG, Katz ER. Alteration of memory in the reduction of children's distress during repeated aversive medical procedures. J Consult Clin Psychol. 1999 Aug;67(4):481-90. doi: 10.1037//0022-006x.67.4.481.</citation>
    <PMID>10450618</PMID>
  </reference>
  <reference>
    <citation>D'Arcy Y. Eyeing capnography to improve PCA safety. Nursing. 2007 Sep;37(9):18-9. doi: 10.1097/01.NURSE.0000287701.56255.80. No abstract available.</citation>
    <PMID>17728629</PMID>
  </reference>
  <reference>
    <citation>Maddox RR, Williams CK, Fields M. Respiratory monitoring in patient-controlled analgesia. Am J Health Syst Pharm. 2004 Dec 15;61(24):2628, 2635. doi: 10.1093/ajhp/61.24.2628. No abstract available.</citation>
    <PMID>15646697</PMID>
  </reference>
  <reference>
    <citation>Whitlock MC. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J Evol Biol. 2005 Sep;18(5):1368-73. doi: 10.1111/j.1420-9101.2005.00917.x.</citation>
    <PMID>16135132</PMID>
  </reference>
  <reference>
    <citation>Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med. 2002;34(2):88-95. doi: 10.1080/07853890252953473.</citation>
    <PMID>12108579</PMID>
  </reference>
  <reference>
    <citation>Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9. doi: 10.1016/s0895-4356(96)00236-3.</citation>
    <PMID>8970487</PMID>
  </reference>
  <reference>
    <citation>Moons KG, Donders AR, Steyerberg EW, Harrell FE. Penalized maximum likelihood estimation to directly adjust diagnostic and prognostic prediction models for overoptimism: a clinical example. J Clin Epidemiol. 2004 Dec;57(12):1262-70. doi: 10.1016/j.jclinepi.2004.01.020.</citation>
    <PMID>15617952</PMID>
  </reference>
  <reference>
    <citation>Nelson KL, Yaster M, Kost-Byerly S, Monitto CL. A national survey of American Pediatric Anesthesiologists: patient-controlled analgesia and other intravenous opioid therapies in pediatric acute pain management. Anesth Analg. 2010 Mar 1;110(3):754-60. doi: 10.1213/ANE.0b013e3181ca749c.</citation>
    <PMID>20185654</PMID>
  </reference>
  <reference>
    <citation>Benhamou D, Viel E, Berti M, Brodner G, De Andres J, Draisci G, Moreno-Azcoita M, Neugebauer EA, Schwenk W, Torres LM. [PATHOS study on postoperative pain management in Europe: French data]. Ann Fr Anesth Reanim. 2008 Sep;27(9):664-78. doi: 10.1016/j.annfar.2008.07.092. Epub 2008 Sep 6. French.</citation>
    <PMID>18774676</PMID>
  </reference>
  <reference>
    <citation>Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin North Am. 2005 Mar;23(1):21-36. doi: 10.1016/j.atc.2004.11.013.</citation>
    <PMID>15763409</PMID>
  </reference>
  <reference>
    <citation>Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology. 2010 Jun;112(6):1494-502. doi: 10.1097/ALN.0b013e3181dcd5a0.</citation>
    <PMID>20460988</PMID>
  </reference>
  <reference>
    <citation>Raja SN, Jensen TS. Predicting postoperative pain based on preoperative pain perception: are we doing better than the weatherman? Anesthesiology. 2010 Jun;112(6):1311-2. doi: 10.1097/ALN.0b013e3181dcd5cc. No abstract available.</citation>
    <PMID>20502114</PMID>
  </reference>
  <reference>
    <citation>Kim H, Ramsay E, Lee H, Wahl S, Dionne RA. Genome-wide association study of acute post-surgical pain in humans. Pharmacogenomics. 2009 Feb;10(2):171-9. doi: 10.2217/14622416.10.2.171.</citation>
    <PMID>19207018</PMID>
  </reference>
  <reference>
    <citation>Skorpen F, Laugsand EA, Klepstad P, Kaasa S. Variable response to opioid treatment: any genetic predictors within sight? Palliat Med. 2008 Jun;22(4):310-27. doi: 10.1177/0269216308089302.</citation>
    <PMID>18541635</PMID>
  </reference>
  <reference>
    <citation>Reyes-Gibby CC, Shete S, Rakvag T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007 Jul;130(1-2):25-30. doi: 10.1016/j.pain.2006.10.023. Epub 2006 Dec 6.</citation>
    <PMID>17156920</PMID>
  </reference>
  <reference>
    <citation>Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66. doi: 10.1038/sj.clpt.6100385. Epub 2007 Sep 26.</citation>
    <PMID>17898703</PMID>
  </reference>
  <reference>
    <citation>Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010 Jul 22;363(4):301-4. doi: 10.1056/NEJMp1006304. Epub 2010 Jun 15. No abstract available. Erratum In: N Engl J Med. 2010 Sep 9;363(11):1092.</citation>
    <PMID>20551152</PMID>
  </reference>
  <reference>
    <citation>Verghese ST, Hannallah RS. Postoperative pain management in children. Anesthesiol Clin North Am. 2005 Mar;23(1):163-84. doi: 10.1016/j.atc.2004.11.008.</citation>
    <PMID>15763417</PMID>
  </reference>
  <reference>
    <citation>Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain. 2001 Feb 15;90(3):261-269. doi: 10.1016/S0304-3959(00)00406-1.</citation>
    <PMID>11207398</PMID>
  </reference>
  <reference>
    <citation>Keogh E, Herdenfeldt M. Gender, coping and the perception of pain. Pain. 2002 Jun;97(3):195-201. doi: 10.1016/S0304-3959(01)00427-4.</citation>
    <PMID>12044616</PMID>
  </reference>
  <reference>
    <citation>Soetanto AL, Chung JW, Wong TK. Are there gender differences in pain perception? J Neurosci Nurs. 2006 Jun;38(3):172-6. doi: 10.1097/01376517-200606000-00006.</citation>
    <PMID>16817669</PMID>
  </reference>
  <reference>
    <citation>Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A, Lao-Villadoniga JI, Garcia-Fructuoso F, Ramos-Kuri M, Hernandez F, Springall R, Bojalil R, Vallejo M, Martinez-Lavin M. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther. 2007;9(5):R110. doi: 10.1186/ar2316.</citation>
    <PMID>17961261</PMID>
  </reference>
  <reference>
    <citation>Tan EC, Lim Y, Teo YY, Goh R, Law HY, Sia AT. Ethnic differences in pain perception and patient-controlled analgesia usage for postoperative pain. J Pain. 2008 Sep;9(9):849-55. doi: 10.1016/j.jpain.2008.04.004. Epub 2008 Jun 12.</citation>
    <PMID>18550441</PMID>
  </reference>
  <reference>
    <citation>Rahim-Williams FB, Riley JL 3rd, Herrera D, Campbell CM, Hastie BA, Fillingim RB. Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics. Pain. 2007 May;129(1-2):177-84. doi: 10.1016/j.pain.2006.12.016. Epub 2007 Feb 12.</citation>
    <PMID>17296267</PMID>
  </reference>
  <reference>
    <citation>Kain ZN, Sevarino FB, Rinder C, Pincus S, Alexander GM, Ivy M, Heninger G. Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology. 2001 Mar;94(3):415-22. doi: 10.1097/00000542-200103000-00009.</citation>
    <PMID>11374599</PMID>
  </reference>
  <reference>
    <citation>Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain. 2005 Sep-Oct;21(5):439-45. doi: 10.1097/01.ajp.0000135236.12705.2d.</citation>
    <PMID>16093750</PMID>
  </reference>
  <reference>
    <citation>Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. doi: 10.1016/S0140-6736(06)68700-X.</citation>
    <PMID>16698416</PMID>
  </reference>
  <reference>
    <citation>Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000 Oct;93(4):1123-33. doi: 10.1097/00000542-200010000-00038. No abstract available.</citation>
    <PMID>11020770</PMID>
  </reference>
  <reference>
    <citation>Woodhouse A, Ward EM, Mather LE. Intra-subject variability in post-operative patient-controlled analgesia (PCA): is the patient equally satisfied with morphine, pethidine and fentanyl? Pain. 1999 Apr;80(3):545-553. doi: 10.1016/S0304-3959(98)00247-4.</citation>
    <PMID>10342416</PMID>
  </reference>
  <reference>
    <citation>Grass JA. Patient-controlled analgesia. Anesth Analg. 2005 Nov;101(5 Suppl):S44-S61. doi: 10.1213/01.ANE.0000177102.11682.20.</citation>
    <PMID>16334492</PMID>
  </reference>
  <reference>
    <citation>Anderson BJ, Palmer GM. Recent developments in the pharmacological management of pain in children. Curr Opin Anaesthesiol. 2006 Jun;19(3):285-92. doi: 10.1097/01.aco.0000192802.33291.6f.</citation>
    <PMID>16735812</PMID>
  </reference>
  <reference>
    <citation>Sinatra RS, Lodge K, Sibert K, Chung KS, Chung JH, Parker A Jr, Harrison DM. A comparison of morphine, meperidine, and oxymorphone as utilized in patient-controlled analgesia following cesarean delivery. Anesthesiology. 1989 Apr;70(4):585-90. doi: 10.1097/00000542-198904000-00005.</citation>
    <PMID>2467588</PMID>
  </reference>
  <reference>
    <citation>Rakvag TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005 Jul;116(1-2):73-8. doi: 10.1016/j.pain.2005.03.032.</citation>
    <PMID>15927391</PMID>
  </reference>
  <reference>
    <citation>Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain. 2007 Apr;128(3):199-208. doi: 10.1016/j.pain.2006.09.022. Epub 2006 Nov 7.</citation>
    <PMID>17084978</PMID>
  </reference>
  <reference>
    <citation>Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. doi: 10.1093/hmg/ddi013. Epub 2004 Nov 10.</citation>
    <PMID>15537663</PMID>
  </reference>
  <reference>
    <citation>Coulbault L, Beaussier M, Verstuyft C, Weickmans H, Dubert L, Tregouet D, Descot C, Parc Y, Lienhart A, Jaillon P, Becquemont L. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther. 2006 Apr;79(4):316-24. doi: 10.1016/j.clpt.2006.01.007.</citation>
    <PMID>16580900</PMID>
  </reference>
  <reference>
    <citation>Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther. 2006 Dec;80(6):682-90. doi: 10.1016/j.clpt.2006.09.011.</citation>
    <PMID>17178268</PMID>
  </reference>
  <reference>
    <citation>Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997 Jan;25(1):1-4.</citation>
    <PMID>9010622</PMID>
  </reference>
  <reference>
    <citation>Darbari DS, van Schaik RH, Capparelli EV, Rana S, McCarter R, van den Anker J. UGT2B7 promoter variant -840G&gt;A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am J Hematol. 2008 Mar;83(3):200-2. doi: 10.1002/ajh.21051.</citation>
    <PMID>17724700</PMID>
  </reference>
  <reference>
    <citation>Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003 Feb 21;299(5610):1240-3. doi: 10.1126/science.1078546.</citation>
    <PMID>12595695</PMID>
  </reference>
  <reference>
    <citation>Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011 Mar;21(3):152-61. doi: 10.1097/FPC.0b013e3283385a1c. No abstract available.</citation>
    <PMID>20216335</PMID>
  </reference>
  <reference>
    <citation>Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH. Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther. 2007 Apr;81(4):539-46. doi: 10.1038/sj.clpt.6100046. Epub 2006 Dec 27.</citation>
    <PMID>17192767</PMID>
  </reference>
  <reference>
    <citation>Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001 Apr;11(3):217-21. doi: 10.1097/00008571-200104000-00005.</citation>
    <PMID>11337937</PMID>
  </reference>
  <reference>
    <citation>Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001 Aug;70(2):189-99. doi: 10.1067/mcp.2001.117412.</citation>
    <PMID>11503014</PMID>
  </reference>
  <reference>
    <citation>Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, Goldman D, Maixner W. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006 Dec 5;125(3):216-224. doi: 10.1016/j.pain.2006.05.024. Epub 2006 Jul 11.</citation>
    <PMID>16837133</PMID>
  </reference>
  <reference>
    <citation>Weinger M. Dangers of postoperative opioids: APSF Workshop and White Paper address prevention of postoperative respiratory complications. APSF Newsletter 21:61-7, 2006</citation>
  </reference>
  <reference>
    <citation>Hutchison R. A Comparison of a Fentanyl, morphine and hydromorphone Patient-controlled intravenous delivery for acute postoperative analgesia: A multicenter study of opioid-induced adverse reactions. Hospital Pharmacy 41:659-63, 2006.</citation>
  </reference>
  <reference>
    <citation>Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997 Sep;25(9):1072-80.</citation>
    <PMID>9311623</PMID>
  </reference>
  <reference>
    <citation>Radovanovic D. The use of transdermal fentanyl in the treatment of cancer pain. Arch Oncol 10:263-66, 2002.</citation>
  </reference>
  <reference>
    <citation>Baselt RC. Disposition of Toxic drugs and Chemicals in Man. 430-33, 2002.</citation>
  </reference>
  <reference>
    <citation>Zheng M. Isolation, identification and synthesis of hydromorphone metabolites: analysis and antinociceptive activities in comparison to morphine. 1997.</citation>
  </reference>
  <reference>
    <citation>Overdyk M. PCA presents serious risks. APSF Newsletter 20, 2005.</citation>
  </reference>
  <reference>
    <citation>D'Argenio DZ, Schumitzky A, Wang X. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.</citation>
  </reference>
  <reference>
    <citation>D'Argenio D. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.</citation>
  </reference>
  <reference>
    <citation>Park MY, Hastie T. Penalized logistic regression for detecting gene interactions. Biostatistics. 2008 Jan;9(1):30-50. doi: 10.1093/biostatistics/kxm010. Epub 2007 Apr 11.</citation>
    <PMID>17429103</PMID>
  </reference>
  <reference>
    <citation>Van Slyke DA, Walker LS. Mothers' responses to children's pain. Clin J Pain. 2006 May;22(4):387-91. doi: 10.1097/01.ajp.0000205257.80044.01.</citation>
    <PMID>16691093</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>November 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <last_update_submitted>September 2, 2020</last_update_submitted>
  <last_update_submitted_qc>September 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>postoperative pain</keyword>
  <keyword>children</keyword>
  <keyword>pharmacogenetic</keyword>
  <keyword>opioid adverse effects</keyword>
  <keyword>respiratory depression</keyword>
  <keyword>analgesia</keyword>
  <keyword>genetic polymorphisms</keyword>
  <keyword>chronic postsurgical pain</keyword>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified data may be shared with additional internal or external data warehouses/investigators. These include but are not limited to the i2b2-Research Data Warehouse protocol at CCHMC (IRB 2008-0834) for the purpose of linking this data to a de-identified copy of the participant's electronic medical record via an i2b2 database. The resulting de-identified i2b2 database will not be part of this research; but will be used to explore secondary phenotypes in future research studies and documented in the NIH-db-GaP (Database of Genotypes and Phenotypes).</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01731873
org study id: 2010-2268
nct id: NCT01731873
lead sponsor: 
has dmc: No
The purpose of this research study is to identify factors and genes (the nucleic acid
      material that determines the makeup of the human body) that may be associated with acute and
      chronic post-surgical pain as well as develop pharmacometric models for response to opioids,
      like morphine and hydromorphone. While children undergioing different surgeries will be
      recruited for acute outcomes, children undergoing spine fusion will be followed for 10-12
      months for evaluation of psychological and genomic factors affecting chronic post-surgical
      pain, with a goal of identifying genetic and epigenetic risk models for prediction of acute
      and chronic post-surgical pain. Although opioids are used every day, some children have bad
      reactions from their use, like breathing problems, sedation, etc. The investigators want to
      study factors that may be associated with pain sensitivity, opioid requirements after
      surgery, their metabolism, efficacy and their side-effects. The investigators expect that the
      information obtained in this research study will help to develop effective, safer, and
      tailored treatment options in the future.
Pain management after surgery is not optimal partly due to great interindividual variability
      in pain perception and coping. This also can lead to persistent pain beyond the healing
      period and disability. Up to two-thirds of the inter-individual variability result from
      genetic variations in pain perception as well as response to the pain medicine. The
      investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles
      contributing to this variability. Opioids are the mainstay for treatment of postoperative
      pain in children. Experience dictates that opioids have narrow therapeutic indices and large
      inter-patient variability in response. This leads to serious side effects like respiratory
      depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is
      evident that there are particular children who are more susceptible to suffering side effects
      and having inadequate pain relief from opioids.

      It is hypothesized that much of the genetic variability can be explained by gene function
      which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins
      involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid
      receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without
      structural changes to the DNA, and c) genes that influence psychological factors.

      Identifying genetic and non-genetic predictors for this susceptibility is vital for safe and
      effective analgesia in children. This is a critical knowledge gap in medical literature that
      significantly impacts pediatric pain management. The investigators' central hypothesis is
      that specific genetic polymorphisms in genes involved in pain perception, opioid transport,
      and opioid receptor signaling pathways contribute significantly to pain sensitivity, opioid
      side-effects, and analgesic efficacy in children.

      The choice and dosing of opioids and pain management approaches have thus far been largely
      empirical, with a frequent need to switch medications, strategies and alter doses due to
      inherent differences in individuals. By this study, the investigators hope to develop
      preemptive approaches and drug targets that can be targeted to individual risk and
      genomic-psychosocial profiles. The study will help determine the 'right' doses of the 'right'
      opioids for optimized and safe postoperative analgesia in children. This will be done by
      first building population pharmacokinetic and pharmacodynamic models for opioid
      concentration-exposure and then investigating covariates.

      Given the unexplored nature of this complex phenomenon, The investigators propose a
      comprehensive study to evaluate gene, drug, and surgical interactions, in a large sample of
      650 children undergoing different surgeries, requiring patient controlled analgesia with
      opioids.

      The investigators' long term goal is to develop more effective, safer, and tailored pediatric
      opioid analgesia, by contributing to better understanding of the underlying genetic basis for
      variations in the sensitivity to pain, pain relief, and development of adverse effects from
      the extended use of postoperative intravenous opioids in children.

      The data collected will include acute and long-term pain data, opioid doses, incidence of
      side-effects of opioids - including respiratory depression, sedation, vomiting, and itching,
      and blood samples for genetic and pharmacometric analyses. Data analysis will use advanced
      logistic regression techniques to uncover the association between the SNP variants and the
      response to specific opioids following various surgeries.
observational model: Cohort
time perspective: Prospective
measure: Post-operative pain
time frame: 48 hours post-operatively
description: Post-surgical pain scores at rest and on mobilization, opioid requirements/48 hours
measure: Chronic post-surgical pain
time frame: 6-12 months after surgery
description: Pain scores several months after surgery
measure: Opioid pharmacometrics
time frame: 24-48 hours postoperatively
description: Drug Concentration-Exposure curves
measure: Chronic post-surgical disability
time frame: 6-12 months after surgery
description: Functional disability scores
A database/ repository will be constructed for future research, analysis, and recruitment.
      De-identified study participants' genetic information, their responses to pain and pain
      medications, and side-effects will be included in a study database. Blood specimens will be
      included in the repository for exploring potentially important SNPs and biomarkers. No
      patient identifiers will be included in the database, and there will be a confidential
      (access limited to investigators only) code or link between the database and other
      information about the participant. Repeat timed blood samples will be collected and analyzed
      for opioid concentrations and metabolite concentrations (morphine, hydromorphone, fentanyl).
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: Vidya Chidambaran, MD
role: Principal Investigator
affiliation: Cincinnati Childrens Hospital Medical Center
facility: 
country: United States
citation: Sadhasivam S, Boat A, Mahmoud M. Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children. J Clin Anesth. 2009 Nov;21(7):493-501. doi: 10.1016/j.jclinane.2008.12.017.
PMID: 20006257
citation: Voepel-Lewis T, Marinkovic A, Kostrzewa A, Tait AR, Malviya S. The prevalence of and risk factors for adverse events in children receiving patient-controlled analgesia by proxy or patient-controlled analgesia after surgery. Anesth Analg. 2008 Jul;107(1):70-5. doi: 10.1213/ane.0b013e318172fa9e.
PMID: 18635469
citation: Aubrun F, Monsel S, Langeron O, Coriat P, Riou B. Postoperative titration of intravenous morphine. Eur J Anaesthesiol. 2001 Mar;18(3):159-65. doi: 10.1046/j.0265-0215.2000.00796.x.
PMID: 11298174
citation: Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU, Du Bois R, Riley J. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5(5):324-36. doi: 10.1038/sj.tpj.6500327.
PMID: 16103897
citation: Ikeda K, Ide S, Han W, Hayashida M, Uhl GR, Sora I. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci. 2005 Jun;26(6):311-7. doi: 10.1016/j.tips.2005.04.001.
PMID: 15925706
citation: White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology. 2010 Jan;112(1):220-5. doi: 10.1097/ALN.0b013e3181c6316e. No abstract available.
PMID: 20010418
citation: Silverstein JH, Rieders MF, McMullin M, Schulman S, Zahl K. An analysis of the duration of fentanyl and its metabolites in urine and saliva. Anesth Analg. 1993 Mar;76(3):618-21. doi: 10.1213/00000539-199303000-00030.
PMID: 8452277
citation: Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos. 1996 Sep;24(9):932-9.
PMID: 8886601
citation: Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10.
PMID: 18695978
citation: Zhang W, Chang YZ, Kan QC, Zhang LR, Li ZS, Lu H, Wang ZY, Chu QJ, Zhang J. CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol. 2010 Jan;66(1):61-6. doi: 10.1007/s00228-009-0726-4. Epub 2009 Sep 26.
PMID: 19784640
citation: D'Arcy Y. One opioid does not fit all. Nurse Pract. 2007 Nov;32(11):7-8. doi: 10.1097/01.NPR.0000298262.47655.14. No abstract available.
PMID: 18075450
citation: Hirota T, Ieiri I, Takane H, Sano H, Kawamoto K, Aono H, Yamasaki A, Takeuchi H, Masada M, Shimizu E, Higuchi S, Otsubo K. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos. 2003 May;31(5):677-80. doi: 10.1124/dmd.31.5.677.
PMID: 12695358
citation: Sadhasivam S, Cohen LL, Szabova A, Varughese A, Kurth CD, Willging P, Wang Y, Nick TG, Gunter J. Real-time assessment of perioperative behaviors and prediction of perioperative outcomes. Anesth Analg. 2009 Mar;108(3):822-6. doi: 10.1213/ane.0b013e318195c115.
PMID: 19224789
citation: Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther. 2003 Jun;73(6):566-74. doi: 10.1016/S0009-9236(03)00053-5.
PMID: 12811366
citation: Takeda S, Ishii Y, Iwanaga M, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H. Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4. Mol Pharmacol. 2005 Mar;67(3):665-72. doi: 10.1124/mol.104.007641. Epub 2004 Dec 20.
PMID: 15611481
citation: Beaulieu P, Cyrenne L, Mathews S, Villeneuve E, Vischoff D. Patient-controlled analgesia after spinal fusion for idiopathic scoliosis. Int Orthop. 1996;20(5):295-9. doi: 10.1007/s002640050081.
PMID: 8930721
citation: Duguay Y, Baar C, Skorpen F, Guillemette C. A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther. 2004 Mar;75(3):223-33. doi: 10.1016/j.clpt.2003.10.006.
PMID: 15001974
citation: Benetton SA, Borges VM, Chang TK, McErlane KM. Role of individual human cytochrome P450 enzymes in the in vitro metabolism of hydromorphone. Xenobiotica. 2004 Apr;34(4):335-44. doi: 10.1080/00498250310001657559.
PMID: 15268978
citation: Hanna MH, Elliott KM, Fung M. Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery. Anesthesiology. 2005 Apr;102(4):815-21. doi: 10.1097/00000542-200504000-00018.
PMID: 15791112
citation: Smith HS. Opioid metabolism. Mayo Clin Proc. 2009 Jul;84(7):613-24. doi: 10.1016/S0025-6196(11)60750-7.
PMID: 19567715
citation: Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994 Jul;270(1):414-23.
PMID: 8035341
citation: Dahan A, Aarts L, Smith TW. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology. 2010 Jan;112(1):226-38. doi: 10.1097/ALN.0b013e3181c38c25.
PMID: 20010421
citation: Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997 May-Jun;23(3):293-7.
PMID: 9220806
citation: von Baeyer CL, Spagrud LJ, McCormick JC, Choo E, Neville K, Connelly MA. Three new datasets supporting use of the Numerical Rating Scale (NRS-11) for children's self-reports of pain intensity. Pain. 2009 Jun;143(3):223-227. doi: 10.1016/j.pain.2009.03.002. Epub 2009 Apr 8.
PMID: 19359097
citation: Duedahl TH, Hansen EH. A qualitative systematic review of morphine treatment in children with postoperative pain. Paediatr Anaesth. 2007 Aug;17(8):756-74. doi: 10.1111/j.1460-9592.2007.02213.x.
PMID: 17596221
citation: Bulloch B, Tenenbein M. Validation of 2 pain scales for use in the pediatric emergency department. Pediatrics. 2002 Sep;110(3):e33. doi: 10.1542/peds.110.3.e33.
PMID: 12205283
citation: Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974 Jun 22;2(5920):656-9. doi: 10.1136/bmj.2.5920.656.
PMID: 4835444
citation: Ramsay MA. Anesthesia and pain management at Baylor University Medical Center. Proc (Bayl Univ Med Cent). 2000 Apr;13(2):151-65. doi: 10.1080/08998280.2000.11927660. No abstract available.
PMID: 16389370
citation: Paqueron X, Lumbroso A, Mergoni P, Aubrun F, Langeron O, Coriat P, Riou B. Is morphine-induced sedation synonymous with analgesia during intravenous morphine titration? Br J Anaesth. 2002 Nov;89(5):697-701.
PMID: 12393765
citation: Gramke HF, de Rijke JM, van Kleef M, Raps F, Kessels AG, Peters ML, Sommer M, Marcus MA. The prevalence of postoperative pain in a cross-sectional group of patients after day-case surgery in a university hospital. Clin J Pain. 2007 Jul-Aug;23(6):543-8. doi: 10.1097/AJP.0b013e318074c970.
PMID: 17575496
citation: Sommer M, de Rijke JM, van Kleef M, Kessels AG, Peters ML, Geurts JW, Gramke HF, Marcus MA. The prevalence of postoperative pain in a sample of 1490 surgical inpatients. Eur J Anaesthesiol. 2008 Apr;25(4):267-74. doi: 10.1017/S0265021507003031. Epub 2007 Dec 6.
PMID: 18053314
citation: Fletcher D, Fermanian C, Mardaye A, Aegerter P; Pain and regional anesthesia committee of the French Anesthesia and Intensive Care Society (SFAR). A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges. Pain. 2008 Jul 15;137(2):441-451. doi: 10.1016/j.pain.2008.02.026. Epub 2008 Apr 15.
PMID: 18417292
citation: Brennan F, Carr DB, Cousins M. Pain management: a fundamental human right. Anesth Analg. 2007 Jul;105(1):205-21. doi: 10.1213/01.ane.0000268145.52345.55.
PMID: 17578977
citation: Joshi GP, Kehlet H, Rawal N; PROSPECT Working Group. Evidence-based guidelines for postoperative pain management. Reg Anesth Pain Med. 2007 Mar-Apr;32(2):173. doi: 10.1016/j.rapm.2006.11.002. No abstract available.
PMID: 17350537
citation: Kain ZN, Mayes LC, Caldwell-Andrews AA, Karas DE, McClain BC. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery. Pediatrics. 2006 Aug;118(2):651-8. doi: 10.1542/peds.2005-2920.
PMID: 16882820
citation: Bringuier S, Dadure C, Raux O, Dubois A, Picot MC, Capdevila X. The perioperative validity of the visual analog anxiety scale in children: a discriminant and useful instrument in routine clinical practice to optimize postoperative pain management. Anesth Analg. 2009 Sep;109(3):737-44. doi: 10.1213/ane.0b013e3181af00e4.
PMID: 19690240
citation: Chen E, Zeltzer LK, Craske MG, Katz ER. Alteration of memory in the reduction of children's distress during repeated aversive medical procedures. J Consult Clin Psychol. 1999 Aug;67(4):481-90. doi: 10.1037//0022-006x.67.4.481.
PMID: 10450618
citation: D'Arcy Y. Eyeing capnography to improve PCA safety. Nursing. 2007 Sep;37(9):18-9. doi: 10.1097/01.NURSE.0000287701.56255.80. No abstract available.
PMID: 17728629
citation: Maddox RR, Williams CK, Fields M. Respiratory monitoring in patient-controlled analgesia. Am J Health Syst Pharm. 2004 Dec 15;61(24):2628, 2635. doi: 10.1093/ajhp/61.24.2628. No abstract available.
PMID: 15646697
citation: Whitlock MC. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J Evol Biol. 2005 Sep;18(5):1368-73. doi: 10.1111/j.1420-9101.2005.00917.x.
PMID: 16135132
citation: Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med. 2002;34(2):88-95. doi: 10.1080/07853890252953473.
PMID: 12108579
citation: Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9. doi: 10.1016/s0895-4356(96)00236-3.
PMID: 8970487
citation: Moons KG, Donders AR, Steyerberg EW, Harrell FE. Penalized maximum likelihood estimation to directly adjust diagnostic and prognostic prediction models for overoptimism: a clinical example. J Clin Epidemiol. 2004 Dec;57(12):1262-70. doi: 10.1016/j.jclinepi.2004.01.020.
PMID: 15617952
citation: Nelson KL, Yaster M, Kost-Byerly S, Monitto CL. A national survey of American Pediatric Anesthesiologists: patient-controlled analgesia and other intravenous opioid therapies in pediatric acute pain management. Anesth Analg. 2010 Mar 1;110(3):754-60. doi: 10.1213/ANE.0b013e3181ca749c.
PMID: 20185654
citation: Benhamou D, Viel E, Berti M, Brodner G, De Andres J, Draisci G, Moreno-Azcoita M, Neugebauer EA, Schwenk W, Torres LM. [PATHOS study on postoperative pain management in Europe: French data]. Ann Fr Anesth Reanim. 2008 Sep;27(9):664-78. doi: 10.1016/j.annfar.2008.07.092. Epub 2008 Sep 6. French.
PMID: 18774676
citation: Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin North Am. 2005 Mar;23(1):21-36. doi: 10.1016/j.atc.2004.11.013.
PMID: 15763409
citation: Werner MU, Mjobo HN, Nielsen PR, Rudin A. Prediction of postoperative pain: a systematic review of predictive experimental pain studies. Anesthesiology. 2010 Jun;112(6):1494-502. doi: 10.1097/ALN.0b013e3181dcd5a0.
PMID: 20460988
citation: Raja SN, Jensen TS. Predicting postoperative pain based on preoperative pain perception: are we doing better than the weatherman? Anesthesiology. 2010 Jun;112(6):1311-2. doi: 10.1097/ALN.0b013e3181dcd5cc. No abstract available.
PMID: 20502114
citation: Kim H, Ramsay E, Lee H, Wahl S, Dionne RA. Genome-wide association study of acute post-surgical pain in humans. Pharmacogenomics. 2009 Feb;10(2):171-9. doi: 10.2217/14622416.10.2.171.
PMID: 19207018
citation: Skorpen F, Laugsand EA, Klepstad P, Kaasa S. Variable response to opioid treatment: any genetic predictors within sight? Palliat Med. 2008 Jun;22(4):310-27. doi: 10.1177/0269216308089302.
PMID: 18541635
citation: Reyes-Gibby CC, Shete S, Rakvag T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007 Jul;130(1-2):25-30. doi: 10.1016/j.pain.2006.10.023. Epub 2006 Dec 6.
PMID: 17156920
citation: Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66. doi: 10.1038/sj.clpt.6100385. Epub 2007 Sep 26.
PMID: 17898703
citation: Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010 Jul 22;363(4):301-4. doi: 10.1056/NEJMp1006304. Epub 2010 Jun 15. No abstract available. Erratum In: N Engl J Med. 2010 Sep 9;363(11):1092.
PMID: 20551152
citation: Verghese ST, Hannallah RS. Postoperative pain management in children. Anesthesiol Clin North Am. 2005 Mar;23(1):163-84. doi: 10.1016/j.atc.2004.11.008.
PMID: 15763417
citation: Bisgaard T, Klarskov B, Rosenberg J, Kehlet H. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain. 2001 Feb 15;90(3):261-269. doi: 10.1016/S0304-3959(00)00406-1.
PMID: 11207398
citation: Keogh E, Herdenfeldt M. Gender, coping and the perception of pain. Pain. 2002 Jun;97(3):195-201. doi: 10.1016/S0304-3959(01)00427-4.
PMID: 12044616
citation: Soetanto AL, Chung JW, Wong TK. Are there gender differences in pain perception? J Neurosci Nurs. 2006 Jun;38(3):172-6. doi: 10.1097/01376517-200606000-00006.
PMID: 16817669
citation: Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A, Lao-Villadoniga JI, Garcia-Fructuoso F, Ramos-Kuri M, Hernandez F, Springall R, Bojalil R, Vallejo M, Martinez-Lavin M. Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther. 2007;9(5):R110. doi: 10.1186/ar2316.
PMID: 17961261
citation: Tan EC, Lim Y, Teo YY, Goh R, Law HY, Sia AT. Ethnic differences in pain perception and patient-controlled analgesia usage for postoperative pain. J Pain. 2008 Sep;9(9):849-55. doi: 10.1016/j.jpain.2008.04.004. Epub 2008 Jun 12.
PMID: 18550441
citation: Rahim-Williams FB, Riley JL 3rd, Herrera D, Campbell CM, Hastie BA, Fillingim RB. Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics. Pain. 2007 May;129(1-2):177-84. doi: 10.1016/j.pain.2006.12.016. Epub 2007 Feb 12.
PMID: 17296267
citation: Kain ZN, Sevarino FB, Rinder C, Pincus S, Alexander GM, Ivy M, Heninger G. Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology. 2001 Mar;94(3):415-22. doi: 10.1097/00000542-200103000-00009.
PMID: 11374599
citation: Granot M, Ferber SG. The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: a prospective study. Clin J Pain. 2005 Sep-Oct;21(5):439-45. doi: 10.1097/01.ajp.0000135236.12705.2d.
PMID: 16093750
citation: Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. doi: 10.1016/S0140-6736(06)68700-X.
PMID: 16698416
citation: Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000 Oct;93(4):1123-33. doi: 10.1097/00000542-200010000-00038. No abstract available.
PMID: 11020770
citation: Woodhouse A, Ward EM, Mather LE. Intra-subject variability in post-operative patient-controlled analgesia (PCA): is the patient equally satisfied with morphine, pethidine and fentanyl? Pain. 1999 Apr;80(3):545-553. doi: 10.1016/S0304-3959(98)00247-4.
PMID: 10342416
citation: Grass JA. Patient-controlled analgesia. Anesth Analg. 2005 Nov;101(5 Suppl):S44-S61. doi: 10.1213/01.ANE.0000177102.11682.20.
PMID: 16334492
citation: Anderson BJ, Palmer GM. Recent developments in the pharmacological management of pain in children. Curr Opin Anaesthesiol. 2006 Jun;19(3):285-92. doi: 10.1097/01.aco.0000192802.33291.6f.
PMID: 16735812
citation: Sinatra RS, Lodge K, Sibert K, Chung KS, Chung JH, Parker A Jr, Harrison DM. A comparison of morphine, meperidine, and oxymorphone as utilized in patient-controlled analgesia following cesarean delivery. Anesthesiology. 1989 Apr;70(4):585-90. doi: 10.1097/00000542-198904000-00005.
PMID: 2467588
citation: Rakvag TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005 Jul;116(1-2):73-8. doi: 10.1016/j.pain.2005.03.032.
PMID: 15927391
citation: Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain. 2007 Apr;128(3):199-208. doi: 10.1016/j.pain.2006.09.022. Epub 2006 Nov 7.
PMID: 17084978
citation: Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. doi: 10.1093/hmg/ddi013. Epub 2004 Nov 10.
PMID: 15537663
citation: Coulbault L, Beaussier M, Verstuyft C, Weickmans H, Dubert L, Tregouet D, Descot C, Parc Y, Lienhart A, Jaillon P, Becquemont L. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther. 2006 Apr;79(4):316-24. doi: 10.1016/j.clpt.2006.01.007.
PMID: 16580900
citation: Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther. 2006 Dec;80(6):682-90. doi: 10.1016/j.clpt.2006.09.011.
PMID: 17178268
citation: Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997 Jan;25(1):1-4.
PMID: 9010622
citation: Darbari DS, van Schaik RH, Capparelli EV, Rana S, McCarter R, van den Anker J. UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am J Hematol. 2008 Mar;83(3):200-2. doi: 10.1002/ajh.21051.
PMID: 17724700
citation: Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003 Feb 21;299(5610):1240-3. doi: 10.1126/science.1078546.
PMID: 12595695
citation: Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011 Mar;21(3):152-61. doi: 10.1097/FPC.0b013e3283385a1c. No abstract available.
PMID: 20216335
citation: Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH. Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther. 2007 Apr;81(4):539-46. doi: 10.1038/sj.clpt.6100046. Epub 2006 Dec 27.
PMID: 17192767
citation: Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001 Apr;11(3):217-21. doi: 10.1097/00008571-200104000-00005.
PMID: 11337937
citation: Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001 Aug;70(2):189-99. doi: 10.1067/mcp.2001.117412.
PMID: 11503014
citation: Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, Goldman D, Maixner W. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006 Dec 5;125(3):216-224. doi: 10.1016/j.pain.2006.05.024. Epub 2006 Jul 11.
PMID: 16837133
citation: Weinger M. Dangers of postoperative opioids: APSF Workshop and White Paper address prevention of postoperative respiratory complications. APSF Newsletter 21:61-7, 2006
citation: Hutchison R. A Comparison of a Fentanyl, morphine and hydromorphone Patient-controlled intravenous delivery for acute postoperative analgesia: A multicenter study of opioid-induced adverse reactions. Hospital Pharmacy 41:659-63, 2006.
citation: Labroo RB, Paine MF, Thummel KE, Kharasch ED. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997 Sep;25(9):1072-80.
PMID: 9311623
citation: Radovanovic D. The use of transdermal fentanyl in the treatment of cancer pain. Arch Oncol 10:263-66, 2002.
citation: Baselt RC. Disposition of Toxic drugs and Chemicals in Man. 430-33, 2002.
citation: Zheng M. Isolation, identification and synthesis of hydromorphone metabolites: analysis and antinociceptive activities in comparison to morphine. 1997.
citation: Overdyk M. PCA presents serious risks. APSF Newsletter 20, 2005.
citation: D'Argenio DZ, Schumitzky A, Wang X. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.
citation: D'Argenio D. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.
citation: Park MY, Hastie T. Penalized logistic regression for detecting gene interactions. Biostatistics. 2008 Jan;9(1):30-50. doi: 10.1093/biostatistics/kxm010. Epub 2007 Apr 11.
PMID: 17429103
citation: Van Slyke DA, Walker LS. Mothers' responses to children's pain. Clin J Pain. 2006 May;22(4):387-91. doi: 10.1097/01.ajp.0000205257.80044.01.
PMID: 16691093
responsible party type: Sponsor
sharing ipd: Yes
ipd description: De-identified data may be shared with additional internal or external data warehouses/investigators. These include but are not limited to the i2b2-Research Data Warehouse protocol at CCHMC (IRB 2008-0834) for the purpose of linking this data to a de-identified copy of the participant's electronic medical record via an i2b2 database. The resulting de-identified i2b2 database will not be part of this research; but will be used to explore secondary phenotypes in future research studies and documented in the NIH-db-GaP (Database of Genotypes and Phenotypes).