Patient Controlled Analgesia Pharmacogenetic Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01731873
Recruitment Status : Enrolling by invitation
First Posted : November 22, 2012
Last Update Posted : August 1, 2017
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:
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 how children respond to pain medication, like morphine, which are called opioids. Though these pain medicines are used every day, some children have bad reactions from their use, like breathing problems, sedation, etc. It is not possible to completely predict which pain medicine is 'right' for a child. The investigators want to study factors that may be associated with pain sensitivity, pain medicine requirements after surgery, 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.

Condition or disease

Detailed Description:

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. Moreover, up to two-thirds of the inter-individual variability in response to opioids results from genetic variations both from variability in pain perception as well as response to the pain medicine. Much of the inter-individual variability in response to opioids following surgical procedures can be explained by Single Nucleotide Polymorphisms (SNPs) in a subset of the genes that encode proteins involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid receptor signaling (pharmacodynamics). It is evident that there are particular children who are more susceptible to suffering side effects and having inadequate pain relief from opioids. 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 has thus far been largely empirical, with a frequent need to switch opioids and alter doses due to inherent differences in individuals. By this study, the investigators hope to determine the 'right' doses of the 'right' opioids for optimized and safe postoperative analgesia in children. 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 proposed research is a preliminary step towards the investigators' long term goal 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 pain scores, opioid doses, incidence of side-effects of opioids ̶ including respiratory depression, sedation, vomiting, and itching. 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.

Study Type : Observational
Estimated Enrollment : 650 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Non-Interventional Pharmacogenetic Study of Patient / Proxy Controlled Analgesia in Children Undergoing Surgery
Actual Study Start Date : May 22, 2011
Estimated Primary Completion Date : May 21, 2021
Estimated Study Completion Date : May 21, 2021

Primary Outcome Measures :
  1. Number of adverse events [ Time Frame: 48 hours post-operatively ]
    Postoperative incidence of significant central adverse effects to opioids (respiratory depression, excessive sedation and postoperative nausea and vomiting - PONV)

Secondary Outcome Measures :
  1. Post-operative pain [ Time Frame: 48 hours postoperatively ]
    Post-surgical pain scores at rest and on mobilization, opioid requirements/48 hours postoperatively.

Biospecimen Retention:   Samples With DNA
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 in future. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children (weighing at least 5 kg, and up to and including 18 year olds) undergoing surgery requiring postoperative Patient Controlled Analgesia (PCA) or PCA by Proxy with opioids (P/NCA), shall be eligible for the study, if inclusion/exclusion criteria are met.

Inclusion criteria include:

  1. Children up to and including the age of 18 years;
  2. Children weighing at least 5kg at time of surgery; and
  3. Children scheduled for surgery requiring opioids PCA or PCA by proxy for postoperative pain relief.

Exclusion criteria include:

  1. Children with a history of active liver or renal dysfunction (generally indicated by current abnormal lab results);
  2. Patients with severe respiratory problems (indicated by an ASA rating > 4, or oxygen/CPAP/BiPAP dependence);
  3. Children with recent chronic preoperative pain, especially those requiring opioids or nerve pain medications within the last 6 months prior to surgery;
  4. Children who are anticipated to receive ketamine (i.e., injection, infusion, IM) or dexmedetomidine/sufentanil/lidocaine infusions perioperatively;
  5. Children with BMI > 35;
  6. Children with certain genetic diseases or chromosomal abnormalities known to affect pain perception and/or breathing; and
  7. Non-English speaking patients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01731873

United States, Ohio
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Principal Investigator: Vidya Chidambaran, MD Cincinnati Childrens Hospital Medical Center

Weinger M. Dangers of postoperative opioids: APSF Workshop and White Paper address prevention of postoperative respiratory complications. APSF Newsletter 21:61-7, 2006
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.
Radovanovic D. The use of transdermal fentanyl in the treatment of cancer pain. Arch Oncol 10:263-66, 2002.
Baselt RC. Disposition of Toxic drugs and Chemicals in Man. 430-33, 2002.
Zheng M. Isolation, identification and synthesis of hydromorphone metabolites: analysis and antinociceptive activities in comparison to morphine. 1997.
Overdyk M. PCA presents serious risks. APSF Newsletter 20, 2005.
D'Argenio DZ, Schumitzky A, Wang X. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.
D'Argenio D. ADAPT 5 User's Guide: Pharmacokinetic/Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical Simulations Resource, 2009.

Responsible Party: Children's Hospital Medical Center, Cincinnati Identifier: NCT01731873     History of Changes
Other Study ID Numbers: 2010-2268
First Posted: November 22, 2012    Key Record Dates
Last Update Posted: August 1, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan 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).

Keywords provided by Children's Hospital Medical Center, Cincinnati:
postoperative pain
opioid adverse effects
respiratory depression
genetic polymorphisms