Pharmacogenomics Analysis of Morphine Pharmacokinetics in Pediatric Tonsillectomy and Adenoidectomy

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: NCT00836264
Recruitment Status : Suspended (Enrollment is on hold dependent upon funding)
First Posted : February 4, 2009
Last Update Posted : January 20, 2017
Children's Anesthesiology Associates, Ltd.
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Brief Summary:

Intravenous (IV) morphine requirement for immediate postoperative pain control depends upon the complex interplay of patient history, wound severity, environment, and genetics. Even for relatively uniform stimulus intensity, such as that associated with tonsillectomy and adenoidectomy (T&A), there can be marked individual variability in response to morphine. Some patients are refractory to standard doses and need increased amounts. Others are sensitive, require less drug to attain acceptable pain levels, and/or experience unwanted side effects that limit dosing. A significant number must be switched to different analgesics altogether. Despite the long clinical history of morphine as a postoperative analgesic, researchers have only begun to examine the origins of response variability.

The investigators will look at 2000 retrospective Tonsillectomy and Adenoidectomy cases and using this data and incorporating additional patient, surgical, and environmental factors that may contribute to response variability, the investigators then propose a prospective genome-wide association (GWA) study of 1500 children ages 4 to 18 y treated with IV morphine sulfate for day surgery T&A.

Condition or disease
Tonsillectomy Adenoidectomy Pharmacokinetics

Detailed Description:

Morphine Tonsilectomy and Adenoidectomy (T&A) Pharmacokinetics (PK) study will be done as a part of the larger institutional Center for Applied Genomics (CAG) project entitled "A Study of the Genetic Causes of Complex Pediatric Disorders" (GCPD study), as approved by the Children's Hospital of Philadelphia (CHOP) IRB, 2006-7-4886. By combining Genome Wide Association (GWA) and PK data, we wish to conduct a Pharmacogenomic (PG) study of IV morphine administered as standard of care during and after pediatric day surgery T&A. Because we expect several genes to play a role in the morphine response, we must use a large, relatively uniform pediatric surgical population such that for T&A. Through observation and minimal-risk blood sampling of this cohort of children, we hope to identify genetic variants that predict analgesic response to (and serum levels of) morphine sulfate. Pediatric patients ages 4-18 y, presenting with significant tonsillar/adenoidal tissue hypertrophy, sleep disordered breathing and/or recurrent infection, and requiring T&A are eligible. Morphine is the most common IV analgesic used for T&A at CHOP. As is necessary for accurately defining analgesic response phenotype, morphine will be administered in a structured manner consistent with standard of care at this institution. As defined below, children resistant to morphine (MR) and those sensitive to it (MS) will be identified as specific phenotypes to be compared with normal responders (NR) in a GWA study.

This study begins with a retrospective electronic database query of 2000 day surgery T&A cases between 11/1/2005 and 10/31/2008 in which morphine was used as the sole IV analgesic. Data from this portion of the study will help us refine phenotype parameters, should robust subpopulations of response types emerge, and provide background information required for eventual project funding by the National Institutes of Health (NIH). The prospective portion of the study will follow an additional 1650 children newly enrolled in the CAG study and now presenting for T&A.

Study Type : Observational
Estimated Enrollment : 1650 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pharmacogenomic Analysis of Morphine Pharmacokinetics and Response Variability Following Pediatric Tonsillectomy and Adenoidectomy: A Genome-Wide Association Approach
Actual Study Start Date : December 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Adenoids Tonsillitis
U.S. FDA Resources

Morphine T & A
Subjects ages 4-18 years of age who have a Tonsillectomy and Adenoidectomy and receive morphine for pain control and who have also enrolled in the CAG study at CHOP, "A Study of the Genetic Causes of Complex Pediatric Disorders" (GCPD study), as approved by the CHOP IRB, 2006-7-4886.

Primary Outcome Measures :
  1. The primary endpoint will be to identify genetic variants that contribute to the variability of morphine analgesic response following pediatric day surgery T&A. [ Time Frame: 2 years ]

Biospecimen Retention:   Samples Without DNA
PK plasma samples will be obtained

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:   4 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children having Tonsillectomy and Adenoidectomy procedures done at The Children's Hospital of Philadelphia, at the Main Hospital and also at the satellite surgical centers, who have also consented to participate in "A Study of the Genetic Causes of Complex Pediatric Disorders" (GCPD study), as approved by the CHOP IRB, 2006-7-4886.

Inclusion Criteria:

  1. Concurrent enrollment in the GCPD study (IRB 2006-7-4886)
  2. Scheduled for day surgery T&A with expected same day discharge at CHOP Main in Philadelphia, Pennsylvania (PA) or the CHOP Ambulatory Surgical Facilities (ASFs) in Chalfont, PA; Exton, PA; or Voorhees, New Jersey (NJ)
  3. Male or female, age 4 - 18 y, all races and ethnic backgrounds
  4. Able to self-report pain on the Faces Pain Scale - Revised (FPS-R).
  5. Informed consent as addendum to GCPD consent document
  6. Assent for children ≥7 y of age

Exclusion Criteria:

  1. Parents/guardians or subjects who, in the opinion of the investigator, may be non-compliant with study schedules or procedures
  2. Non-English speaking subjects or parents. The reliability of the morphine analgesic requirement phenotype could be adversely affected by subtle communication differences between subjects and nursing staff assessing pain and administering morphine during patient recovery should language barriers exist. Parents must also be fluent in English as they will be at the bedside shortly after their child's arrival in recovery and could influence how their child understands pain scoring and how they interact with the nursing and research staff.
  3. Those parents/guardian or subjects not consenting to, or willing to participate in the GCPD study (IRB 2006-7-4886)
  4. Patients < 4 y of age were excluded to improve phenotype reliability. Due to a higher empirical risk of postoperative obstruction following T&A, children < 4 y of age are admitted for overnight observation. The titration of morphine is more difficult in these patients as clinicians generally follow more restrictive dosing regimens and the total morphine dose is drawn out over an extended period. Furthermore, the self-report Faces Pain Scale - Revised (FPS-R) has been validated for children ≥ 4 y and will be used to corroborate the morphine response phenotypes that are primarily based on morphine doses administered to achieve low Face, Legs, Activity, Cry, Consolability (FLACC) scores. The latter behavioral scoring is required for early morphine administration as children and adolescents emerging from anesthesia may have difficulty expressing themselves in the first 30 min. In addition, it is important for our statistical analysis to have a sequential scoring system over time that is applicable to all ages. Finally, the incidence of emergence agitation/delirium, a clinical phenomenon that shares some features of pain, but becomes distinct over 15-30 min, is higher in younger patients. (Sikich, 2004; Vlajkovic, 2007) By excluding children < 4 y we decrease the proportion of subjects whose FLACC scores may be high on the basis of emergence agitation/delirium.
  5. Significant comorbid conditions requiring a non-standard anesthetic regimen such as a history of severe post-operative nausea and vomiting requiring propofol infusion, a total intravenous anesthestic (TIVA) technique and/or mandating planned post-operative hospital admission
  6. Documented allergy or adverse reaction to morphine in the patient
  7. Use of opioids (e.g. codeine, oxycodone, morphine, hydromorphone) within the previous month
  8. Use of non-steroidal anti-inflammatory agents or acetaminophen in the 3 days preceding the T&A. No acetaminophen will be included in the premedication regimen on the day of surgery.

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): NCT00836264

United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
Children's Anesthesiology Associates, Ltd.
Principal Investigator: Scott Cook-Sather, MD Children's Hospital of Philadelphia

Responsible Party: Children's Hospital of Philadelphia Identifier: NCT00836264     History of Changes
Other Study ID Numbers: 08-007023
First Posted: February 4, 2009    Key Record Dates
Last Update Posted: January 20, 2017
Last Verified: January 2017

Keywords provided by Children's Hospital of Philadelphia:
Opioid Receptors
Genome-Wide Association

Additional relevant MeSH terms:
Analgesics, Opioid
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents