CYP2D6 Screening for Adverse Drug Reactions to Codeine in Breast Milk

The purpose of this study is to determine if non-invasive salivary genetic screening of breastfeeding mothers taking codeine will allow for the successful identification of mother-infant pairs susceptible to adverse events and to prevent these adverse events by personalizing their medication to their genetics.

Study Overview

• Status: Completed
• Conditions: Cytochrome P450 2D6 Ultra-rapid Metabolism
• Intervention / Treatment: Genetic: Cytochrome P450 2D6 (CYP2D6) genetic screening.

Detailed Description

Currently, the opioid analgesic codeine is commonly administered to breastfeeding mothers after Caesarean section for pain relief. Codeine was originally considered safe to use while breastfeeding however, increased risk of adverse drug reactions has been demonstrated in mothers taking codeine, as well as their breastfed infants, when the mother possesses a genetic variation resulting in cytochrome P450 2D6 (CYP2D6) ultra-rapid metabolizer (UM) phenotype. On average, most people convert about 10-15% of their codeine dose to morphine resulting in pain relief however, UM individuals can convert up to 50% of their codeine doses into active morphine. As many as 4% of North Americans may be UMs and these mothers and their breastfed infants are at high risk of serious adverse events despite "safe" codeine dosing due to morphine overproduction and accumulation in the mother and her breast milk. Observed side effects include severe sedation, decreased rate and depth of breathing and even infant death. In response to this problem, our hospital-based clinical trial strives to identify at-risk UM mother-infant pairs by performing a genetic test on non-invasive, voluntary saliva samples from mothers giving birth by Caesarean section and who will need codeine for pain relief while breastfeeding. We believe that this test will allow us to reliably identify at-risk UM mother-infant pairs and prevent adverse drug reactions in both by tailoring analgesic therapy to their genetic results: mothers identified as being UMs will be given other suitable analgesics, such as ibuprofen, in place of codeine-containing preparations. We propose that this prospective study will generate high-level data supporting the cost-effective genetic screening of mothers who will be taking codeine while breastfeeding before they begin taking their medications. Such testing is currently possible on a nation-wide scale through collaboration with the Canadian Pharmacogenomics Network for Drug Safety (CPNDS).

• Study Type: Observational
• Enrollment (Actual): 330

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Women undergoing elective caesarian section surgery and planning to breastfeed while concurrently taking codeine for post-partum pain relief within St. Joseph's Hospital in London and St. Michael's Hospital in Toronto.

Description

Inclusion Criteria:

Women who:

• Have a pre-scheduled Caesarean section
• Provide DNA for CYP2D6 genetic analysis
• Breastfeed their infants
• Take codeine-containing medication during breastfeeding (retrospective screening group and non-CYP2D6 ultrarapid metabolizers in prospective screening group)

Exclusion Criteria:

• Mothers who do not provide consent prior to Caesarian section surgery
• Mothers who take other sedative medications besides codeine during breastfeeding (these include benzodiazepines, skeletal muscle relaxants, psychotropic agents).

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Observant; Individuals within this group will receive pharmacotherapy according to the established institutional guidelines.	Genetic: Cytochrome P450 2D6 (CYP2D6) genetic screening.; Genetic screening for cytochrome P450 2D6 (CYP2D6) polymorphism will be conducted on genetic information obtained from non-invasive salivary samples.
Prospective CYP2D6 genetic screening; Individuals within the prospective group will receive their CYP2D6 genotype results prior to pharmacotherapy and their analgesic regimen will be tailored to their genetic results.	Genetic: Cytochrome P450 2D6 (CYP2D6) genetic screening.; Genetic screening for cytochrome P450 2D6 (CYP2D6) polymorphism will be conducted on genetic information obtained from non-invasive salivary samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of maternal and neonatal CNS depression in the prospective pharmacogenetic screening group to that of a retrospectively screened population	5-8 days post c-section surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of the phase II uridine diphosphate glucuronyltransferase 2B7 (UGT2B7)*2/*2 variant which has been associated with higher morphine 6-glucuronide to morphine ratios.	Minimum 1 week prior to c-section
Incidence of the C3435T polymorphism in the multi-drug resistance gene (MDR1) which has been associated with significantly greater pain relief from morphine treatment.	Minimum 1 week prior to c-section
Incidence of the A118G polymorphism in the opioid receptor 1 (OPRM1) which has been associated with reduced response to morphine treatment.	Minimum 1 week prior to c-section

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Investigators: Principal Investigator: Gideon Koren, MD, Western University, Canada

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2009
• Primary Completion (Actual): December 31, 2012
• Study Completion (Actual): December 31, 2012

Study Registration Dates

• First Submitted: January 11, 2010
• First Submitted That Met QC Criteria: January 13, 2010
• First Posted (Estimate): January 15, 2010

Study Record Updates

• Last Update Posted (Actual): August 28, 2017
• Last Update Submitted That Met QC Criteria: August 25, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: breastfeeding; Genetic Polymorphism; CYP2D6; codeine
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions
• Other Study ID Numbers: R-09-442