CYP2D6 Screening for Adverse Drug Reactions to Codeine in Breast Milk

Official Title: “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.

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).

Intervention(s) in this Clinical Trial

• 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.

Arms, Groups and Cohorts in this Clinical Trial

• : Observant
  • Individuals within this group will receive pharmacotherapy according to the established institutional guidelines.
• : 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.

Primary Measures

• Incidence of maternal and neonatal CNS depression in the prospective pharmacogenetic screening group to that of a retrospectively screened population
  • Time Frame: 5-8 days post c-section surgery
    Safety Issue?: No

Secondary Measures

• 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.
  • Time Frame: Minimum 1 week prior to c-section
    Safety Issue?: No
• Incidence of the C3435T polymorphism in the multi-drug resistance gene (MDR1) which has been associated with significantly greater pain relief from morphine treatment.
  • Time Frame: Minimum 1 week prior to c-section
    Safety Issue?: No
• Incidence of the A118G polymorphism in the opioid receptor 1 (OPRM1) which has been associated with reduced response to morphine treatment.
  • Time Frame: Minimum 1 week prior to c-section
    Safety Issue?: No

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).

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Investigator: Lawson Health Research Institute Other

Overall Clinical Trial Officials and Contacts

Gideon Koren, MD Principal Investigator University of Western Ontario, Canada  

Overall Contact: Catherine Ciszkowski, BMSc 519-661-2111 dnastudy@uwo.ca

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01050400

Study ID Number: R-09-442

ClinicalTrials.gov Identifier: NCT01050400

Health Authority: Canada: Ethics Review Committee