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Tramadol, Codeine, and Opioid-Containing Cough and Cold Medicines - New Contraindications and Warnings Regarding Risk of Serious Breathing Problems and Death in Pediatric Patients - UPDATED

Jan 25, 2018

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The FDA previously issued warnings regarding the use of tramadol and codeine in children due to the risk of serious breathing problems and death. As of January 2018, these warnings have been extended to prescription cough and cold medicines containing codeine and hydrocodone. Tramadol, single-ingredient codeine products, and prescription cough and cold medicines containing codeine or hydrocodone are labeled only for use in adults. The FDA is now requiring new information in the labeling of these products describing the risks of use in children or breastfeeding women.

Tramadol is an opioid analgesic converted by the liver to its active form, O-desmethyltramadol. This conversion may occur at different rates, depending on genetic variations in CYP2D6 liver enzymes. Patients with an increased capacity to metabolize tramadol to O-desmethyltramadol (ie, CYP2D6 ultra-rapid metabolizers) are at an increased risk of breathing difficulties. Tramadol and its active metabolite are both passed into breast milk of lactating women.

Codeine is commonly used for pain control and cough. Codeine is converted to morphine by the CYP2D6 liver enzyme. This conversion may occur at a faster rate in people who have genetic variations of CYP2D6. Patients who are CYP2D6 ultra-rapid metabolizers have higher concentrations of morphine in their body after taking typical doses of codeine, and may be at an increased risk for adverse effects (eg, respiratory depression).
Prescription cough and cold medicines can contain codeine or hydrocodone in combination with antihistamines, decongestants, or other medications to manage cold symptoms. Several states have codeine available in over-the-counter cough medicines as well. A list of the prescription medications is included in the FDA Drug Safety Communication below. Nonopioid cough suppressants are available including over-the-counter dextromethorphan or prescription benzonatate products. Cough associated with the common cold will generally clear on its own without treatment.
The FDA reviewed adverse event reports of serious breathing problems in children taking tramadol or codeine. Nine reports of serious breathing problems in children taking tramadol, including 3 deaths, were submitted to FDA between 1969 and 2016. The 3 deaths occurred in children younger than 6 years who were using a tramadol oral drop formulation that is not available in the United States. One nonfatal case of serious breathing problems occurred in a 5-year-old following a single dose of tramadol The child was later confirmed to be a CYP2D6 ultra-rapid metabolizer. Four nonfatal cases of somnolence or unresponsiveness occurred in adolescents who were using tramadol for sciatica or musculoskeletal pain.

Sixty-four reports of serious breathing problems in children taking codeine-containing products, including 24 deaths, were submitted to FDA between 1969 and 2015. Most (50/64) cases and most deaths (21/24) occurred in children younger than 12 years. Seven cases involved a patient who was a CYP2D6 ultra-rapid metabolizer, 5 of which were fatal. Three additional patients were CYP2D6 extensive metabolizers, 1 of whom died.

The FDA conducted a literature review and found several case reports of serious breathing problems and excessive sleepiness, including 1 death, in breastfed infants whose mothers were using codeine-containing products. The death occurred in an infant whose mother was a CYP2D6 ultra-rapid metabolizer, and likely secreted higher levels of morphine into the breast milk than expected. The FDA did not identify any published reports breathing problems in breastfed infants whose mothers were using tramadol.

The FDA conducted a thorough review and determined with a panel of experts that the risks associated with prescription opioid cough and cold medicines such as slowed breathing, abuse, addiction, and overdose, outweigh the benefits of these medications in patients under 18 years of age. This will be reflected in new safety labeling in these products as well as an updated Boxed Warnings stating the risks of these medications similar to what is described in the labels of prescription opioid pain medications (eg, misuse, abuse, addiction, overdose, difficult breathing, or death). A list of affected prescription cough and cold medicines is included in the FDA Drug Safety Communication below. This currently applies only to the prescription cough and cold medicines containing opioids.

Tramadol product labeling will now include a contraindication against use in children younger than 12 years for treating any type of pain, and against use in children under 18 years to treat pain following removal of the tonsils or adenoids. Prescription codeine product labels will now include a contraindication against use in children younger 12 years for treating pain or cough. Tramadol and prescription codeine product labels will include a new warning against use in patients aged 12-18 years with comorbidities that can increase the risk of breathing difficulties (eg, lung disease, obesity, obstructive sleep apnea) and a strengthened warning against use in breastfeeding mothers. 

Due to the risks of serious breathing problems associated with tramadol and codeine, consider using a pain medication labeled for use in pediatric patients, particularly if the patient is a known or suspected CYP2D6 ultra-rapid metabolizer. If the use of tramadol or codeine is necessary in a pediatric patient, instruct parents or caregivers to monitor closely for signs of shallow or difficult breathing, confusion, or oversedation. Seek emergency medical attention if these or other adverse effects occur. Report adverse events with tramadol to the FDA MedWatch program.

Additional information:

  • MedWatch Safety Alert - January 11, 2018:
    www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm592053.htm
  • Drug Safety Communication – January 11, 2018:
    www.fda.gov/Drugs/DrugSafety/ucm590435.htm
  • Drug Safety Communication – April 21, 2017:
    www.fda.gov/Drugs/DrugSafety/ucm549679.htm
  • MedWatch Safety Alert – September 21, 2015:
    www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm463499.htm
  • FDA Drug Safety Communication – September 21, 2015:
    www.fda.gov/Drugs/DrugSafety/ucm462991.htm
  • Drug Safety Communication – July 1, 2015:
    www.fda.gov/Drugs/DrugSafety/ucm453125.htm
  • FDA Consumer Update – June 10, 2015:
    www.fda.gov/ForConsumers/ConsumerUpdates/ucm315497.htm
  • Drug Safety Communication – February 20, 2013:
    www.fda.gov/Drugs/DrugSafety/ucm339112.htm
  • MedWatch Alert – February 20, 2013:
    www.fda.gov/Drugs/DrugSafety/ucm315627.htm
  • MedWatch Alert – August 15, 2012:
    www.fda.gov/Drugs/DrugSafety/ucm313631.htm