If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Codeine and tramadol are opioid analgesics approved for the management of pain in the United States. Both agents are metabolized in the liver to active compounds via the cytochrome P450 2D6 enzyme. Case reports of pediatric patients with overactive CYP2D6 enzymes have been reported. These ultra-rapid metabolizers experience an increase in the production of active metabolites of codeine and tramadol, which can lead to oversedation, respiratory depression, and death. In 2017, the U.S. Food and Drug Administration updated their warnings regarding codeine and tramadol use in the pediatric population, making their use contraindicated in patients under the age of 12 years.
State the new FDA warnings regarding codeine and tramadol use in the pediatric population.
2.
Describe the metabolism of codeine and tramadol.
3.
Summarize adverse events from the use of codeine and tramadol reported in the literature.
4.
Identify alternative non-opioids and opioids for the management of pain in children.
Introduction
Management of pain in the pediatric setting constitutes a significant challenge for members of the health care team as well as patients and parents. Achieving adequate pain control in various pediatric disease states, such as cancer and sickle cell anemia, is a delicate balance between efficacy and the potential harm from medications. Medications used in these cases often include opioids because of their potent analgesic properties (
). A myriad of adverse effects has created justifiable concern over the use of these drugs for pediatric pain management.
Achieving adequate pain control in various pediatric disease states… is a delicate balance between efficacy and the potential harm from medications.
Despite a 2013 warning from the U.S. Food and Drug Administration (FDA) regarding the use of codeine for analgesia in pediatric patients, a recently published study showed that 1 out of 20 pediatric patients was still prescribed codeine after adenotonsillectomy (
). Both of these drugs can be used for pain management, with codeine having an additional off-label use for cough suppression. The FDA has also recently restricted the use of codeine-containing cough and cold medications in the pediatric population (
). The major concern in restricting the ages at which the drugs can be used lies in their potential to cause harmful and even fatal respiratory depression in children (
). The purpose of this article is to review the pharmacology of codeine and tramadol and case reports that led to the recent warning regarding the use of these medications in pediatric patients.
Guidance From the FDA
A 2013 warning from the FDA had previously cautioned against the use of codeine for postoperative pain management in children younger than 18 years after adenotonsillectomy (
). Citing the risk of respiratory depression, which is particularly more pronounced in children than adults, several warnings have been added. For children younger than 12 years, the use of codeine for pain or cough and the use of tramadol for pain are contraindicated. Additionally, the use of tramadol in children younger than 18 years for pain management after adenotonsillectomy is also contraindicated (
). The label of contraindication is the strongest warning the FDA issues. Besides these contraindications, warning labels have been given for the use of codeine or tramadol for children ages 12 to 18 years who are obese or have any conditions associated with breathing problems, such as obstructive sleep apnea or severe lung disease (
Codeine is an opioid analgesic approved for use in the United States for the treatment of pain. In addition, codeine has been used off label in certain patients for the management of cough. Codeine is a prodrug, which means analgesic effects are dependent on the medication being metabolized by the liver. Codeine is metabolized via three major pathways. The majority (i.e., more than 70%) of codeine is metabolized by the enzyme UDP-glucuronosyltransferase-2B7 (UGT2B7) into active codeine-6-glucuronide, and 5% to 10% is metabolized by the cytochrome P450 (CYP) 3A4 (3A4) enzyme into inactive norcodeine (
Similarly, tramadol, another opioid analgesic approved for pain management in the United States, is metabolized by two main pathways in the liver. Tramadol is metabolized by CYP3A4 into inactive N-desmethyltramadol. Most importantly, tramadol is metabolized by CYP2D6 into its active metabolite, O-desmethyltramadol (
Variations in CYP2D6 alleles can alter the metabolism of codeine and tramadol and can therefore affect the analgesic and toxic effects of their administration (
). CYP2D6*1 is considered a wild-type with normal enzymatic activity, and CYP2D6*2, *33, and *35 are considered to have near-normal enzymatic activity. In comparison, variants CYP2D6*3, *4, *5, and *6 have nonfunctioning activity, and variants CYP2D6*10, *17, and *41 have decreased enzymatic activity (
). CYP2D6 genotypes are reported as both the maternal and paternal variants, known as diplotypes. Overall, enzymatic activity of CYP2D6 is related to the activity of both variants (Table 2). For example, duplications of normal functional alleles are denoted as CYP2D6*1/*1 × N or CYP2D6*1/*2 × N (each asterisk represents the maternal and paternal variants), and multiple copies of the allele are indicated by “ × N,” where N signifies the number of copies.
TABLE 2Major polymorphisms of the CYP2D6 enzyme
Enzymatic activity/phenotype
Genotype
Examples
Incidence, %
Ultra-rapid metabolizer
More than two copies of normally functioning alleles
*1/*1 × N *1/*2 × N
1-2
Normal metabolizer
Two normally functioning alleles, or two near-functioning alleles, or a combination of a normally functioning allele and a decreased or nonfunctioning allele
*1/*1 *1/*2 *2/*2 *1/*12 *1/*3 *2/*4
77-92
Intermediate metabolizer
One decreased-functioning allele and one nonfunctioning allele
). The presence of ultra-rapid metabolizing CYP2D6 enzymes shifts metabolism of codeine and tramadol more extensively toward morphine and O-desmethyltramadol, respectively. Increased levels of morphine and O-desmethyltramadol can lead to complications of opioid overdose, such as oversedation, respiratory depression, and death, even at lower doses (
). Ultra-rapid variations of CYP2D6 are found primarily in North Africans (28%) but can also be found in White (10%), African Americans (3%), and Chinese, Hispanics, and Japanese (1%) individuals (
Case reports of ultra-rapid metabolizers have become increasingly common in the medical literature. Most of these cases were documented in patients after tonsillectomy because in these patients the airway is already compromised because of the surgery. A case published in 2009 reported on a previously healthy 2-year-old boy (13 kg) who underwent an adenotonsillectomy for history of snoring and sleep apnea confirmed by sleep study (
). The patient was sent home approximately 6 hours after surgery with instructions to take 10.0 to 12.5 mg of codeine and 100 to 125 mg of acetaminophen orally every 4 to 6 hours as needed for pain. On the second evening after surgery, parents noticed the development of wheezing and fever. The child was found unresponsive the following morning, and resuscitation efforts were unsuccessful. Both codeine and morphine were detected in the blood. The morphine level was found to be 32 ng/ml (therapeutic level = 4.5 ng/ml). After a cytochrome P450 genotype was performed, it was discovered that the child had a functional duplication of the CYP2D6 allele, which classified him as an ultra-rapid metabolizer (
. One of those cases was in a 5-year-old boy (29 kg) who presented for bilateral myringotomy tube placement and an adenotonsillectomy for snoring and recurrent tonsillitis. He was prescribed acetaminophen/codeine (12 mg codeine) every 4 hours. However, around 24 hours after surgery, the child was found dead. Post mortem codeine and morphine levels were both elevated, at 79 ng/ml and 30 ng/ml, respectively. A pharmacokinetic model was built using age, weight, and dosing schedule to predict expected levels of codeine and morphine. The authors determined that the measured codeine dose at 79 ng/ml was in the 56th percentile and that the morphine level of 30 ng/ml was in the 99th percentile, which is consistent with respiratory failure due to endogenous metabolism producing higher than expected levels of morphine. Based on this information, the authors speculated that it was highly probable that the patient was a CYP2D6 ultra-metabolizer. Other recently reported adverse events from codeine use are summarized in Table 3.
TABLE 3Summary of recently reported cases on adverse events from codeine and tramadol use after adenotonsillectomy for sleep apnea in the pediatric population
). The patient was a 5.5-year-old boy (21 kg) who presented for an adenotonsillectomy for obstructive sleep apnea. He had an uneventful 6-hour perioperative stay and was discharged home. Approximately 8 hours after arriving home, he received one oral dose of tramadol of 20 mg. The following morning, he was found to be lethargic and was taken to the emergency department. Upon arrival, the patient had a pediatric Glasgow coma scale score of 8, pinpoint pupils, minimal respiratory effort, frequent apneic events, and an oxygen saturation of 48% on room air. In light of this, the patient was transferred to the pediatric intensive care unit, where he received noninvasive ventilation and a total of three doses of 0.5 mg naloxone with great response. Urinary laboratory test results showed a tramadol level of 38 µg/ml (positive drug level, ≥ 50 ng/ml), as well as urinary concentrations of O-desmethyltramadol and N-desmethyltramadol at 24 µg/ml (positive drug level, ≥ 100 ng/ml) and 4.6 µg/ml (positive drug level, ≥ 100 ng/ml), respectively (
Because of recent FDA warnings, codeine and tramadol should not be used for pain relief in most of the pediatric population. It is beyond the scope of this article to discuss alternative analgesia for every pediatric indication. Because this new FDA guidance mainly pertains to patients after adenotonsillectomy, recommendations for nonopioids and opioids will be summarized for this specific indication. Regardless of the indication, a stepwise analgesic approach should be followed (
Because of recent FDA warnings, codeine and tramadol should not be used for pain relief in most of the pediatric population.
Historically, nonsteroidal anti-inflammatory drugs like ibuprofen have been considered suboptimal for relieving pain because of concerns about increasing bleeding after adenotonsillectomy (
). However, recent literature refuted this fear, and more otolaryngologists now recommend using ibuprofen as an initial regimen to relieve pain in patients who do not have a history of opioid use (
). If ibuprofen is chosen as an analgesic option, the clinician needs to ensure that the patient is well hydrated, because recent literature has documented acute kidney injury related to nonsteroidal anti-inflammatory drug use in children (especially younger than 5 years) who are dehydrated or at risk of dehydration (
). The child's caregivers need to be counseled on how to alternate acetaminophen and ibuprofen, because the literature has documented medication errors from this combination due to misunderstanding dosing directions (
Association between an excess risk of acute kidney injury and concomitant use of ibuprofen and acetaminophen in children, retrospective analysis of a spontaneous reporting system.
European Journal of Clinical Pharmacology.2014; 70: 479-482
). Acetaminophen and ibuprofen can be alternated every 3 hours (i.e., administer a dose of acetaminophen, then 3 hours later give ibuprofen, then 3 hours later give acetaminophen, etc.). It is generally recommended that such alternation should not exceed 24 to 48 hours.
Other opioids can be considered if the child's pain is not controlled by alternating ibuprofen and acetaminophen, and such options include hydrocodone and oxycodone. Morphine can also be used, but it is not as often prescribed at the outpatient setting for reliving pain post tonsillectomy because one study showed that it caused more oxygen desaturations without apneic events on the first postoperative day (
). Hydrocodone is metabolized by CYP2D6, but cases of apneic events similar to those involving tramadol and codeine have not been reported in the literature with its use in pediatric patients after adenotonsillectomy. Oxycodone is mainly metabolized by UGT2B7 and morphine by CYP3A4 (
). Nonetheless, extra caution is warranted when using these opioids in patients with history of obstructive sleep apnea or severe lung disease because they have compromised airways at baseline, and respiratory depression remains a known adverse effect (
); however, the evidence supporting their use is limited, and their use should be reserved for refractory cases. Table 4 summarizes the dosing of oral medications for pain management in children after adenotonsillectomy.
TABLE 4Oral medications for pain management in pediatric patients after adenotonsillectomy
Best to alternate acetaminophen with ibuprofen every 3 hours for adequate pain relief (i.e., administer a dose of acetaminophen, then 3 hours later give ibuprofen, then 3 hours later give acetaminophen, etc.). It is generally recommended that such alternation should not exceed 24-48 hours.
10-15 mg/kg/dose every 4-6 hours as needed (maximum = 75 mg/kg/day up to 4,000 mg/day or 5 doses in a 24-hour period)
Best to alternate acetaminophen with ibuprofen every 3 hours for adequate pain relief (i.e., administer a dose of acetaminophen, then 3 hours later give ibuprofen, then 3 hours later give acetaminophen, etc.). It is generally recommended that such alternation should not exceed 24-48 hours.
4-10 mg/kg/dose every 6-8 hours as needed (maximum = 400 mg/dose and 40 mg/kg/day up to 1,600 mg/day)
a Best to alternate acetaminophen with ibuprofen every 3 hours for adequate pain relief (i.e., administer a dose of acetaminophen, then 3 hours later give ibuprofen, then 3 hours later give acetaminophen, etc.). It is generally recommended that such alternation should not exceed 24-48 hours.
b Maximum = 5 doses in a 24-hour period because of the acetaminophen component.
Considering these new and more restrictive guidelines by the FDA, health care teams should use more acetaminophen alternating with ibuprofen for initial pain management in the pediatric population. If this combination is not effective, other properly dosed opioids such as oxycodone and hydrocodone should be considered. Although analgesic options are now more limited in the wake of these warnings, these restrictions are an important step in ensuring that the safest possible regimens are used for pain control in pediatric patients.
Health care teams should use more acetaminophen alternating with ibuprofen for initial pain management in the pediatric population.
in: Pratt V. McLeod H. Dean L. Malheiro A. Rubinstein W. Medical Genetics Summaries. National Center for Biotechnology Information,
Bethesda, MD2012 (Retrieved from)
Association between an excess risk of acute kidney injury and concomitant use of ibuprofen and acetaminophen in children, retrospective analysis of a spontaneous reporting system.
European Journal of Clinical Pharmacology.2014; 70: 479-482
30636-3&id=gr1.jpg){kind=link}
30636-3&id=gr2.jpg){kind=link}