By: Azia Tariq, Section Editor

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With the deaths of thirteen pediatric patients undergoing tonsillectomy and/or adenoidectomy occurring post operation between 1969 to 2012, the Food and Drug Administration (FDA) reviewed the safety of codeine in children in its August 2012 Drug Safety Communication. The FDA subsequently issued a black box warning and a contraindication on the use of codeine in pediatric patients after tonsillectomy and/or adenoidectomy.¹ Though all children had received doses of codeine for postoperative pain management that were within the typical dose range, it was discovered that these patients had a genetic ability to convert codeine into life-threatening or fatal amounts of morphine in the body.

Codeine is an opioid and a prodrug to morphine used as an analgesic and an antitussive agent. The World Health Organization (WHO) has devised a three‐step analgesic ladder for the progressive treatment of increasing pain, in which codeine holds a significant place. The first step contains non-opioids, and the third step includes strong opioids such as methadone, fentanyl, morphine, and oxycodone. Codeine occupies a position on the second step, meaning it is a weak opioid.² In addition to other cough and cold medications, it is available as both a single-ingredient product and a combination product with acetaminophen or aspirin. In 2011, approximately 1.7 million pediatric patients (0-17 years old) filled a prescription for a codeine/acetaminophen combination product or single ingredient codeine product at outpatient pharmacies in the United States.³ With so many receiving this drug, it is important to understand concerns over its use in patients, particularly infants and children.

When codeine is ingested, it is metabolically converted to morphine in the liver via cytochrome P450 2D6 (CYP2D6).⁴ Patients known as ultra-rapid metabolizers possess multiple copies of the CYP2D6 gene responsible for codeine metabolism, which has been linked to serious morbidity and mortality in pediatric patients. These DNA variations increase activity of the enzyme, causing codeine to be converted to morphine faster and more completely. Patients with the ultra-rapid metabolizer (UM) genotype are more likely to have increased amounts of morphine in their blood after taking codeine.⁵ High levels of morphine can result in adverse drug reactions such as sedation, dry mouth, constipation, nausea, vomiting, urinary retention, and orthostatic hypotension. The UM genotype, which is particularly frequent in those of African and Arab descent, also indicates an increased risk of codeine-induced respiratory depression.⁶

In a case report study by Friedrichsdorf et al, the death of three pediatric patients aged 4-10 years old due to codeine toxicity were examined, and it was determined that codeine should no longer be prescribed to pediatric patients. Though the codeine doses were within the recommended dosage ranges, all three obese children were at risk due to their comorbid states.⁷

The associated benefits of the usage of codeine for pain management must be analyzed. Studies may suggest that adding codeine to pediatric pain therapy may not necessarily lead to an improvement in care. In a randomized, double blind study by Moir et al, results demonstrated that there was little difference in patient response when uu using acetaminophen with codeine over acetaminophen alone. Over the course of ten postoperative days, 51 children (ages 3 to 12 years) who were scheduled for outpatient tonsillectomy and/or adenoidectomy were studied. Patients were randomly assigned to receive acetaminophen alone or acetaminophen with codeine for postoperative pain control. The Wong-Baker FACES pain rating scale was utilized to help the children quantify their level of pain after surgery. Results comprised of the level of pain, quantity of pain medication required, presence of side effects, and the percentage of a normal diet consumed. No significant difference in the level of pain control was found (P > .05, all time points) in the level of postoperative pain reported by the parents and children in the two groups.  The acetaminophen with codeine group had increased problems with vomiting, nausea, and constipation, but these differences did not reach statistical significance. Children in the acetaminophen group consumed a significantly higher percentage of a normal diet on the first six postoperative days (P < .05, all time points). It was determined that there was no difference in the level of pain control provided by acetaminophen and acetaminophen with codeine as measured by the Wong-Baker FACES pain rating scale, however, postoperative oral intake of food was markedly higher in children treated with acetaminophen alone, which can be explained by the increased gastrointestinal side effects of acetaminophen with codeine.⁸

Though there is abundant information on codeine’s effect on adults, there is a lack of clinical data to support its usage in the pediatric population. Available research findings suggest that there may be significant age specific differences in the pharmacokinetics of codeine when used in adult or pediatric populations and even among various pediatric age groups. A study by McEwan et al compared intramuscular and rectal administration of codeine in children aged 3 months to 12 years for post‐operative analgesia. While the purpose of the study was to evaluate differences in toxicity, it also showed that peak plasma levels of codeine were achieved between 30 minutes and 60 minutes in both groups, but rectal bioavailability was found to be lower.⁹

In Quiding et al’s study of rectal administration of codeine for postoperative analgesia in infants and children aged between six months and four years, the mean initial half‐life was 2.6 hours, but in infants of the lowest body weight, the half-life was over 2 hours longer than the mean value. This demonstrates that age and weight may have an effect on the duration of codeine levels among different groups of children as well, despite the observation of similar peak levels among the many age groups in the first study. In addition, plasma drug concentration data displayed that a rectal dose of codeine of 0.5 mg kg^–1 in children can result in similar, or slightly greater, plasma concentrations of codeine and its metabolites than over 60 mg orally in adults. This may indicate that there are vast differences in how codeine affects pediatric and adult populations.⁹

There has been limited research on the benefits and side effects of codeine use in children. Doses of codeine should be adjusted according to the severity of pain and the response of the patient. In addition, patients’ renal and liver functions must be taken into account. More clinical studies are needed in order to better assess its safety and efficacy in the pediatric population.¹⁰

 

SOURCES:

1. Traynor, K. Hospitals Don’t Miss Codeine After it’s Gone. ASHP. 2014. Available at: http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4058. Accessed January 7, 2015.
2. Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. Br J Anaesth. 2001;86(3):413-21.
3. FDA Drug Safety Communication: Safety review update of codeine use in children; new boxed warning and contraindication on use after tonsillectomy and/or adenoidectomy. FDA. 2014. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm. Accessed January 7, 2015.
4. FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or ade-noidectomy may lead to rare, but life-threatening ad-verse events or death. FDA. 2014. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm. Accessed January 7, 2015.
5. Cartabuke RS, Tobias JD, Taghon T, Rice J. Current practices regarding codeine administration among pediatricians and pediatric subspecialists. Clin Pediatr (Phila). 2014;53(1):26-30.
6. Tremlett M, Anderson BJ, Wolf A. Pro-con debate: is codeine a drug that still has a useful role in pediatric practice?. Paediatr Anaesth. 2010;20(2):183-94.
7. Friedrichsdorf SJ, Nugent AP, Strobl AQ. Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports. J Opioid Manag. 2013;9(2):151-5.
8. Moir MS, Bair E, Shinnick P, Messner A. Acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy. Laryngoscope. 2000;110(11):1824-7.
9. Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. Br J Anaesth. 2001;86(3):413-21.
10. TYLENOL®with Codeine (acetaminophen and codeine phosphate) [package insert]. Titusville, NJ; Janssen Pharmaceuticals; Revised August 2014.

[pubmed_related keyword1=”codeine” keyword2=”pediatric” keyword3=”patient”]

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