Are you still prescribing codeine? .

Pediatrics

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Codeine is an opioid alkaloid naturally found in opium poppy resin, along with morphine and more than 20 distinct alkaloid chemicals. The opium poppy has been known for more than 2,000 years to have beneficial effects upon the human body, and its use is referenced in ancient writings dating back several thousand years. Codeine has been used medicinally for more than a century. Pediatric health care practitioners trained years ago likely were taught to prescribe codeine, especially acetaminophen plus codeine products, for many uses, namely for cough or mild-to-moderate pain. Post-tonsillectomy pain was a common indication for prescribing acetaminophen plus codeine. It is best, however, that these prescribing habits “die easy,” and not “die hard.”

Edward A. Bell

An argument can be made that codeine no longer has a safe and effective role in the treatment of any pediatric maladies, namely pain or cough. Thus, it is best that pediatric health care providers no longer prescribe codeine — for anything.

FDA and AAP’s position on codeine

The FDA and the AAP have published a series of statements and recommendations on the role of codeine over the past several years. In 2017, the FDA put new restrictions on the use of codeine in children. The labeling of all prescription products containing codeine was required to contain these new restrictions (see Table). In some children, the restrictions included a contraindication. In 2018, the FDA removed the labeled indications for cough products containing codeine or hydrocodone in children aged younger than 18 years.

In 2016, the AAP published the document, “Codeine: Time to Say ‘No,’” which called for more formal restrictions on the use of codeine in children, regardless of age.

What is the reasoning underlying these relatively new recommendations from the FDA and the AAP? The FDA has published a series of communications about the potential dangers of codeine use in the pediatric population since 2013. The agency reviewed reports of adverse events associated with codeine from 1969 to 2015, including 64 worldwide cases of significant respiratory problems — and 24 deaths — among children. Fifty of these cases occurred in children aged younger than 12 years, and 21 of the 24 deaths occurred in this age group. There may be additional cases that were not reported to the FDA.

An important pharmacologic characteristic of codeine that has undergone increased evaluation in recent years, along with significant increases in our understanding of codeine’s pharmacokinetic profile, is its polymorphic hepatic metabolism. Codeine does not have clinically useful analgesic effects, and it is partially metabolized to an active compound — morphine (the remaining metabolites are inactive). Approximately 10% of a codeine dose is metabolized by the cytochrome P450 (CYP450) enzyme 2D6 to morphine and an active morphine metabolite, which accounts for its analgesic effects. However, there is a wide variation in this hepatic conversion to morphine. Some individuals may metabolize codeine to more than 10% morphine, whereas others may metabolize codeine to less than 10% morphine, potentially resulting in toxicity or a lack of therapeutic pain control, respectively. Thus, although codeine historically has been considered a useful analgesic and cough suppressant, these assumptions are now increasingly scrutinized. In a 1997 report, the AAP stated that no well-controlled scientific studies support the efficacy and safety of codeine as an antitussive agent in children.

AAO-HNSF guideline

A common historical use of codeine (typically in combination with acetaminophen) in children has been for post-tonsillectomy pain control. However, this use is no longer recommended. In 2019, the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO- HNSF) published an update to their previous 2011 clinical practice guideline on tonsillectomy in children. It states that “clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years.” In support of this statement, the AAO-HNSF recommends the use of ibuprofen and/or acetaminophen as appropriate analgesic agents for post-tonsillectomy pain in children. Published studies cited in the guideline demonstrated the efficacy of ibuprofen and acetaminophen for post-tonsillectomy pain control. Specifically, ibuprofen has demonstrated adequate post-tonsillectomy pain control in several well-designed clinical trials. Rates of post-surgical bleeding did not differ between children who received ibuprofen compared with children who received placebo or other analgesic agents. Ibuprofen is classified as a nonsteroidal anti- inflammatory agent, but unlike aspirin, it does not irreversibly inhibit cyclooxygenase (COX) activity and platelet aggregation. Because platelets do not have a nucleus (for protein synthesis), inhibition of platelet COX by ibuprofen does not occur for the life of the platelet (8-12 days).

If not codeine, then what?

If codeine should not be prescribed to children for pain control or cough, what can be prescribed? This question is actively discussed in the medical literature and online chat rooms. The vast majority of pediatric institutions have either taken codeine off their drug formularies or have placed significant restrictions on its use. Clinicians should consider that ibuprofen has good analgesic effects and can be an acceptable pharmacotherapy for the treatment of mild-to-moderate pain in children. Some published evidence shows that alternating doses of ibuprofen and acetaminophen, and scheduled dosing (vs. as-needed administration), are additional effective tools to control post-tonsillectomy pain in children. Replacement opioid analgesic agents include hydrocodone, oxycodone or morphine. Although the hepatic metabolic profiles of hydrocodone and oxycodone are complex, it is important to consider that both hydrocodone and oxycodone are metabolized by CYP450 2D6 and 3A4 to active metabolites and thus may be susceptible to genetic hepatic polymorphisms, resulting in clinical effects of toxicity or ineffective analgesia (although case reports describing this have not been published). Morphine is hepatically conjugated with glucuronic acid to active metabolites, and these metabolites are renally excreted. Thus, morphine is not affected by CYP450 polymorphisms. Some have suggested that morphine, an excellent analgesic agent, should be used as the primary analgesic agent for moderate-to-severe pain in children. If morphine is used, it is very important to consider that morphine liquid products are available in several concentrations (2 mg/mL, 4 mg/mL and 20 mg/mL — a 10-fold difference in strengths). Some clinicians are hesitant to prescribe morphine because of a potential for dosing, dispensing and administration errors.

The treatment of pediatric cough has long frustrated pediatric prescribers. Codeine and hydrocodone are best not prescribed, especially in light of recent recommendations from the FDA. The 1997 AAP statement similarly discusses the lack of effective and safe data to support the use of dextromethorphan in children. Although benzonatate is labeled as an antitussive for children aged 10 years and older, numerous case reports of toxicity associated with its use, some resulting in death, are concerning — sufficient reason not to prescribe this agent. Benzonatate functions as anesthetizing agent on cough nerve fibers. It is available as liquid-filled small capsules and resembles a candylike product. If the capsule is bitten or chewed, the immediate release of the liquid into the oral cavity can be deleterious, and it has been reported to result in fatal outcomes in young children. Thus, when treating a pediatric patient for cough, prescribers should consider honey, mentholated rubs, cough drops or warm liquids, and avoid codeine, hydrocodone and benzonatate.

Conclusions

The role of codeine in the pediatric population is zero — it should not be prescribed. Although screening for genetic hepatic CYP450 enzyme function is available, results can be difficult to interpret and apply clinically, and this testing may not be widely available to many health care providers. Other analgesic agents can be used in place of codeine. The use of codeine in a pediatric patient may result in little or no analgesic effect, or it may result in respiratory suppression or death. Risk factors for toxicity include young age (< 12 years), obesity and obstructive sleep apnea, among others. However, even children without these risk factors may be susceptible to the toxic effects of codeine administration. Women breastfeeding an infant should not be given codeine, because case reports have shown that toxic concentrations of morphine from an ultrarapid hepatic codeine-metabolizing mother have been found in breast milk.

Disclosure: Bell reports no relevant financial disclosures.

Codeine is an opioid alkaloid naturally found in opium poppy resin, along with morphine and more than 20 distinct alkaloid chemicals. The opium poppy has been known for more than 2,000 years to have beneficial effects upon the human body, and its use is referenced in ancient writings dating back several thousand years. Codeine has been used medicinally for more than a century. Pediatric health care practitioners trained years ago likely were taught to prescribe codeine, especially acetaminophen plus codeine products, for many uses, namely for cough or mild-to-moderate pain. Post-tonsillectomy pain was a common indication for prescribing acetaminophen plus codeine. It is best, however, that these prescribing habits “die easy,” and not “die hard.”

Edward A. Bell

An argument can be made that codeine no longer has a safe and effective role in the treatment of any pediatric maladies, namely pain or cough. Thus, it is best that pediatric health care providers no longer prescribe codeine — for anything.

FDA and AAP’s position on codeine

The FDA and the AAP have published a series of statements and recommendations on the role of codeine over the past several years. In 2017, the FDA put new restrictions on the use of codeine in children. The labeling of all prescription products containing codeine was required to contain these new restrictions (see Table). In some children, the restrictions included a contraindication. In 2018, the FDA removed the labeled indications for cough products containing codeine or hydrocodone in children aged younger than 18 years.

In 2016, the AAP published the document, “Codeine: Time to Say ‘No,’” which called for more formal restrictions on the use of codeine in children, regardless of age.

What is the reasoning underlying these relatively new recommendations from the FDA and the AAP? The FDA has published a series of communications about the potential dangers of codeine use in the pediatric population since 2013. The agency reviewed reports of adverse events associated with codeine from 1969 to 2015, including 64 worldwide cases of significant respiratory problems — and 24 deaths — among children. Fifty of these cases occurred in children aged younger than 12 years, and 21 of the 24 deaths occurred in this age group. There may be additional cases that were not reported to the FDA.

An important pharmacologic characteristic of codeine that has undergone increased evaluation in recent years, along with significant increases in our understanding of codeine’s pharmacokinetic profile, is its polymorphic hepatic metabolism. Codeine does not have clinically useful analgesic effects, and it is partially metabolized to an active compound — morphine (the remaining metabolites are inactive). Approximately 10% of a codeine dose is metabolized by the cytochrome P450 (CYP450) enzyme 2D6 to morphine and an active morphine metabolite, which accounts for its analgesic effects. However, there is a wide variation in this hepatic conversion to morphine. Some individuals may metabolize codeine to more than 10% morphine, whereas others may metabolize codeine to less than 10% morphine, potentially resulting in toxicity or a lack of therapeutic pain control, respectively. Thus, although codeine historically has been considered a useful analgesic and cough suppressant, these assumptions are now increasingly scrutinized. In a 1997 report, the AAP stated that no well-controlled scientific studies support the efficacy and safety of codeine as an antitussive agent in children.

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AAO-HNSF guideline

A common historical use of codeine (typically in combination with acetaminophen) in children has been for post-tonsillectomy pain control. However, this use is no longer recommended. In 2019, the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO- HNSF) published an update to their previous 2011 clinical practice guideline on tonsillectomy in children. It states that “clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years.” In support of this statement, the AAO-HNSF recommends the use of ibuprofen and/or acetaminophen as appropriate analgesic agents for post-tonsillectomy pain in children. Published studies cited in the guideline demonstrated the efficacy of ibuprofen and acetaminophen for post-tonsillectomy pain control. Specifically, ibuprofen has demonstrated adequate post-tonsillectomy pain control in several well-designed clinical trials. Rates of post-surgical bleeding did not differ between children who received ibuprofen compared with children who received placebo or other analgesic agents. Ibuprofen is classified as a nonsteroidal anti- inflammatory agent, but unlike aspirin, it does not irreversibly inhibit cyclooxygenase (COX) activity and platelet aggregation. Because platelets do not have a nucleus (for protein synthesis), inhibition of platelet COX by ibuprofen does not occur for the life of the platelet (8-12 days).

If not codeine, then what?

If codeine should not be prescribed to children for pain control or cough, what can be prescribed? This question is actively discussed in the medical literature and online chat rooms. The vast majority of pediatric institutions have either taken codeine off their drug formularies or have placed significant restrictions on its use. Clinicians should consider that ibuprofen has good analgesic effects and can be an acceptable pharmacotherapy for the treatment of mild-to-moderate pain in children. Some published evidence shows that alternating doses of ibuprofen and acetaminophen, and scheduled dosing (vs. as-needed administration), are additional effective tools to control post-tonsillectomy pain in children. Replacement opioid analgesic agents include hydrocodone, oxycodone or morphine. Although the hepatic metabolic profiles of hydrocodone and oxycodone are complex, it is important to consider that both hydrocodone and oxycodone are metabolized by CYP450 2D6 and 3A4 to active metabolites and thus may be susceptible to genetic hepatic polymorphisms, resulting in clinical effects of toxicity or ineffective analgesia (although case reports describing this have not been published). Morphine is hepatically conjugated with glucuronic acid to active metabolites, and these metabolites are renally excreted. Thus, morphine is not affected by CYP450 polymorphisms. Some have suggested that morphine, an excellent analgesic agent, should be used as the primary analgesic agent for moderate-to-severe pain in children. If morphine is used, it is very important to consider that morphine liquid products are available in several concentrations (2 mg/mL, 4 mg/mL and 20 mg/mL — a 10-fold difference in strengths). Some clinicians are hesitant to prescribe morphine because of a potential for dosing, dispensing and administration errors.

PAGE BREAK

The treatment of pediatric cough has long frustrated pediatric prescribers. Codeine and hydrocodone are best not prescribed, especially in light of recent recommendations from the FDA. The 1997 AAP statement similarly discusses the lack of effective and safe data to support the use of dextromethorphan in children. Although benzonatate is labeled as an antitussive for children aged 10 years and older, numerous case reports of toxicity associated with its use, some resulting in death, are concerning — sufficient reason not to prescribe this agent. Benzonatate functions as anesthetizing agent on cough nerve fibers. It is available as liquid-filled small capsules and resembles a candylike product. If the capsule is bitten or chewed, the immediate release of the liquid into the oral cavity can be deleterious, and it has been reported to result in fatal outcomes in young children. Thus, when treating a pediatric patient for cough, prescribers should consider honey, mentholated rubs, cough drops or warm liquids, and avoid codeine, hydrocodone and benzonatate.

Conclusions

The role of codeine in the pediatric population is zero — it should not be prescribed. Although screening for genetic hepatic CYP450 enzyme function is available, results can be difficult to interpret and apply clinically, and this testing may not be widely available to many health care providers. Other analgesic agents can be used in place of codeine. The use of codeine in a pediatric patient may result in little or no analgesic effect, or it may result in respiratory suppression or death. Risk factors for toxicity include young age (< 12 years), obesity and obstructive sleep apnea, among others. However, even children without these risk factors may be susceptible to the toxic effects of codeine administration. Women breastfeeding an infant should not be given codeine, because case reports have shown that toxic concentrations of morphine from an ultrarapid hepatic codeine-metabolizing mother have been found in breast milk.

PAGE BREAK

Disclosure: Bell reports no relevant financial disclosures.