Is codeine a useful medication in pediatrics?

July 2006

Codeine is likely a widely used medication in pediatric medicine, due to its analgesic actions, its liquid formulation that makes it easily administered to children and the perception that it is an effective cough suppressant. Because of its potential for frequent use in children, codeine will be the subject of this month’s Pharmacology Consult column.

Codeine and morphine are naturally occurring opiates from the opium poppy. Similar agents, opioids (compounds related to opium), are not natural chemicals from the opium poppy, but are chemical modifications (eg, fentanyl, oxycodone) of opiates. The analgesic properties and pharmacology of codeine, morphine and opioids are relatively complex and beyond the scope of this column.

Briefly, codeine and morphine interact primarily with endogenous µ opioid receptors ( and are other endogenous opioid receptors). The codeine molecule has very low affinity for endogenous opioid receptors; its analgesic actions result from its hepatic conversion to morphine. Approximately 10% of codeine is demethylated to morphine. In essence, administering codeine is analogous to administering a smaller dose of morphine. Although the pharmacologic potency ratio of morphine to codeine has been described as 10:1, listed equianalgesic and starting doses of codeine are often less than this 10:1 ratio, adverse effects of codeine (eg, nausea, constipation) limit the usefulness of larger doses. Thus, a clinically useful analgesic dose of codeine may be greater than usual starting doses, but such dosing may be limited by adverse effects more likely to be experienced with these doses. Codeine, morphine and opioids also possess cough-suppressant effects. They depress the cough reflex in part by directly affecting the cough center in the medulla.

A beneficial characteristic of codeine is its relatively high oral bioavailability – approximately 60%. Once absorbed, codeine undergoes hepatic metabolism to inactive metabolites. Approximately 10% of administered codeine is hepatically demethylated to morphine by the cytochrome P450 enzyme system (2D6 isoenzyme). An important characteristic of this metabolic process is the effect of genetic polymorphism. It is known that approximately 10% of Caucasians are not able to convert codeine to morphine through CYP2D6, in effect leading to reduced or no pharmacologic effect and inadequate analgesia. Other ethnic differences in genetic polymorphism also exist, eg, Chinese produce less morphine from codeine as compared with Caucasians. Additionally, other polymorphisms are responsible for enhanced metabolic conversion to morphine (termed extensive metabolizers). Overall, a large number of different genetic variants of CYP2D6 (greater than 50) are known to exist, resulting in a wide range of possible effects (ie, no analgesia or enhanced adverse effects). Even though a wide range of metabolic differences is possible for codeine, very little study has occurred on the efficacy and adverse effects of codeine in infants and children. Much of the known pharmacokinetic characteristics of codeine come from studies of adults. Investigations of the activity of CYP2D6 suggest that infants have reduced metabolic capacity to convert codeine.

Clinical uses and studies

Codeine is mostly used in pediatric medicine for the treatment of mild-moderate pain and as a cough suppressant. Advantages of codeine include its availability in a variety of dosage forms, including liquids, and in combination with acetaminophen. It has been suggested that codeine use is popular because clinicians believe its adverse effect profile to be safer than other opioids. However, there are few data to support the contention that codeine is safer than other opioids at equi-analgesic doses. The use of low doses of codeine may appear to result in few adverse effects at the expense of reduced analgesia and clinical efficacy. Some evidence from published studies indicates that codeine itself may be responsible for adverse effects, irrespective of polymorphisms of metabolic morphine formation. Few data exist on the safety of codeine in comparison to other opioids in children.

Studies of codeine in adults have shown that codeine in combination with acetaminophen provides more effective analgesia than acetaminophen alone. Other studies have shown similar results when codeine is combined with nonsteroidal antiinflammatory drugs. Relatively few data are available from controlled studies evaluating the efficacy of codeine for pain in children. One trial compared intramuscular morphine with intramuscular codeine in children receiving an adenotonsillectomy. Notable for this study was the use of equi-analgesic dosing – 1.5 mg/kg for codeine and 0.15 mg/kg for morphine. This codeine dose is greater than dosing recommendations found in dosing handbooks (0.5-1 mg/kg/dose). At this dose, codeine was found to have similar analgesic activity as morphine. Review articles of pain management typically list codeine as an analgesic for use in mild to moderate pain. Codeine’s dosing is limited by adverse effects, notably nausea and vomiting, which may be greater than other opioids. This may limit the usefulness of codeine and may prevent its use in equi-analgesic doses. Many adult studies have shown that codeine is most useful when combined with non-opioid analgesics, namely acetaminophen or nonsteroidal antiinflammatory drugs. A Cochrane Database review concluded that codeine significantly increases analgesic efficacy of acetaminophen.

Codeine may also be commonly used as an antitussive in children. Pharmacologically, codeine and other opioids suppress the cough reflex partly by directly affecting the cough center in the medulla. Pediatric codeine doses typically listed for cough suppression are lower than analgesic doses. These doses, however, are not based upon controlled studies, but rather are likely extrapolations from adult data. Evidence for the clinical efficacy of codeine as a cough suppressant is limited. A recent evidence-based review (Bolser) of the efficacy of pharmacologic cough suppression concluded that central cough suppressants (eg, codeine and dextromethorphan) effectively reduce chronic cough in adults with chronic bronchitis. In subjects with acute cough due to upper respiratory tract infection, codeine has little, if any, documented efficacy and was not recommended. This recommendation is similar to that endorsed by the AAP in 1997, when the AAP Committee on Drugs concluded that no controlled trials are available to support the efficacy and safety of codeine as a cough suppressant in children. A controlled trial of codeine and dextromethorphan compared with placebo in children found that neither agent reduced acute cough compared with placebo (Taylor). Twenty-five states allow sale of codeine-containing cough products without a prescription.

Conclusions

Despite its popularity in pediatric medicine, relatively little is known about codeine with respect to pharmacokinetics, and safe and effective dosing in children.

Although it is used as an antitussive, no clinical evidence from controlled studies has documented its efficacy in the pediatric population for treatment of acute cough. Doses typically used and found in drug dosing handbooks are extrapolated from adult data. These doses may be too small with respect to pharmacologic equianalgesic dosing. Larger doses, however, cannot be routinely recommended without efficacy and safety data. Hepatic drug metabolizing polymorphism may affect a patient’s response to codeine, causing some children to receive reduced or no analgesic effect, or others to suffer increased adverse effects. Tests to determine a specific child’s hepatic metabolic capabilities are not widely available.

As an opiate, codeine use may yield adverse effects known to this class of compounds. Other adverse effects, such as nausea and vomiting, may be more limiting with short-term use. Codeine is available in numerous dosage forms, and is best used when combined with a non-opioid compound, such as acetaminophen.

Thus, is codeine a useful medication in pediatrics? It may be for specific indications for some children. When combined with a non-opioid, eg, acetaminophen-codeine, codeine may be useful for mild pain in some children. When prescribing codeine for analgesia, clinicians should consider the potential for reduced response in some children (eg, up to 10% of the Caucasian population) or enhanced adverse effects in others because of genetic metabolic polymorphism. Because no data support the use of codeine as a cough suppressant in children, clinicians should consider educating caregivers about cough and non-pharmacologic therapy.

For more information:

• Williams DG. Codeine phosphate in paediatric medicine. Br J Anesthesia. 2001;86:413-421
• Eckhardt K. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain. 1997;76:27-33
• Moore A. Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain. Cochrane Database of Systemic Reviews. (2): CD001547,2000
• Bolser DC. Cough suppressant and pharmacologic protussive therapy. Chest. 2006;129(Supplement 1):238S-249S
• Taylor JA. Efficacy of cough suppressants in children. J Pediatr. 1993;122:799-802
• Committee on Drugs, American Academy of Pediatrics. Use of codeine-and dextromethorphan-containing cough remedies in children. Pediatrics. 1997;99:918-920
• Taketomo CK. Pediatric Dosage Handbook. 12th ed. American Pharmaceutical Association, Hudson, Ohio. 2005