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Analgesics for mild-moderate pain in children
Study concluded that ibuprofen is more effective than acetaminophen or codeine when given in maximally recommended doses.
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Despite their frequency of use, few controlled studies have evaluated the efficacy of acetaminophen, ibuprofen and codeine in the treatment of mild-moderate pain in children. A newly published study adds to our knowledge on the efficacy of these medications.
Clark and colleagues compared acetaminophen, ibuprofen and codeine in children aged 6 to 17 years with pain from musculoskeletal injury. Due to the frequency of use of these medications and of musculoskeletal injuries in children, this study has important implications. This month’s Pharmacology Consult will review this study and the literature on the use of these commonly used analgesics.
Patient evaluation
Clark and colleagues evaluated a single dose of acetaminophen, ibuprofen and codeine in the treatment of pain from musculoskeletal trauma (extremities, neck, back) in children aged 6 to 17 years (n=300) presenting to an emergency department.
Patients were randomly assigned to one of the three treatments, and neither the research assistant administering and evaluating the medication nor the patient were made aware of the specific study drug received.
Dosages
This study is notable for the dosing used – 15 mg/kg for acetaminophen and 10 mg/kg for ibuprofen. These doses are the maximum weight-based doses from normal dosing ranges commonly found in pediatric dosing references. Codeine was dosed at 1 mg/kg, which is also the maximum weight-based dose commonly found in dosing handbooks.
Efficacy was assessed by a visual analog scale, given every 30 minutes, for up to 120 minutes. The primary outcome measure was change in the patient’s self-reported pain from baseline at 60 minutes. The mean baseline pain score (51 mm to 57 mm on a 100 mm scale) did not differ among the groups.
Ibuprofen was significantly more effective as an analgesic compared with acetaminophen and codeine in the primary outcome measure, change in pain score at 60 minutes and at other time points up to 120 minutes. Acetaminophen and codeine did not differ at any time in the analgesia data provided.
Ibuprofen also proved more effective than acetaminophen or codeine in a secondary outcome measure – adequate analgesia (defined as achieving a score of less than 30 mm on the 100 mm visual analog scale). Only 52% of children receiving ibuprofen achieved a score of less than 30 mm (adequate analgesia), implying that ibuprofen treatment alone may be inadequate.
It is interesting to note that there was no difference in pain relief among the three analgesics in children with soft tissue injuries as opposed to fractures, where ibuprofen was more effective than acetaminophen and codeine at 60 and 120 minutes. All of the study patients tolerated the analgesics well, and there were no differences among the agents in adverse effects.
Relatively few studies have directly compared the analgesic effects of ibuprofen, acetaminophen and codeine in a controlled manner in children. The results of these few studies differ, with several studies demonstrating better efficacy of ibuprofen over acetaminophen.
Two studies have compared ibuprofen with a combined acetaminophen-codeine product for pain from tonsillectomy. One study demonstrated equivalence, whereas the other found ibuprofen to be more effective.
Review articles of pain management often describe enhanced analgesic effects of codeine when combined with acetaminophen or a nonsteroidal antiinflammatory drug, such as ibuprofen. This is perhaps a limitation of the study by Clark, especially considering that acetaminophen and codeine are commonly used as a combined product in clinical practice.
Codeine less effective
Why was codeine found to be inferior to ibuprofen in the study by Clark and equivalent or inferior to ibuprofen when combined with acetaminophen in other studies?
Codeine, a naturally occurring opiate, is often described as a therapeutic option for mild-moderate pain. It is available in liquid and tablet formulations and has relatively good bioavailability from oral dosage forms.
However, pharmacologically, codeine is a relatively weak analgesic, as it has low affinity for endogenous opioid receptors. Codeine’s analgesic effects result from its conversion to morphine via hepatic demethylation.
Approximately 10% of codeine is transformed to morphine. Dosing guides and guidelines typically list a codeine oral dose (0.5 mg/kg/dose to 1 mg/kg/dose) that is two- to threefold greater than morphine (0.2 mg/kg/dose to 0.5 mg/kg/dose), when an equal-analgesic dose is likely much greater. Higher doses, however, are likely to be limited by codeine’s adverse effect profile, including gastrointestinal upset.
Another important pharmacologic consideration includes codeine’s metabolic polymorphism. Codeine is metabolized by the hepatic cytochrome P450 system (isoenzymes 2D6). There are known population differences in the ability to metabolize codeine, with approximately 10% of whites unable to convert codeine to morphine. Such subjects would derive no analgesic effects from codeine. Some Asian groups also demonstrate reduced metabolic conversion of codeine.
Thus, it is possible that, given in larger doses, codeine may be a more effective analgesic agent. When used in younger children unable to swallow tablets or capsules, increased dosing of the popular acetaminophen-codeine liquid product would be limited by the ratio of acetaminophen to codeine (ie, higher doses of codeine would result in excessive acetaminophen dosing).
Conclusions
Acetaminophen and ibuprofen are easily available to patients and caregivers as over-the-counter medications and are commonly used by pediatric clinicians. Acetaminophen-codeine combination products are commonly used by clinicians when pain is judged to be more significant.
Considering the frequency of their use, relatively few controlled studies have evaluated the comparative efficacy of these analgesic agents. The most recently published study concludes that ibuprofen is more effective than acetaminophen or codeine when given in maximally recommended doses.
Additional studies have demonstrated the analgesic efficacy of ibuprofen in children. Acetaminophen and ibuprofen share the practical benefits of availability as numerous dosage forms and over-the-counter status. Both drugs are very well tolerated when given in appropriate doses. Codeine may often be perceived as a more effective analgesic, as it is an opioid and it is a controlled substance. However, because of its unique pharmacologic and pharmacokinetic characteristics, its analgesic efficacy is likely inferior to ibuprofen when given in doses recommended by dosing guidelines and references. Use of larger, more pharmacologically appropriate doses increases the risk of adverse effects, such as nausea and vomiting. When used, codeine should be given in combination with acetaminophen or ibuprofen.
Due to codeine’s metabolic polymorphism, some patients may derive little or no analgesic efficacy from its use. Treating mild-moderate pain with ibuprofen (using maximal doses when necessary) may be an appropriate initial treatment strategy. If codeine is considered, it should be used in combination with either acetaminophen or ibuprofen, with the caveat that many children may not adequately respond to typical dosing guidelines.
For more information:
- Edward A Bell, PharmD, BCPS, is a Professor of Pharmacy Practice at Drake University College Pharmacy and a Clinical Specialist at Blank Children’s Hospital, Des Moines, Iowa.
- Clark E. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007;119:460-467.
- St. Charles C. A comparison of ibuprofen versus acetaminophen with codeine in the young tonsillectomy patient. Otolaryngol Head Neck Surg. 1997;117:76-82.
- Bertin L. Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. J Pediatr. 1991;119:811-814.
- Williams DG. Codeine phosphate in paediatric medicine. Br J Anesth. 2001;86:413-421.
- Golianu B. Pediatric acute pain management. Pediatr Clin North Am. 2000;47:559-587.
- Williams DG. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anesth. 2002;89:839-845.