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Codeine was considered a suitable analgesic for children after adenotonsillectomy. It has been used extensively in the UK1 for over 40 years and appeared effective.2 It was listed in the WHO as the second step on the Analgesic Ladder for the treatment of cancer pain. Adult data suggest the combination paracetamol 1000 mg/codeine 60 mg provides better analgesia (number needed to treat, (NNT) 1.9) than codeine 60 mg (NNT 17), or paracetamol 1000 mg (NNT 4.6), illustrating the synergistic effect of analgesic combinations.3 The addition of codeine to paracetamol increased duration of analgesia by about 1 hour, and reduced the need for rescue medication.4 Consequently, many clinicians have expressed surprise at moves by regulatory bodies (US Food and Drug Administration (FDA), European Medicines Agency, Medicines and Healthcare Products Regulatory Agency) to impose restrictions on its use in children, particularly after adenotonsillectomy.
Children suffer considerable pain with severe functional limitation for at least 7 days after this common procedure.5 Although part of the problem may be inadequate parent education and information concerning analgesia,6 there are also gaps in our pharmacologic armamentarium. Non-steroidal anti-inflammatory drugs (NSAID) have been frowned upon because of fears concerning their effects on platelet function and subsequent postoperative bleeding despite studies demonstrating that NSAIDs did not cause any increase in bleeding requiring a return to operating room.7 Paracetamol dosing recommendations have been lowered in recent years; these recommendations are not based on pharmacokinetic or pharmacodynamic knowledge,8 but rather on fears of potential hepatotoxicity due to paracetamol's oxidative metabolite (N-acetyl-p-benzoquinone imine).9 This adverse effect is rare but devastating when the drug is routinely given, and the reason why some children are so afflicted remains unknown. Opioid use at home is generally discouraged because of dispensing regulations and the knowledge that these drugs can cause respiratory depression. Children presenting for tonsillectomy often suffer obstructive sleep apnoea and have an increased sensitivity to morphine, reflected by increased episodes of arterial oxygen desaturations.10 Removal of codeine may further restrict analgesic alternatives after adenotonsillectomy.
Limiting codeine use
Restrictions governing codeine use followed reports of deaths after adenotonsillectomy associated with codeine use11 ,12 in North American children. Apnoea associated with codeine use has been previously reported,13 but the current cluster of deaths led to re-evaluation of the safety of this medication in children. Eight of thirteen children (21 months to 9 years) identified as having life-threatening respiratory depression and/or death after codeine use had undergone adenotonsillectomy.14 Codeine is a prodrug of morphine and it is thought that single nuclear polymorphisms causing increased activity of cytochrome P-450 isoenzyme 2D6 (CYP2D6), the enzyme responsible for morphine production from codeine, was a major contributor to these events.
codeine is a prodrug of morphine
morphine can cause respiratory depression
conversion of codeine to morphine varies between individuals and is dependent upon genotype
ultraextensive metabolisers are at greater risk of drug toxicity (secondary to increased systemic morphine concentrations).
The FDA now requires that manufacturers of codeine-containing products add a boxed warning to the labelling of their product so that the risk posed by codeine after a child has undergone tonsillectomy or adenoidectomy are clear. This move by the FDA has been rapidly followed by other regulatory bodies recommending restricted codeine use in children. Some children's hospitals have removed codeine from their formularies while others have constrained use. It is increasingly common for hospital guidelines to dictate that codeine should only be used to relieve acute moderate pain in children older than 12 years, and only if pain cannot be relieved by other analgesics, such as paracetamol or ibuprofen, or that codeine is contraindicated in all children (ie, younger than 18 years) who undergo tonsillectomy or adenoidectomy (or both) for obstructive sleep apnoea.
More than 60 alleles in the CYP2D6 gene have been identified. Phenotype can be classified as poor, intermediate, or extensive metaboliser. Individuals with duplicated active CYP2D6 genes are classified as ultraextensive metabolisers; 7–10% of Caucasians are slow metabolisers; this percentage varies with ethnicity.15 Codeine has minimal analgesic effect in the poor metabolisers, but adverse effects (eg, sedation, pruritus or nausea) persist.16 Gastrointestinal motility is affected only in extensive metabolisers; suggestive of a morphine-dependent mechanism of action for this.17
Factors that might decrease conversion of codeine to morphine affect the amount of morphine available from codeine. Selective serotonin reuptake inhibitors, such as fluoxetine and citalopram, inhibit CYP2D6 activity. Rifampicin and dexamethasone induce expression of CYP450 isozymes and increase the rate of metabolism. Concomitant medications competing for the CYP2D6 enzyme pathway (eg, amiadorone, cimetidine, celecoxib, metoclopramide) may reduce clearance.
Reassessing codeine's analgesic effectiveness
Codeine is just not that good an analgesic. Single dose codeine 60 mg provides good analgesia to few adults (NNT 12) and does not compare favourably with commonly used alternatives such as paracetamol or NSAIDs, especially after dental surgery (NNT 21).18 Codeine is less potent than morphine (potency ratio 1:10). Consequently, 60 mg of codeine only has morphine equivalence of 6 mg. Oral codeine is rapidly absorbed with approximately 50% of the dose undergoing first-pass metabolism. Codeine has a higher oral parenteral potency ratio (2:3) because hepatic conversion to morphine is necessary for codeine's analgesic activity.
Codeine has lower affinity for μ-receptors than morphine and reduced effectiveness. An analgesic ceiling effect for codeine is apparent with increasing dose only causing increased adverse effects. Analgesia may be mediated through morphine but codeine receptor occupancy contributes to adverse effects.19 There is little evidence for the broad belief that codeine causes less adverse effects, such as sedation and respiratory depression, compared with other opioids.20
There are limited data concerning the effectiveness of codeine as an analgesic in children. Although a Cochrane review suggested that the paracetamol–codeine combination is good in adults,3 paediatric studies comparing ibuprofen with paracetamol–codeine are not in codeine's favour. Comparison between ibuprofen 10 mg/kg and paracetamol–codeine 1 mg/kg/dose (codeine component) have shown that ibuprofen was at least as effective as paracetamol–codeine for outpatient analgesia for children with acute traumatic extremity pain. There was no significant difference in analgesic failure or pain scores, but children receiving ibuprofen had better functional outcomes. Children aged 4–18 years receiving ibuprofen had significantly fewer adverse effects, and both children and parents were more satisfied with ibuprofen.21 ,22 Additionally, the authors comment that the poor palatability of codeine suspension alienates children to this medication.21 Adult data demonstrate good analgesic effect with the combination of ibuprofen 400 mg plus codeine 25.6–60 mg, but there are very limited data to suggest that the combination is better than the same dose of either drug alone.23
Even in chronic pain, paracetamol–codeine combinations are considered not as effective as other alternatives.24 Codeine was considered second-line management for cancer pain after simple analgesics, such as the NSAIDs and paracetamol; recent amendments to the WHO Analgesic Ladder have simplified management by removing this second step.25
Glucuronidation (UGTB27) is the major metabolic clearance pathway for codeine, but minor pathways are N-demethylation (cytochrome P450 enzyme CYP3A4) to norcodeine (10–20%) and O-demethylation (CYP2D6) to morphine (5–15%). Codeine is also excreted unchanged in the urine (5–15%).20 The pharmacokinetics of codeine are poorly described in children despite use over decades. A volume of distribution (V) of 3.6 L/kg, a clearance (CL) of 0.85 L/h and a plasma half-life is 3–3.5 h26 have been described in adults, but there are few data detailing paediatric pharmacokinetic developmental changes. The neonatal half-life is longer due to immature clearance (eg, 4.5 h), while that of an infant is shorter (eg, 2.6 h)27 attributable to size factors.28
It would be useful to understand the maturation of the CYP2D6 enzyme because this enzyme is central to analgesic effect. In vitro studies suggest that CYP2D6 enzyme activity develops over the first month of life to reach 60% of adult activity by 28 days.29 There are no in vivo data describing or quantifying this maturation in neonates. However, tramadol is another drug with metabolism predominantly by CYP2D6. Tramadol clearance increases from 25 weeks postmenstrual age (PMA) (5.52 L/h/70 kg to reach 84% of the mature value by 44 weeks PMA.30 We might anticipate that maturation of morphine production from codeine is faster than morphine clearance,31 suggesting that infants may have greater morphine plasma concentrations than older children given similar doses.
Are increasing restrictions on codeine use warranted?
The continued use of codeine has been questioned for some time.2 ,32 ,33 Restricting use only in those who are very young, or those with obstructive sleep apnoea or breathing disorders, would be too difficult because of uncertainty about how wide to spread the net. The suggestion that codeine-containing drugs be given at the lowest effective dose for the shortest time period needed is difficult to implement when there is only limited information about the pharmacokinetics and pharmacodynamics. Near-bedside testing of genotypes has been suggested. Unfortunately, genotype does not always equate with phenotype, and there may be other reasons for reduced CYP2D6 activity (eg, liver failure is an extreme example). A single nuclear polymorphism affecting clearance is not the only determinant of drug response. Clearance is also affected by age, size, organ function and drug interactions, among others. Pharmacogenomics also impact on pharmacodynamic aspects of the pain pathway, for example, adrenergic drug hormones concentrations, the inflammatory response, µ-opioid receptor gene, efflux transporters, ion channels.34 Interactions between the multiplicity of genetic components that regulates the opioid response is a continuing investigation.
Paracetamol–ibuprofen is a powerful analgesic combination.35 Although reasonable analgesia after tonsillectomy may be achieved with paracetamol–NSAID combinations, these combinations have a ceiling effect36 that may not be satisfactory in some children. Codeine retained much of its popularity because it was easy to dispense. However, dilute morphine solutions (eg, 10 mg/5 mL) are available in some countries and fall under similar dispensing regulations as codeine. It would appear sensible to simply replace codeine, the prodrug of morphine, with morphine. However, morphine has a reputation that is associated with addiction, chronic pain and respiratory depression. All opioids cause respiratory depression. Oxycodone is gaining increasing prevalence in USA and Australia, but CYP2D6 has also been implicated in deaths associated with that drug.37 Poor metabolisers may also accumulate hydrocodone.38 Tramadol may serve as an adjunct to paracetamol–NSAID combinations.39 Respiratory depressant effects are minimal. Its active metabolite is formed through the CYP2D6 enzyme, but the parent drug does have activity, so at least poor metabolisers will get some pain relief.
Codeine will undoubtedly eventually disappear from our formularies. It is a prodrug and the amount of morphine delivered varies with CYP2D6 genotype. Its effectiveness when added to paracetamol–NSAID mixes has never been quantified. Should we simply
Replace codeine, the prodrug of morphine, with morphine?
However, all opioids cause respiratory depression.
Our energies should be towards improving parent education and information about analgesia. If improved information and administration of simple analgesics remains inadequate, what will replace codeine for children suffering pain after tonsillectomy when paracetamol and NSAIDs are inadequate?
Competing interests I have done consultancy work for a number of pharmaceutical in the past (McNeil, Angelini, AFT), but this article is not related to that work in any way.
Provenance and peer review Commissioned; internally peer reviewed.
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