Wither codeine?

On August 15, 2012, the United States Food and Drug Administration (FDA) issued a safety alert 1 on ‘the use of codeine in certain children after tonsillectomy and/or adenoidectomy’. Six weeks later, the European Medicines Agency (EMA), the equivalent organization in the European Union (EU), announced that it also was starting a review of ‘the safety of codeine containing medications used as pain relief in children 2’. A further update from the FDA, on February 20, 2013, stated that a ‘boxed warning’, the strongest warning they have, would be added to the drug label of codeine containing preparations. It advises healthcare professionals to ‘prescribe an alternative analgesic (to codeine) for postoperative pain control in children who are undergoing tonsillectomy and or adenoidectomy 3’. The two regulatory bodies are both assessing the safety of codeine in children but are taking two different approaches. The FDA has asked healthcare professionals and patients to report any adverse events relating to codeine to their Medwatch Adverse Event reporting program. The EMA has written to ‘marketing authorization holders’ of codeine containing medicinal products asking for answers to a series of questions relating to the safety and efficacy of codeine in all areas of pain relief in children (not just postoperative). Both organizations wish to clarify the balance of benefit vs risk of the use of codeine containing medicines in children. The reviews were triggered by two papers reporting four serious adverse outcomes (three deaths and one near miss) in children who received codeine as postoperative pain relief. Codeine was implicated as the cause of death/morbidity in all the children reported. To understand the link between codeine and these four serious outcomes, we need to understand the pharmacokinetics of codeine. Codeine is a prodrug. It has no analgesic effect itself and weak affinity for mu opioid receptors. The analgesic properties arise from the conversion of the codeine stem to morphine and morphine-6-phosphate. The majority of a dose of codeine (typically 80%) is metabolized to inactive, water soluble metabolites by two routes; glucuronidation by UDP glucuronosyltransferase to form codeine 6 glucuronide, and N-demethylation by the cytochrome P450 3A4 enzymes to norcodeine. A minority of codeine administered is O-demethylated to morphine in the liver by cytochrome P 450 2D6 (CYP2D6) enzymes. The CYP2D6 enzyme system represents only a small percentage (2–4%) of all the CYP hepatic enzymes, but is responsible for metabolism of 25% of all commonly used drugs. It shows a large range of clinical activity due to genetic polymorphism. At least 70 different alleles exist and each allele defines a particular level of enzyme activity (normal function = 1, reduced function = 0.5, and no function = 0). Any individual inherits one allele from their mother and one from their father to form a diplotype, and allele activity scores are additive. Individuals having total activity scores of 1.0–2.0 are called ‘extensive metabolizers’ and represent the majority of a Caucasian population (77–92% of Caucasians). Other individuals may have total activity scores of 0.5 (‘intermediate metabolizers’) or 0 (‘poor metabolizers’). Poor metabolizers form 5–10% of Northern European Caucasian populations, are unable to convert codeine to morphine, and therefore have no analgesia when given codeine. CYP2D6 allele frequencies vary greatly from ethnic group to ethnic group. In some individuals, there are more than two copies of the CYP2D6 gene (gene duplication). The multiple gene copies can result in activity scores of 3 or greater and phenotypically have increased functional enzyme activity. These individuals are termed ‘ultrarapid metabolizers (UM)’, and they may produce potentially high blood concentrations of morphine after the administration of normally therapeutic doses of codeine. The frequency of gene duplication and therefore the percentage of a population that are ultrarapid metabolizers vary greatly between ethnic groups (Table 1). A direct relationship between steady state morphine concentration in blood and respiratory response has been demonstrated. A study in children (2–570 days postnatal age) demonstrated hypercarbia and depressed ventilatory response to carbon dioxide at plasma morphine concentrations above 20 ng·l−1 4. Plasma morphine concentrations were measured in all four children with severe adverse events secondary to codeine. The four children with adverse events linked to codeine need to be considered in detail (Table 2). The first death reported was from Canada in 2009 (Case 1) 5. He was 2 years old, 13 kg in weight who underwent adeno-tonsillectomy (AT) for sleep study proven obstructive sleep apnea. He received pethidine (meperidine) postoperatively and was then discharged home on the day of surgery with advice to take paracetamol and codeine 10–12.5 mg regularly, 4–6 hourly. He was found dead on the second morning after surgery. Analysis of femoral blood at postmortem showed a blood morphine concentration of 32 ng·l−1. CYP2D6 genotyping revealed functional duplication of the CYP2D6 allele consistent with the ultrarapid metabolizer genotype. The authors concluded that there was increased conversion of codeine to morphine due to ultrarapid metabolism resulted in a toxic accumulation of morphine. Three further adverse outcomes have since been reported by the same Canadian group in a paper in 2012 (Cases 2–4) 6. Case 2 was a 4-year-old (27.6 kg) First Nations (North American Indian) boy who underwent AT for obstructive sleep apnea (diagnostic method not defined). After an overnight stay, he was discharged home on 8 mg doses of codeine and received four doses in total. He was found dead on the second afternoon after surgery. Postmortem morphine concentration was 17.8 ng·ml−1. Genotyping revealed he was an ultrarapid metabolizer due to gene duplication, with death attributed to increased morphine concentration leading to respiratory arrest. Case 3 was a 3-year-old girl (14.4 kg) of ‘Middle Eastern’ descent undergoing tonsillectomy for obstructive sleep apnea (again method of diagnosis undefined). She received two doses of codeine in hospital (15 mg each), stayed overnight and was discharged home on a codeine 15 mg per paracetamol 150 mg combination every 4–6 h. After an unspecified number of hours, she was found unresponsive, with markedly reduced respirations and an oxygen saturation of 65%. She was resuscitated and survived. Blood morphine concentration was 17 ng·ml−1. Her genotype was an extensive metabolizer, but the authors state that overlap of the EM and UM phenotypes accounts for her high morphine levels. Case 4 was a 5-year-old (29 kg) boy undergoing tonsillectomy for recurrent tonsillitis and snoring. He was prescribed paracetamol and codeine 12 mg every 4 h and was discharged home on the day of operation. He was found dead 24 h after surgery. His postmortem morphine concentration was 30 ng·ml−1. Genotyping was not undertaken but analysis of blood codeine, and morphine concentrations suggest the child was an ultrarapid metabolizer. The four children share a number of common features. They: These case reports raise a number of questions for the practicing pediatric anesthetist. They include: The place of codeine as an analgesic agent for children and the limited number of studies assessing the effectiveness of codeine as an analgesic agent was considered in a Pro–Con debate in this journal 3 years ago 7. Our increased understanding of codeine's pharmacokinetics and these adverse events provide additional evidence against the use of codeine in children. There are two key problems Firstly, codeine is a prodrug; it is converted to an effective analgesic by an enzyme system which shows considerable genetic variation. Any dose of codeine will result in a large spread of different morphine concentrations across a population. The morphine concentration resulting will vary substantially not only between poor–intermediate metabolizers and extensive metabolizers, but also within the broad range of ‘normal’ children who are extensive metabolizers. This was demonstrated in a comparative study of codeine vs morphine, in addition to regular paracetamol and ibuprofen as part of a multimodal postoperative analgesic regime in children, who were predominately extensive metabolizers 8. Codeine showed more variable efficacy than morphine. There are no new studies in children in the last 3 years describing either positively or negatively the effectiveness of codeine as an analgesic agent in children. Secondly, high morphine concentrations may occur in a further subgroup of patients (ultrarapid metabolizers) leading to profound respiratory depression in a very small number of cases. The size of this risk is undefined. The two reviews by the FDA and EMA aim to identify any additional cases of significant morbidity, quantify this risk, perhaps calculating a numerator and denominator. Some additional information is already available. A recent review article searched databases for case reports of opioid induced respiratory depression in children less than 12 years of age 9. They identified one potential additional case of severe respiratory depression after an operation 10. This case was a 2-year-old, 14 kg, child of North African descent who underwent tonsillectomy for sleep study proven OSA. He was discharged home as a day case and received four doses of paracetamol with codeine, 12–24 mg per dose after the operation. He was found apneic and unresponsive by his mother on the second night after surgery; emergency medical services were called, and he was successfully resuscitated. The genotype is not clearly described, and on reassessment, he was probably not an ultrarapid metabolizer 11. Blood morphine and codeine levels were not obtained. A number of adverse outcomes linked to codeine in nonoperative settings have also been reported. Three infants, all less than 4 months of age, requiring resuscitation for severe respiratory depression, after receiving codeine as a cough linctus, have been reported. A case is also reported of death of a newborn infant who was breastfeeding. The baby's mother was an ultrarapid metabolizer receiving codeine for episiotomy pain and she converted significant amounts of codeine to morphine which subsequently passed into breast milk. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) 12 reviewed all deaths in children within 30 days of planned and unplanned surgery in England and Wales between April 1, 2008 and March 31, 2010 11. No unexplained cluster of deaths following AT was reported. We know that 26 000 tonsillectomy operations were undertaken in England in 2011/12 in children under 14 years of age (Hospital Episode Statistics for England, Health and Social Care Information Centre HSCIS, Leeds, UK). A survey of APA members in 2009 reported 39% used codeine to provide postoperative pain relief following tonsillectomy, and so, we have some measure of a denominator. Unfortunately, we do not know the numerator. The HSCIS declined to undertake a database run to identify the number of deaths within 30 days within this cohort despite a freedom of information request. In summary, we continue to lack detailed information on both the effectiveness and scale of risks associated with using codeine in children, but the increased areas of concern mean alternatives require active consideration. It is well recognized that a subgroup of children with SDB are acutely sensitive to the respiratory depressant effects of opioids. In children with obstructive sleep apnea (OSA) the opioid concentration–ventilator response relationship is moved to the left 13. The time after surgery before the opioid–respiratory response relationship returns to the right is unknown. The children most likely to develop significant respiratory problems in the initial perioperative period are well described 14. Risk factors include age under 2 years, weight <15 kg, failure to thrive, obesity (z score >2.5), and severe OSA on sleep study. In addition, we know that in at least 25% of children with OSA, the operation does not reverse the abnormal respiratory findings on overnight sleep study (PSG) and therefore is not curative. Cure rates (defined by respiratory variables on a PSG) are even lower in obese children undergoing AT for OSA. None of these deaths occurred in the first 24 h after surgery. Although a number of the children were discharged home on a day case basis, some had received a dose of codeine in hospital prior to discharge without incident. There is no evidence in the literature to suggest that witnessed doses of codeine in hospital increase the safety of subsequent home administration. Taking these factors together all the children so far reported who developed severe respiratory depression and/or death postoperatively had an operation for a condition associated with increased sensitivity to opioids, and all fell into ‘at-risk’ groups for perioperative respiratory complications. It is interesting that no similar deaths have been reported as yet from UK, Europe, or Australasia. This cannot be accounted for differences in the genetic makeup of populations. Spain for instance has a high percentage of UMs in its population and so would be expected to report problems. In addition, major international cities such as London have children from multiple ethnic backgrounds, and so, problems would be expected in children of Ethiopian, North African, or Arabian descent. It is important to recognize that genotype is not the same as phenotype. Genotype is the genetic makeup of an individual. The characteristic the individual displays (phenotype) is the result of the interaction of environmental factors on the genotype. Many factors including, the presence of other drugs, renal function, coexisting conditions, impact on the activity of an enzyme system. Looking at genotype alone may be simplistic. The fact that all reports come from North America may reflect a difference in management of postoperative pain in children following AT in North America from other continents. In UK, the most common approach is to send children home after AT with regular prescriptions of paracetamol and nonsteroidal anti-inflammatory (NSAIDs) drugs, with codeine prescribed as an ‘as required’ medicine for breakthrough pain. The North American approach may be slightly different, with avoidance of NSAIDs, because of concerns of postoperative bleeding, and discharge home on regular codeine and paracetamol. NSAIDs and paracetamol have a powerful additive analgesic effect potentially reducing the frequency of administration of codeine prescribed on an as required basis 15. The North American population may receive codeine more frequently after AT than children in other continents. Codeine is certainly not the ideal analgesic agent. It will be ineffective in a minority of individuals and potentially life-threatening in an unquantified number of individuals. It is theoretically possible to identify individuals with the UM genotype preoperatively by commercial gene testing. This is increasingly undertaken for a number of conditions where the main drug treatments are active drugs broken down to inactive metabolites by the CYP4502D6 enzyme systems. Many tricyclic antidepressants (amitriptyline in part, desipramine, nortriptyline) and antipsychotic medications (fluoxetine, haloperidol, venlafzaxine) are metabolized to nonactive metabolites by CYP2D6 enzymes and so are ineffective as treatments or lead to high levels of metabolites causing side effects in ultrametabolizers. A number of testing kits are available to identify an individual's CYP4502D6 genotype (e.g., Roche. AmpliChip CYP450 test.) It is therefore perfectly feasible to test all individuals to match future drug therapy to their genetic makeup and avoid ineffective or toxic drug–patient combinations. In practice, it is unlikely to become routine practice in the foreseeable future, and even if undertaken, will not identify all individuals at potential risk of high morphine concentrations after standard doses of codeine. This is in part because of the effect of environment on genotype as previously described. Codeine is commonly used both in hospital and at home in two situations: firstly, on an ‘as required’ (prn) basis as step-up analgesia if pain relief from simple analgesics has been inadequate, and secondly, on a regular basis in combination with paracetamol. The effectiveness and safety of alternative agents in both at home In codeine administration is equivalent to small amounts of morphine, and so, an alternative approach may be to weak morphine than codeine. A weak concentration of morphine mg per is available in the United and under of the of same as codeine. It may be and without the required for of morphine. The pharmacokinetics and of morphine are It has a of use as a postoperative agent in It has been to provide more postoperative analgesia than codeine 15. It is therefore an alternative to codeine. codeine with morphine for analgesia either on a regular or as required is more It multiple of morphine into the with all the potential for individual and by other It may not represent a alternative to codeine. is a opioid codeine, it is not a prodrug. The drug a significant of the analgesic effect and so is less on metabolism for It N-demethylation by the CYP450 3A4 enzyme system predominately to inactive A minority of is metabolized by the CYP450 2D6 enzyme system to an active has potential for as is in and already in the It is an effective analgesic but limited information is available on its use in children as a postoperative analgesic agent. may represent the most alternative to codeine, its of and pharmacokinetics are It is a analgesic of It to provide analgesia by a number of These are to mu opioid of of and increased of It is a of with the two drugs the majority of its analgesic in the liver is by N-demethylation by the cytochrome enzyme system to an inactive and to a to by the cytochrome 2D6 is an active to mu opioid receptors. A study of 24 children from showed that administered as was with concentrations within 30 of administration. In addition, the concentration of the was the drug concentration is not a it will be an effective analgesic in children who lack the CYP2D6 but the of the active concentrations and in ultrarapid metabolizers is The concentration of in children who are ultrarapid metabolizer has not been is for use in children 1 of age in European has no 12 years of There is extensive clinical of use in children from where it has been used in a similar to codeine to provide both regular and postoperative pain relief for more than a The dose used is The available is so, this is used in children children kg, an with is available. of either or mg are prescribed this extensive studies describing the use of for postoperative pain relief in children exist in the and may be a this to be dose It would be if the be agent on the is This is an analgesic agent two opioid and of In it is in the liver and then There is limited in children to alternatives to codeine, two further factors require consideration. alternatives to codeine are more and will on already drug Secondly, one of the factors the of effective pain relief in children is a failure of administration of drugs by Any alternative agents be available in a which is to the child and administered by the We only continue to use codeine if it represents the most effective and agent available for children. the of postoperative pain codeine has been as an effective agent for is The fact that codeine is a that does not form an active in a significant minority of children would suggest that other agents are likely to be more effective and on genotype alone may be We also a number of other factors which may a more agent than codeine, but it has not codeine in due to lack of pediatric possible side and the limited information of we are in using a small number of drugs which and in time in most We therefore may have and in the effectiveness of the drug treatments we It is well recognized that major drugs are effective in only of It is important that we do not have of any drug can for we codeine, we need to know more the effectiveness of the alternative agents in clinical The case reports do raise important questions on the safety of codeine in children. the adverse events were in children with and therefore at increased to opioid induced respiratory agents may or may not represent with OSA have reduced for opioid analgesia in the postoperative period due to of opioid There are no case series of the use of regular simple analgesia or with dose morphine, or for breakthrough pain in this group of patients as In summary, on the basis of the limited evidence the FDA has that codeine in future not be used to provide postoperative pain control after tonsillectomy and or adenoidectomy in children It does not suggest any alternative agents and provide of the efficacy and safety of on both the limited evidence and alternatives agents it would The has no in any or organization or to the of this No of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.